NCCN临床实践指南：非小细胞肺癌（2025.V3）

指南肿瘤内科· 肺癌 · 2025

• Section added for Monitoring and Managing Survivorship Needs During Systemic Therapy • The following added under NSCLC Long-Term Follow-up Care Lung cancer-specific exercise recommendations ◊ Consider perioperative pulmonary rehab for patients with comorbid COPD and those who have undergone lung surgery Smoking cessation: NCCN Guidelines for Smoking Cessation Chronic cancer pain management: NCCN Guidelines for Adult Cancer Pain Psychosocial evaluation and referrals Financial toxicity/SDOH monitoring and referrals Care coordination with primary care clinicians Fatigue: ◊ NCCN Guidelines for Cancer-Related Fatigue ◊ Cancer-Related Fatigue in Lung Cancer: A Research Agenda: An Official American Thoracic Society Research Statement • References added

Authors

# NCCN Guidelines Index

NCCN Guidelines Index

Abstract

Table of Contents Discussion UPDATES Continued NSCL-20 • Testing Results NRG1 gene fusion positive added NSCL-21 • First-Line Therapy EGFR mutation discovered during first-line systemic therapy ◊ The following removed: Complete planned systemic therapy, including maintenance therapy ◊ The following added: Add osimertinib to pemetrexed + (cisplatin or carboplatin) (nonsquamous) ◊ The following modified: Interrupt current therapy and start, followed by Osimertinib (preferred) or Amivantamab-vmjw + lazertinib Footnote xx added: If there is a good response to current therapy, it is reasonable to continue therapy.

NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer Version 3.2025, 01/14/25 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

# NCCN Guidelines Index Table of Contents Discussion

NCCN Guidelines Index Table of Contents Discussion

DIAG-1

a Multidisciplinary evaluation including thoracic surgeons, thoracic radiologists, and pulmonologists to determine the likelihood of a cancer diagnosis and the optimal diagnostic or follow-up strategy. b Risk calculators can be used to quantify individual patient and radiologic factors but do not replace evaluation by a multidisciplinary diagnostic team with substantial experience in the diagnosis of lung cancer. c Principles of Diagnostic Evaluation (DIAG-A 1 of 3). d The most important radiologic factor is change or stability compared with a previous imaging study.

DIAG-A 1 OF 3

# PRINCIPLES OF DIAGNOSTIC EVALUATION

PRINCIPLES OF DIAGNOSTIC EVALUATION

• The decision to pursue preoperative biopsy of a potential stage I lung cancer should be informed by the pre-test probability of malignancy.

Factors that might be considered in pre-test probability assessment include risk factors, radiologic appearance (including comparison to prior chest imaging if available or FDG-PET/CT if performed), and current or prior residence in regions with prevalent endemic infectious lung disease (ie, fungal, mycobacterial), among other potential factors. Patients with very high pre-test probability of stage IA lung cancer do not require a biopsy before surgery. A biopsy adds time, costs, and procedural risk and may not be needed for treatment decisions. If a preoperative tissue diagnosis has not been obtained, then an intraoperative diagnosis (ie, wedge resection, needle biopsy) is necessary before lobectomy, bilobectomy, or pneumonectomy. Situations in which a preoperative biopsy may be appropriate:

◊ A non-lung cancer diagnosis that can be diagnosed by minimally invasive biopsy is at least moderately likely (eg, granulomatous nodule due to endemic fungus). ◊ Suspected stage IB or higher lung cancer in patients who may be candidates for systemic therapy prior to surgery. ◊ An intraoperative diagnosis appears difficult or very risky. 1 ◊ To establish the diagnosis prior to stereotactic ablative radiotherapy (SABR). 2 NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer Version 3.2025, 01/14/25 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NSCL-1

a Principles of Pathologic Review (NSCL-A).

b Enhanced frailty or geriatric assessments may predict complications better following treatment modalities, particularly surgery. A preferred frailty assessment system has not been established. c Temel JS, et al. N Engl J Med 2010;363:733-742.

d For patients where more than one treatment modality (surgery, radiation therapy

[RT], or systemic therapy) is usually considered, a multidisciplinary evaluation should be performed. e Based on the CT of the chest: Peripheral = outer third of lung; Central = inner two thirds of lung. f T3, N0 related to size or satellite nodules. Note: All recommendations are category 2A unless otherwise indicated.

NSCL-2 g Testing is not listed in order of priority and is dependent on clinical circumstances, institutional processes, and judicious use of resources. h Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a clinically (FDG-PET/CT and/or CT) positive mediastinum should undergo subsequent mediastinoscopy prior to surgical resection. i There is low likelihood of positive mediastinal lymph nodes when these nodes are CT and FDG-PET/CT negative in peripheral tumors (outer third of lung) ≤3 cm. Thus, pretreatment pathologic mediastinal evaluation is optional in these settings. Invasive mediastinal staging is recommended for central tumors. j In patients who are medically inoperable, while mediastinal biopsy is generally preferred, the risks in selected patients may outweigh the benefits. k FDG -PET/CT performed skull base to mid-thigh. Positive FDG-PET/CT scan findings for distant disease need pathologic or other radiologic confirmation.

If FDG-PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation.

l Surgical resection is considered the first option for operable patients with stage IA lung cancer, but patients may also be informed about SABR as an alternative option through shared decision-making. m Principles of Surgical Therapy (NSCL-B). n Principles of Radiation Therapy (NSCL-C). o Image-guided thermal ablation (IGTA) therapy (eg, cryotherapy, microwave, radiofrequency) may be an option for select patients. See Principles of Image-Guided Thermal Ablation Therapy (NSCL-D). p Prior to treatment, multidisciplinary evaluation that includes treating physicians and specialists in obtaining tissue diagnosis (thoracic surgery, interventional pulmonology, and interventional radiology) is required to determine the safest and most efficient approach for biopsy, or to provide consensus that a biopsy is too risky or difficult, that a clinical diagnosis of lung cancer is appropriate, and that treatment is warranted. NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer Version 3.2025, 01/14/25 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NSCL-3

f T3, N0 related to size or satellite nodules. g Testing is not listed in order of priority and is dependent on clinical circumstances, institutional processes, and judicious use of resources. h Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a clinically (FDG-PET/CT and/or CT) positive mediastinum should undergo subsequent mediastinoscopy prior to surgical resection. k FDG-PET/CT performed skull base to mid-thigh. Positive FDG-PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If FDG-PET/ CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. m Principles of Surgical Therapy (NSCL-B). n Principles of Radiation Therapy (NSCL-C). p Prior to treatment, multidisciplinary evaluation that includes treating physicians and specialists in obtaining tissue diagnosis (thoracic surgery, interventional pulmonology, and interventional radiology) is required to determine the safest and most efficient approach for biopsy, or to provide consensus that a biopsy is too risky or difficult, that a clinical diagnosis of lung cancer is appropriate, and that treatment is warranted. q Perioperative Systemic Therapy (NSCL-E). r If MRI is not possible, CT of head with contrast.

NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer

Version 3.2025, 01/14/25 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NSCL-8

h Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a clinically (FDG-PET/CT and/or CT) positive mediastinum should undergo subsequent mediastinoscopy prior to surgical resection. k FDG -PET/CT performed skull base to mid-thigh. Positive FDG-PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If FDG-PET/ CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. q Perioperative Systemic Therapy (NSCL-E). r If MRI is not possible, CT of head with contrast. Note: All recommendations are category 2A unless otherwise indicated.

NSCL-9

l Surgical resection is considered the first option for operable patients with stage IA lung cancer, but patients may also be informed about SABR as an alternative option through shared decision-making. m Principles of Surgical Therapy (NSCL-B). n Principles of Radiation Therapy (NSCL-C). o IGTA therapy (eg, cryotherapy, microwave, radiofrequency) may be an option for select patients. See Principles of Image-Guided Thermal Ablation Therapy (NSCL-D). p Prior to treatment, multidisciplinary evaluation that includes treating physicians and specialists in obtaining tissue diagnosis (thoracic surgery, interventional pulmonology, and interventional radiology) is required to determine the safest and most efficient approach for biopsy, or to provide consensus that a biopsy is too risky or difficult, that a clinical diagnosis of lung cancer is appropriate, and that treatment is warranted. q Perioperative Systemic Therapy (NSCL-E). Note: All recommendations are category 2A unless otherwise indicated.

MEDIASTINAL BIOPSY

NSCL-10

m Principles of Surgical Therapy (NSCL-B). n Principles of Radiation Therapy (NSCL-C). q Perioperative Systemic Therapy (NSCL-E).

t Concurrent Chemoradiation Regimens (NSCL-F).

v For patients who have received sequential chemoradiation, durvalumab can be considered as consolidation immunotherapy or, if EGFR exon 19 deletion or L858R, osimertinib is recommended. y Selected patients with N2 disease (fit, single-station, non-bulky N2, requiring only lobectomy) may be considered for systemic therapy followed by surgery. z Chest CT with contrast and/or FDG-PET/CT to evaluate progression. NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer Version 3.2025, 01/14/25 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

MEDIASTINAL

NSCL-11

If FDG-PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. m Principles of Surgical Therapy (NSCL-B). r If MRI is not possible, CT of head with contrast. q Perioperative Systemic Therapy (NSCL-E).

aa Lesions with different cell types (eg, squamous cell carcinoma, adenocarcinoma) are usually different primary tumors. This analysis may be limited by small biopsy samples. However, lesions of the same cell type are not necessarily metastases. Single contralateral lung nodules with clinical, radiologic, or pathologic features suggestive of a synchronous primary lung cancer (eg, long disease-free survival, ground glass components, different histologic characteristics) that are amenable to local therapy should be considered as probable separate primary cancers and eligible for local therapy (NSCL-11). Multiple studies suggest that next-generation sequencing (NGS) testing with broad gene coverage may allow for unambiguous determination of clonal relatedness among separate lung nodules. bb For guidance regarding the evaluation, workup, and management of subsolid pulmonary nodules, please see the diagnostic evaluation of a nodule suspicious for lung cancer (DIAG-1).

CLINICAL PRESENTATION ADJUVANT TREATMENT

Separate pulmonary nodule(s), same lobe (T3, N0-1), or ipsilateral non-primary lobe (T4, N0-

NSCL-12

m Principles of Surgical Therapy (NSCL-B). n Principles of Radiation Therapy (NSCL-C). o IGTA therapy (eg, cryotherapy, microwave, radiofrequency) may be an option for select patients. See Principles of Image-Guided Thermal Ablation Therapy (NSCL-D). cc Multidisciplinary evaluation including thoracic radiology, pulmonary medicine, thoracic surgery, medical oncology, and radiation oncology. dd Lesions at low risk of becoming symptomatic can be observed (eg, small subsolid nodules with slow growth). However, if the lesion(s) show accelerating growth or increasing solid component or increasing FDG uptake, even while small, treatment should be considered. ee Lung-sparing resection is preferred, but tumor distribution and institutional expertise should guide individual treatment planning. Patients should be evaluated in a multidisciplinary setting; ie, surgery, radiation oncology, medical oncology (interventional pulmonology and/or interventional radiology as needed). NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer Version 3.2025, 01/14/25 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

CLINICAL

NSCL-13

k FDG-PET/CT performed skull base to mid-thigh. Positive FDG-PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If FDG-PET/ CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. n Principles of Radiation Therapy (NSCL-C). r If MRI is not possible, CT of head with contrast. t Concurrent Chemoradiation Regimens (NSCL-F). v For patients who have received sequential chemoradiation, durvalumab can be considered as consolidation immunotherapy or, if EGFR exon 19 deletion or L858R, osimertinib is recommended.

NSCL-14

k FDG-PET/CT performed skull base to mid-thigh. Positive FDG-PET/CT scan findings for distant disease need pathologic or other radiologic confirmation.

If FDG-PET/CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. n Principles of Radiation Therapy (NSCL-C). r If MRI is not possible, CT of head with contrast. t Concurrent Chemoradiation Regimens (NSCL-F).

v For patients who have received sequential chemoradiation, durvalumab can be considered as consolidation immunotherapy or, if EGFR exon 19 deletion or L858R, osimertinib is recommended. ff Most pleural (pericardial) effusions with lung cancer are a result of the tumor. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumor, and fluid is non-bloody and not an exudate. If these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging descriptor. NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer Version 3.2025, 01/14/25 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NSCL-15

k FDG-PET/CT performed skull base to mid-thigh. Positive FDG-PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If FDG-PET/ CT scan is positive in the mediastinum, lymph node status needs pathologic confirmation. r If MRI is not possible, CT of head with contrast. gg Including selected patients with stage M1c and limited number and volume of metastatic lesions amenable to definitive local therapy. Clinical trials have included up to 3 to 5 metastatic sites. hh Note: All recommendations are category 2A unless otherwise indicated.

NSCL-17 r If MRI is not possible, CT of head with contrast. jj Timing of CT scans within Guidelines parameters is a clinical decision. kk FDG-PET/CT is currently not warranted in the routine surveillance and follow-up of patients with NSCLC. However, many benign conditions (such as atelectasis, consolidation, and radiation fibrosis) are difficult to differentiate from neoplasm on standard CT imaging, and FDG-PET/CT can be used to differentiate true malignancy in these settings. However, if FDG-PET/CT is to be used as a problem-solving tool in patients after RT, histopathologic confirmation of recurrent disease is needed because areas previously treated with RT can remain FDG avid for up to 2 years. Note: All recommendations are category 2A unless otherwise indicated.

No evidence of clinical

NSCL-18

m Principles of Surgical Therapy (NSCL-B). n Principles of Radiation Therapy (NSCL-C). o IGTA therapy (eg, cryotherapy, microwave, radiofrequency) may be an option for select patients.See Principles of Image-Guided Thermal Ablation Therapy (NSCL-D). r If MRI is not possible, CT of head with contrast. NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer Version 3.2025, 01/14/25 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated. Treatment is guided by available results and, if unknown, these patients are treated as though they do not have driver oncogenes. nn Principles of Molecular and Biomarker Analysis (NSCL-H). oo Testing for HER2 IHC is recommended at some point during progression. Timing should be balanced with tissue conservation. pp The NCCN NSCLC Guidelines Panel strongly advises broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is defined as molecular testing that identifies all biomarkers identified in NSCL-20 in either a single assay or a combination of a limited number of assays, and optimally also identifies emerging biomarkers (NSCL-I). Tiered approaches based on low prevalence of co-occurring biomarkers are acceptable. Broad molecular profiling is a key component of the improvement of care of patients with NSCLC. See Emerging Biomarkers to Identify Patients for Therapies (NSCL-I). qq

TESTING RESULTS mm,nn

mm Complete genotyping for EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET, RET, ERBB2 (HER2), and NRG1 via biopsy and/or plasma testing. Combinations of tissue and plasma testing, either concurrently or in sequence are acceptable. Concurrent testing can improve time to test results and should be considered in the appropriate clinical situation. Negative results (meaning absence of definitive driver mutation) by one method suggests the use of a complementary method. Treatment is guided by available results and, if unknown, these patients are treated as though they do not have driver oncogenes. nn Principles of Molecular and Biomarker Analysis (NSCL-H). Note: All recommendations are category 2A unless otherwise indicated.

NSCL-20

EGFR

NSCL-21

nn Principles of Molecular and Biomarker Analysis (NSCL-H). rr Molecular or Biomarker-Directed Therapy for Advanced or Metastatic Disease (NSCL-J). ss For performance status (PS) 0-4. tt Prophylactic anticoagulation is recommended at the time of initiation to prevent venous thromboembolic events. uu Criteria for treatment with bevacizumab: nonsquamous NSCLC, and no recent history of hemoptysis. vv An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

ww If systemic therapy regimen contains an immune checkpoint inhibitor, physicians should be aware of the long half-life of such drugs and data reporting adverse events when using osimertinib in combination with or following checkpoint inhibitors. The rate of side effects (pneumonitis) is higher within 3 months. Schoenfeld

o IGTA therapy (eg, cryotherapy, microwave, radiofrequency) may be an option for select patients. See Principles of Image-Guided Thermal Ablation Therapy (NSCL-D). nn Principles of Molecular and Biomarker Analysis (NSCL-H). rr Molecular or Biomarker-Directed Therapy for Advanced or Metastatic Disease (NSCL-J). tt Prophylactic anticoagulation is recommended at the time of initiation to prevent venous thromboembolic events. yy Beware of flare phenomenon in subset of patients who discontinue tyrosine kinase inhibitor (TKI). If disease flare occurs, restart TKI. zz Clinical trials have included up to 3 to 5 progressing sites. aaa Consider a biopsy at time of progression to rule out small cell lung cancer (SCLC) transformation (approximately 6%) and biopsy or plasma testing to evaluate mechanisms of resistance. See Principles of Molecular and Biomarker Analysis (NSCL-H) and NCCN Guidelines for Small Cell Lung Cancer. bbb Definitive local therapy of CNS disease can include asymptomatic lesions at risk for symptomatic progression based on factors including site, location, and edema. ccc Not an option for EGFR S768I, L861Q, and/or G719X mutations. ddd Afatinib + cetuximab may be considered in patients with disease progression on EGFR TKI therapy. eee The data in the second-line setting suggest that programmed cell death protein 1 (PD-1)/PD-L1 inhibitor monotherapy is less effective, irrespective of PD-L1 expression, in EGFR exon 19 deletion or exon 21 L858R, ALK+ NSCLC.

SUBSEQUENT THERAPY rr

NSCL-23

ddd Afatinib + cetuximab may be considered in patients with disease progression on EGFR TKI therapy. eee The data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is less effective, irrespective of PD-L1 expression, in EGFR exon 19 deletion or exon 21 L858R, ALK+ NSCLC. fff Plasma or tissue-based testing via broad molecular profiling should be considered at progression, for the T790M mutation and other genomic resistance mechanisms. If plasma-based testing is negative, tissue-based testing with rebiopsy material is strongly recommended. Practitioners may want to consider scheduling the biopsy concurrently with plasma testing referral. ggg Consider osimertinib (regardless of T790M status) for progressive CNS disease or leptomeningeal disease. In the BLOOM study, osimertinib was used at 160 mg once daily for patients with leptomeningeal disease. hhh In the randomized phase III trial of dacomitinib, patients with brain metastases were not eligible for enrollment. In the setting of brain metastases, consider other options.

Progression rr Molecular or Biomarker-Directed Therapy for Advanced or Metastatic Disease (NSCL-J). ss For PS 0-4. ww If systemic therapy regimen contains an immune checkpoint inhibitor, physicians should be aware of the long half-life of such drugs and data reporting adverse events when using osimertinib in combination with or following checkpoint inhibitors. The rate of side effects (pneumonitis) is higher within 3 months. Schoenfeld Note: All recommendations are category 2A unless otherwise indicated.

nn Principles of Molecular and Biomarker Analysis (NSCL-H).

rr Molecular or Biomarker-Directed Therapy for Advanced or Metastatic Disease (NSCL-J).

NSCL-25

NSCL-26

KRAS G12C mutation

nn Principles of Molecular and Biomarker Analysis (NSCL-H). rr Molecular or Biomarker-Directed Therapy for Advanced or Metastatic Disease (NSCL-J).

iii Monitoring During Initial Therapy: Response assessment after 2 cycles, then every 2-4 cycles with CT of known or high-risk sites of disease (eg, chest, abdomen, pelvis) with or without contrast or when clinically indicated. Timing of CT scans within Guidelines parameters is a clinical decision. jjj In general, 4 cycles of initial systemic therapy (ie, with carboplatin or cisplatin) are administered prior to maintenance therapy. However, if patient is tolerating therapy well, consideration can be given to continue to 6 cycles. kkk Monitoring During Subsequent Therapy or Maintenance Therapy: Response assessment with CT of known or high-risk sites of disease (eg, chest, abdomen, pelvis) with or without contrast every 6-12 weeks. Timing of CT scans within Guidelines parameters is a clinical decision. lll Sotorasib or adagrasib may be used after at least one line of therapy (or second-line and beyond), if no previous KRAS G12C-targeted therapy. Note: All recommendations are category 2A unless otherwise indicated. o IGTA therapy (eg, cryotherapy, microwave, radiofrequency) may be an option for select patients. See Principles of Image-Guided Thermal Ablation Therapy (NSCL-D). nn Principles of Molecular and Biomarker Analysis (NSCL-H). rr Molecular or Biomarker-Directed Therapy for Advanced or Metastatic Disease (NSCL-J). yy Beware of flare phenomenon in subset of patients who discontinue TKI. If disease flare occurs, restart TKI. zz Clinical trials have included up to 3 to 5 progressing sites. bbb Definitive local therapy of CNS disease can include asymptomatic lesions at risk for symptomatic progression based on factors including site, location, and edema. eee The data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is less effective, irrespective of PD-L1 expression, in EGFR exon 19 deletion or exon 21 L858R, ALK+ NSCLC. fff Plasma or tissue-based testing via broad molecular profiling should be considered at progression for genomic resistance mechanisms. If plasma-based testing is negative, tissue-based testing with rebiopsy material is strongly recommended. Practitioners may want to consider scheduling the biopsy concurrently with plasma testing referral. mmm Lorlatinib is an option for resistant mutations, such as ALK G1202R and L1196M (except compound L1196M/G1202R). Note: All recommendations are category 2A unless otherwise indicated. Note: All recommendations are category 2A unless otherwise indicated. Note: All recommendations are category 2A unless otherwise indicated. Note: All recommendations are category 2A unless otherwise indicated. Note: All recommendations are category 2A unless otherwise indicated. Note: All recommendations are category 2A unless otherwise indicated. Note: All recommendations are category 2A unless otherwise indicated.

FIRST-LINE THERAPY iii

KRAS

NSCL-31

Limited

NSCL-36

ERBB2 (HER2) mutation sss

with or without contrast every 6-12 weeks. Timing of CT scans within Guidelines parameters is a clinical decision. rrr For HER2 protein overexpression (IHC3+) treatment options, see NSCL-K 4 of 5. sss For oncogenic or likely oncogenic HER2 mutations, refer to definitions at oncokb.org.

ERBB2 (HER2) MUTATION

NSCL-37

NRG1 GENE FUSION nn

NRG1 gene fusion

NSCL-38

ttt Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents; some oncogenic drivers (ie, EGFR exon 19 deletion or L858R; ALK, RET, or ROS1 rearrangements) have been shown to be associated with less benefit from PD-1/PD-L1 inhibitors. If there are contraindications, refer to NSCL-K 1 of 5 (adenocarcinoma) or NSCL-K 2 of 5 (squamous cell carcinoma). uuu For patients who require an urgent start to therapy but molecular testing is pending, consider holding immunotherapy for one cycle, unless confirmed that no driver mutations are present. vvv If patient has not received platinum-doublet chemotherapy, refer to "systemic therapy." If patient received platinum chemotherapy and anti-PD-1/PD-L1, refer to "subsequent therapy." Note: All recommendations are category 2A unless otherwise indicated.

FIRST-LINE THERAPY

NSCL-39

iii Monitoring During Initial Therapy: Response assessment after 2 cycles, then every 2-4 cycles with CT of known or high-risk sites of disease (eg, chest, abdomen, pelvis) with or without contrast or when clinically indicated. Timing of CT scans within Guidelines parameters is a clinical decision. jjj In general, 4 cycles of initial systemic therapy (ie, with carboplatin or cisplatin) are administered prior to maintenance therapy. However, if patient is tolerating therapy well, consideration can be given to continue to 6 cycles. kkk Monitoring During Subsequent Therapy or Maintenance Therapy: Response assessment with CT of known or high-risk sites of disease (eg, chest, abdomen, pelvis) with or without contrast every 6-12 weeks. Timing of CT scans within Guidelines parameters is a clinical decision. In small biopsies or cytology specimens intended for initial diagnosis, the primary purpose is a) to make an accurate diagnosis using the 2021 WHO classification; and b) to preserve the tissue for molecular studies, especially if the patient has advanced-stage disease. In small biopsies of poorly differentiated carcinomas, the terms "non-small cell carcinoma (NSCC)" 1 or "non-small cell carcinoma not otherwise specified (NSCC-NOS)" should be used as little as possible and only when a more specific diagnosis is not possible by morphology and/or special staining. The following terms are acceptable: "NSCC favor adenocarcinoma" and "NSCC favor squamous cell carcinoma." "NSCC-NOS" should be reserved only for cases in which IHC testing is uninformative or ambiguous (see section on Immunohistochemistry). Preservation of material for molecular testing is critical. Efforts should be undertaken to minimize block reorientation and the number of IHC stains for cases that cannot be classified on histologic examination alone (see section on Immunohistochemistry). • In resection specimens, the primary purpose is a) to classify the histologic type; and b) to determine all staging parameters, as recommended by the American Joint Committee on Cancer (AJCC), including tumor size, extent of invasion, adequacy of surgical margins, and presence or absence of lymph node metastases.

INITIAL SYSTEMIC THERAPY

NSCL

The number of involved lymph node stations should be documented since it has prognostic significance (AJCC 8th ed). Direct extension of the primary tumor into an adjacent lymph node is considered as nodal involvement. All lobectomy specimens should be extensively dissected to search for involved lymph nodes.

• In small biopsies or cytology specimens-obtained for molecular testing in the context of an established diagnosis after progression on

targeted therapies-the primary purpose is a) to confirm the original pathologic type with minimal use of tissue for IHC only in suspected small cell carcinoma transformation or a different histology; and b) to preserve material for molecular analysis. • Formalin-fixed paraffin-embedded (FFPE) material is suitable for most molecular analyses, except bone biopsies that were previously treated with acid decalcifying solutions. Non-acid decalcification approaches may be successful for subsequent molecular testing. While many molecular pathology laboratories currently also accept cytopathology specimens such as cell blocks, direct smears, or touch preparations, laboratories that do not currently do so are strongly encouraged to identify approaches to testing on non-FFPE cytopathology specimens. 1 Non-small cell carcinomas (NSCC, without the L for lung) that show no clear adenocarcinoma or squamous cell carcinoma morphology or IHC markers are regarded as NSCC-NOS. In this setting, it is recommended that pathologists use the term NSCC rather than NSCLC, because the lack of pneumocyte marker expression in small biopsies or cytology leaves open the possibility of a metastatic carcinoma and the determination of a lung primary must be established clinically after excluding other primary sites. Note: All recommendations are category 2A unless otherwise indicated. • IHC should be used to differentiate primary lung adenocarcinoma from squamous cell carcinoma, large cell carcinoma, metastatic carcinoma, and primary pleural mesothelioma (particularly for pleural specimens).

Continued

• Primary pulmonary adenocarcinoma:

In patients for whom the primary origin of the carcinoma is uncertain, an appropriate panel of IHC stains is recommended to assess for metastatic carcinoma to the lung. TTF-1 is a homeodomain-containing nuclear transcription protein of the NKX2 gene family that is expressed in epithelial cells of the embryonal and mature lung and thyroid. TTF-1 immunoreactivity is seen in primary pulmonary adenocarcinoma in the majority (70%-90%) of non-mucinous adenocarcinoma subtypes. Metastatic adenocarcinoma to the lung is nearly always negative for TTF-1 except in metastatic thyroid malignancies, in which case thyroglobulin and PAX8 are also positive. Rare cases of TTF-1 positivity in tumors of other organs (gynecologic tract, pancreatobiliary) have been noted, and may be dependent on the specific TTF-1 clone utilized, stressing the importance of correlation with clinical and radiologic features. Napsin A-an aspartic proteinase expressed in normal type II pneumocytes and in proximal and distal renal tubules-appears to be expressed in > 80% of lung adenocarcinomas and may be a useful adjunct to TTF-1. The panel of TTF-1 (or alternatively napsin A) and p40 (or alternatively p63) may be useful in refining the diagnosis to either adenocarcinoma or squamous cell carcinoma in small biopsy specimens previously classified as NSCC-NOS.

PRINCIPLES OF PATHOLOGIC REVIEW

NSCL-A 4 OF 4

Immunohistochemistry

• IHC should be used to confirm neuroendocrine differentiation when there is morphologic evidence of neuroendocrine morphology (eg, speckled chromatin pattern, nuclear molding, peripheral palisading): NCAM (CD56), chromogranin, synaptophysin, and INSM1 are used to identify neuroendocrine tumors in cases in which morphologic suspicion of neuroendocrine differentiation exists.

A panel of markers is useful, but one positive marker is enough if the staining is unambiguous in > 10% of the tumor cells.

• Pleural mesothelioma versus pulmonary adenocarcinoma

The distinction between pulmonary adenocarcinoma and pleural mesothelioma (epithelioid type) can be made by correlation of the histology with the clinical impression, imaging studies, and a panel of immunomarkers. Immunostains sensitive and specific for pleural mesothelioma include WT-1, calretinin, CK5/6, and D2-40 (usually negative in adenocarcinoma). Immunostains sensitive and specific for adenocarcinoma include pCEA, Claudin-4, TTF-1, and napsin A (negative in pleural mesothelioma).

Other potentially useful markers that can be considered include B72.

NSCL-B 2 OF 6 PRINCIPLES OF SURGICAL THERAPY

Resection

• Anatomic pulmonary resection is preferred for the majority of patients with NSCLC.

• Sublobar resection -Segmentectomy and wedge resection should be strongly considered for peripheral T1ab, N0 tumors.

NSCL-B 4 OF 6

The Role of Surgery in Patients with N2 NSCLC • Repeat mediastinoscopy, while possible, is technically difficult and has a lower accuracy compared to primary mediastinoscopy. One possible strategy is to perform EBUS (± EUS) in the initial pretreatment evaluation and reserve mediastinoscopy for nodal restaging after neoadjuvant therapy. 10 • Patients with a single lymph node < 3 cm can be considered for a multimodality approach that includes surgical resection. 6, 11, 12 Restaging after induction therapy is difficult to interpret, but CT ± FDG-PET/CT should be performed to exclude disease progression or interval development of metastatic disease. • Patients with negative mediastinum after neoadjuvant therapy have a better prognosis. 12, 13 Neoadjuvant chemoradiotherapy is used in one-third of the NCCN Member Institutions, while neoadjuvant chemotherapy is used in the other two-thirds. Overall survival appears similar provided RT is given postoperatively, if not given preoperatively. 10, 14 Neoadjuvant chemoradiotherapy is associated with higher rates of pathologic complete response and negative mediastinal lymph nodes. 15 However, that is achieved at the expense of higher rates of acute toxicity and increased cost. • When neoadjuvant chemoradiotherapy is used with doses lower than those used for standard definitive therapy, all efforts should be made to minimize any possible breaks in radiotherapy for surgical evaluation. Treatment breaks of > 1 week are considered unacceptable. • When timely surgical evaluation is not available, the strategy of neoadjuvant chemoradiotherapy should not be used. Another option in individual cases, and with the agreement of the thoracic surgeon, is to complete definitive chemoradiotherapy prior to re-evaluation and consideration for surgery. 16, 17 If a surgeon or center is uncertain about the feasibility or safety of resection after definitive doses of radiation, consider obtaining an additional surgical opinion from a high-volume specialized center. These operations may also benefit from additional considerations of soft tissue flap coverage in the radiation field at the time of resection. • Data from a large multi-institutional trial indicate that pneumonectomy after neoadjuvant chemoradiotherapy has unacceptable morbidity and mortality. 7 However, it is not clear if this is also true with neoadjuvant chemotherapy alone. Further, many groups have challenged that cooperative group finding with single-institution experiences demonstrating safety of pneumonectomy after induction therapy.

SABR for Node-Negative Early-Stage NSCLC

• The high-dose intensity and conformity of SABR require minimizing the PTV.

• Dosing regimen

For SABR, intensive regimens of biologically effective dose (BED) ≥100 Gy are associated with significantly better local control and survival than less intensive regimens. 36, 37 In the United States, only regimens of ≤5 fractions meet the arbitrary billing code definition of SBRT, but slightly more protracted regimens are appropriate as well. 36, 38 For centrally located tumors (defined variably as within 2 cm of the proximal bronchial tree and/or abutting mediastinal pleura) and even ultra-central tumors (defined as abutting the proximal bronchial tree or, in some definitions, other critical mediastinal structures as well), 4 to 10 fraction risk-adapted SABR regimens appear to be effective and safe, 39- 42 while 54 to 60 Gy in 3 fractions is unsafe and should be avoided. 43 However, particular attention should be paid to tumors abutting the bronchial tree and esophagus to avoid severe toxicity. RTOG 0813 evaluated the toxicity of 5-fraction regimens and found no high-grade toxicities at 50 Gy in 5 fractions. 44 SABR is most commonly used for tumors up to 5 cm in size, though selected larger isolated tumors can be treated safely if normal tissue constraints are respected. 44, 45 Retrospective data suggest that chemotherapy in addition to SABR provides a survival advantage for patients with large tumors (≥5 cm). 46 djuvant chemotherapy may be considered for large tumors in selected patients for whom it is safe. Definitive RT doses delivered as preoperative chemotherapy/RT can safely be administered and achieve promising nodal clearance and survival rates, [90] [91] [92] [93] but require experience in thoracic surgical techniques to minimize the risk of surgical complications after high-dose RT. In PORT, the CTV includes the bronchial stump and high-risk draining lymph node stations. 94 6] [97] Lung dose constraints should be more conservative, because tolerance appears to be reduced after surgery. The LungART and PORT-C trials provide useful guidelines for PORT technique. 98 Highly conformal techniques to minimize lung and heart dose are preferred.

Advanced/Metastatic NSCLC (stage IV)

• RT is recommended for local palliation or prevention of symptoms (such as pain, bleeding, or obstruction).

• Definitive/consolidative local therapy to isolated or limited metastatic sites (oligometastases) (including but not limited to brain, lung, and adrenal gland) achieves prolonged survival in a small proportion of well-selected patients with good performance status (PS) who have also received radical therapy to the intrathoracic disease. 99 Definitive RT to oligometastases (limited number is not universally defined but clinical trials have included 3-5 metastases), particularly SABR, is an appropriate option in such cases if it can be delivered safely to the involved sites. 100, 101 n two randomized phase II trials, significantly improved progression-free survival and overall survival in one trial 102, 103 were found for local consolidative therapy (RT or surgery) to oligometastatic lesions versus maintenance systemic therapy or observation for patients whose disease was not progressing on systemic therapy. § Use V20 < 35%, especially for the following: patients ≥70 years, taxane chemotherapy, and poor PFTs (such as FEV1 or DLCO < 50% normal). Use more conservative limits with a diagnosis or radiologic evidence of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) (the tolerance of these patients is lower though not well characterized). -H ). • Patients with completely resected tumors ≥4 cm or node-positive NSCLC should be evaluated for additional systemic therapy.

References

• Alectinib 600 mg twice daily for 24 months 14 For patients with NSCLC positive for ALK rearrangements (category 1). • Osimertinib 80 mg daily for 3 years 15 For patients with NSCLC positive for EGFR (exon 19 deletion, exon 21 L858R) mutations who received previous adjuvant chemotherapy or are ineligible to receive platinum-based chemotherapy (category 1). • Atezolizumab 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks for up to 1 year 16 For patients with NSCLC with PD-L1 ≥1% and negative for EGFR exon 19 deletion or exon 21 L858R mutations or ALK rearrangements who received previous adjuvant chemotherapy and with no contraindications to immune checkpoint inhibitors (category 1). Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-tqjs has different dosing and administration instructions compared to IV atezolizumab.

• Pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks

For up to a year for patients with NSCLC negative for EGFR exon 19 deletion or exon 21 L858R mutations or ALK rearrangements who received previous adjuvant chemotherapy and with no contraindications to immune checkpoint inhibitors (category 1). 17 The benefit for patients with PD-L1 < 1% is unclear. For up to 39 weeks for patients who received previous neoadjuvant pembrolizumab + chemotherapy (category 1). 3 • Durvalumab 1500 mg every 4 weeks for up to 12 cycles 4 For patients who received previous neoadjuvant durvalumab + chemotherapy and no known EGFR mutations or ALK rearrangements (category 1). • Nivolumab 480 mg every 4 weeks for up to 13 cycles 2 For patients who received previous neoadjuvant nivolumab + chemotherapy and no known EGFR mutations or ALK rearrangements (category 1). Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and administration instructions compared to IV nivolumab.

a Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents; some oncogenic drivers (ie, EGFR exon 19 deletion or exon 21 L858R; ALK, RET, or ROS1 rearrangements) have been shown to be associated with less benefit from PD-1/PD-L1 inhibitors. c In general, perioperative therapy should be given as a single regimen and change of immunotherapy is not recommended. b Regimens can be used as preoperative/adjuvant chemotherapy/RT. c Regimens can be used as definitive concurrent chemotherapy/RT. d For eligible patients, durvalumab may be used after noted concurrent chemotherapy/RT regimens. e For eligible patients, osimertinib may be used after noted concurrent chemotherapy/RT regimens in patients with EGFR exon 19 deletion or L858R. f If using durvalumab or osimertinib, additional chemotherapy after radiation is not recommended. If not using durvalumab or osimertinib, an additional 4 cycles of pemetrexed 500 mg/m² may be used. g If using durvalumab or osimertinib, additional chemotherapy after radiation is not recommended. If not using durvalumab or osimertinib, an additional 2 cycles every 21 days of paclitaxel 200 mg/m² and carboplatin AUC 6 may be used. h In patients with tumors that are positive for EGFR exon 19 deletion of exon 21 L858R mutations there is risk of toxicity when TKI is administered in temporal proximity to immunotherapy. i For patients who have received sequential chemoradiation, durvalumab can be considered as consolidation immunotherapy or, if EGFR exon 19 deletion or L858R, osimertinib is recommended.

Neoadjuvant Systemic Therapy for

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CANCER SURVIVORSHIP CARE 7 American Cancer Society Guideline for Diet and Physical Activity for Cancer Prevention: https://www.cancer.org/cancer/risk-prevention/diet-physical-activity/acsguidelines-nutrition-physical-activity-cancer-prevention.html. 8 Memorial Sloan Kettering Cancer Center Screening Guidelines: https://www.mskcc.org/cancer-care/risk-assessment-screening/screening-guidelines. 9 American Cancer Society Guidelines for the Early Detection of Cancer: http://www.cancer.org/healthy/findcancerearly/cancerscreeningguidelines/american-cancer-society-guidelines-for-the-early-detection-of-cancer?sitearea=PED. Note: All recommendations are category 2A unless otherwise indicated.

Counseling Regarding Health Promotion and Wellness

• Testing Methodologies (continued)

◊ It is recommended at this time that when feasible, testing be performed via a broad, panel-based approach, most typically performed by NGS. For patients who, in broad panel testing don't have identifiable driver oncogenes, consider RNA-based NGS if not already performed, to maximize detection of fusion events.

-Broad molecular profiling is defined as molecular testing that identifies all biomarkers identified in NSCL-20 in either a single assay or a combination of a limited number of assays, and optimally also identifies emerging biomarkers (NSCL-I). Tiered approaches based on low prevalence of co-occurring biomarkers are acceptable. ◊ Real-time polymerase chain reaction (PCR) can be used in a highly targeted fashion (specific mutations targeted). When this technology is deployed, only those specific alterations that are targeted by the assay are assessed and the potential for mutations outside of the testing scope of the specific assay must be considered. ◊ Any method that interrogates sequences other than a subset of highly specific alterations (eg, NGS) has the potential to identify variants of uncertain significance (VUS). Any variant classified as a VUS, even if in a gene in which other variants are clinically actionable, should not be considered as a basis for targeted therapy selection. ◊ Other methodologies may be utilized, including multiplex approaches not listed above. ◊ Fluorescence in situ hybridization (FISH) analysis is utilized for many assays examining copy number, amplification, and structural alterations such as gene rearrangements. FISH may have better sensitivity for gene amplification events in some circumstances.

• Specimen Selection

Testing platforms using tissue and peripheral blood are available.

• Molecular Targets for Analysis

In general, the mutations/alterations described below are seen in a non-overlapping fashion, although between 1%-3% of NSCLC may harbor concurrent alterations.

EGFR (Epidermal Growth

NSCL-H 7 OF 8

PRINCIPLES OF MOLECULAR AND BIOMARKER ANALYSIS

• Testing in the setting of a limited number of pulmonary nodules can aid in distinguishing separate primary lung carcinoma versus intrapulmonary metastatic disease.

Studies to explore tumor relatedness by testing tissue from separately sampled lesions using a broad gene coverage NGS approach suggest it may be superior to histopathologic assessment. Tumor pairs exhibiting entirely non-overlapping, unique mutations are considered clonally unrelated separate primary lung cancers, even if histologically similar. Tumors that share multiple (≥2) mutations are more likely to be clonally related; however, this may depend on the extent to which any individual mutation is extremely common in NSCLC and whether identified alterations are driver or passenger alterations. Results in which no mutations or only one mutation are identified are not informative for this evaluation.

• Testing in the Setting of Progression on Targeted Therapy:

For any patient with progression on targeted therapy, histologic transformation (such as small cell) is a possible mechanism of resistance.

Tissue biopsy of a progressing lesion should be considered to evaluate morphology and biomarker analysis.

NSCL-I 1 Wolf J, Seto T, Han JY, et al; GEOMETRY mono-1 Investigators. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med 2020;383:944-957.

FGFR alterations c

Erdafitinib 5

a The definition of high-level MET amplification is evolving and may differ according to the assay used for testing. For NGS-based results, a copy number ≥10 is consistent with high-level MET amplification. b In patients with EGFR-mutant NSCLC who develop high-level MET amplifications, administration of these agents with continuation of osimertinib is acceptable. c For oncogenic or likely oncogenic FGFR mutations, refer to definitions at oncokb.org.

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a Monitoring During Initial Therapy: Response assessment after 2 cycles, then every 2-4 cycles with CT of known or high-risk sites of disease (eg, chest, abdomen, pelvis) with or without contrast or when clinically indicated. Timing of CT scans within Guidelines parameters is a clinical decision. b Monitoring During Subsequent Therapy or Maintenance Therapy: Response assessment with CT of known or high-risk sites of disease (eg, chest, abdomen, pelvis)

with or without contrast every 6-12 weeks. Timing of CT scans within Guidelines parameters is a clinical decision. c An FDA-approved biosimilar is an appropriate substitute for bevacizumab. d For agents with a similar mechanism of action, it is not recommended to switch between these drugs at the time of progression. Note: All recommendations are category 2A unless otherwise indicated.

PD-L1 ≥50% First-Line Therapy

PD-L1 ≥1%-49% First-Line Therapy

MOLECULAR AND BIOMARKER-DIRECTED THERAPY FOR ADVANCED OR METASTATIC DISEASE

NSCL-J 2 OF 6

with or without contrast every 6-12 weeks. Timing of CT scans within Guidelines parameters is a clinical decision. c An FDA-approved biosimilar is an appropriate substitute for bevacizumab. e Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-tqjs has different dosing and administration instructions compared to IV atezolizumab. f Criteria for treatment with bevacizumab: nonsquamous NSCLC, and no recent history of hemoptysis. g Atezolizumab monotherapy is a treatment option for patients with PS 3, regardless of PD-L1 status.

MOLECULAR AND BIOMARKER-DIRECTED THERAPY FOR ADVANCED OR METASTATIC DISEASE a,b

References Continuation Maintenance

PD-L1 ≥50% FIRST-LINE THERAPY (PS 0-2) Adenocarcinoma, Large Cell, NSCLC NOS Squamous Cell Carcinoma Preferred • Pembrolizumab (category 1) 54, 55 • (Carboplatin or cisplatin) + pemetrexed + pembrolizumab (category 1) 56, 57 • Atezolizumab e (category 1) 58 • Cemiplimab-rwlc (category 1) 59 • Cemiplimab-rwlc + pemetrexed + (carboplatin or cisplatin) (category 1) 60 Other Recommended • Carboplatin + paclitaxel + bevacizumab c,f + atezolizumab e (category 1) 61 • Carboplatin + albumin-bound paclitaxel + atezolizumab e,62 • Nivolumab + ipilimumab + pemetrexed + (carboplatin or cisplatin) (category 1) 63 • Cemiplimab-rwlc + paclitaxel + (carboplatin or cisplatin) (category 1)

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with or without contrast every 6-12 weeks. Timing of CT scans within Guidelines parameters is a clinical decision. c An FDA-approved biosimilar is an appropriate substitute for bevacizumab. e Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-tqjs has different dosing and administration instructions compared to IV atezolizumab. f Criteria for treatment with bevacizumab: nonsquamous NSCLC, and no recent history of hemoptysis. g Atezolizumab monotherapy is a treatment option for patients with PS 3, regardless of PD-L1 status. h Pembrolizumab monotherapy can be considered in PD-L1 1%-49%, when there are contraindications to combination chemotherapy.

PD-L1 ≥50% First-Line Therapy PD-L1 ≥1%-49% FIRST-LINE THERAPY (PS 0-2) Adenocarcinoma, Large Cell, NSCLC NOS Squamous Cell Carcinoma Preferred • (Carboplatin or cisplatin) + pemetrexed + pembrolizumab (category 1) 56, 57 • Cemiplimab-rwlc + pemetrexed + (carboplatin or cisplatin) (category 1) 60 Other Recommended • Carboplatin + paclitaxel + bevacizumab c,f + atezolizumab e (category 1) Useful in Certain Circumstances • Bevacizumab g /carboplatin/paclitaxel h,i,j (category 1) 9 • Bevacizumab g /carboplatin/pemetrexed h,i,j,9,10 • Bevacizumab g /cisplatin/pemetrexed h,i,j,11

• Atezolizumab e,l • Nivolumab + ipilimumab (category 1) m • Cemiplimab-rwlc (category 1) n • Cemiplimab-rwlc o ± pemetrexed p (category 1) • Durvalumab q ± pemetrexed r • Pembrolizumab (category 1) i,s • Atezolizumab e,l • Nivolumab + ipilimumab (category 1) m • Cemiplimab-rwlc (category 1) n,o • Durvalumab q PD-L1 ≥1%-49% CONTINUATION MAINTENANCE Adenocarcinoma, Large Cell, NSCLC NOS Squamous Cell Carcinoma • Pembrolizumab (category 2B) i • Pembrolizumab + pemetrexed (category 1) j • Atezolizumab

• Carboplatin-combination therapy (category 1) Combination options include: albumin-bound paclitaxel, 12 docetaxel, 13 etoposide, 14, 15 gemcitabine, 16 paclitaxel, 17 or pemetrexed 18 • Cisplatin-combination therapy (category 1) Combinations options include: docetaxel, 13 etoposide, 19 gemcitabine, 17, 20 paclitaxel, 21 or pemetrexed 20 • Gemcitabine/docetaxel 22 • Gemcitabine/vinorelbine 23 • Albumin-bound paclitaxel 24, 25 • Docetaxel 26, 27 • Gemcitabine [28] [29] [30] • Paclitaxel [31] [32] [33] • Pemetrexed 34

ADENOCARCINOMA, LARGE CELL, NSCLC NOS (PS 3-4) f,k

Best supportive care (NCCN Guidelines for Palliative Care) e If progression on PD-1/PD-L1 inhibitor, using a PD-1/PD-L1 inhibitor is not recommended. f Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab.

Atezolizumab and hyaluronidase-tqjs has different dosing and administration instructions compared to IV atezolizumab. g An FDA-approved biosimilar is an appropriate substitute for bevacizumab. h Bevacizumab should be given until progression. i Any regimen with a high risk of thrombocytopenia and the potential risk of bleeding should be used with caution in combination with bevacizumab. j Criteria for treatment with bevacizumab: nonsquamous NSCLC, and no recent history of hemoptysis.

Bevacizumab should not be given as a single agent, unless as maintenance if initially used with chemotherapy. k Atezolizumab monotherapy is a treatment option for patients with PS 3, regardless of PD-L1 status. Useful in Certain Circumstances • Carboplatin/albumin-bound paclitaxel (category 1) 12 • Carboplatin/docetaxel (category 1) 13 • Carboplatin/gemcitabine (category 1) 16 • Carboplatin/paclitaxel (category 1) 17 • Carboplatin/etoposide 14, 15 • Cisplatin/docetaxel (category 1) 13 • Cisplatin/etoposide (category 1) 19 • Cisplatin/gemcitabine (category 1) 19, 20 • Cisplatin/paclitaxel (category 1) 21 • Gemcitabine/docetaxel 22 • Gemcitabine/vinorelbine 23 • Albumin-bound paclitaxel 24, 25 • Docetaxel 26, 27 • Gemcitabine [28] [29] [30] • Paclitaxel [31] [32] [33]

SQUAMOUS CELL CARCINOMA (PS 3-4) f,k

Best supportive care (NCCN Guidelines for Palliative Care) a Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in patients who have experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despite premedication, or for patients where the standard premedications (ie, dexamethasone, H2 blockers, H1 blockers) are contraindicated. b Carboplatin-based regimens are often used for patients with comorbidities or those who cannot tolerate cisplatin. C If first-line systemic therapy completed before treatment for an actionable mutation, and disease has progressed, see Subsequent Therapy (NSCL-K 4 of 5).

d Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents; some oncogenic drivers (ie, EGFR exon 19 deletion or L858R; ALK, RET, or ROS1 rearrangements) have been shown to be associated with less benefit from PD-1/PD-L1 inhibitors. e If progression on PD-1/PD-L1 inhibitor, using a PD-1/PD-L1 inhibitor is not recommended. f Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab.

Atezolizumab and hyaluronidase-tqjs has different dosing and administration instructions compared to IV atezolizumab. k Atezolizumab monotherapy is a treatment option for patients with PS 3, regardless of PD-L1 status.

ADENOCARCINOMA, LARGE CELL, NSCLC NOS (PS 0-2)

SQUAMOUS CELL CARCINOMA (PS 0-2) Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus) T1mi Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension T1a Tumor ≤1 cm in greatest dimension. A superficial, spreading tumor of any size whose invasive component is limited to the bronchial wall and may extend proximal to the main bronchus also is classified as T1a, but these tumors are uncommon. T1b Tumor > 1 cm but ≤2 cm in greatest dimension T1c Tumor > 2 cm but ≤3 cm in greatest dimension T2

Continuation maintenance • Bevacizumab (category 1) • Pemetrexed (category 1) • Bevacizumab/pemetrexed m • Pembrolizumab/pemetrexed (category 1) n • Atezolizumab f /bevacizumab (category 1) o • Nivolumab/ipilimumab p • Atezolizumab f,q • Gemcitabine (category 2B) • Cemiplimab-rwlc r ± pemetrexed s (category 1) • Durvalumab t ± pemetrexed u Switch maintenance • Pemetrexed Continuation maintenance • Pembrolizumab v • Nivolumab/ipilimumab p • Gemcitabine (category 2B) • Cemiplimab-rwlc r (category 1) • Durvalumab t

Tumor > 3 cm but ≤5 cm or having any of the following features: (1) Involves the main bronchus, regardless of distance to the carina, but without involvement of the carina; (2) Invades visceral pleura (PL1 or PL2); (3) Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung T2a Tumor > 3 cm but ≤4 cm in greatest dimension T2b Tumor > 4 cm but ≤5 cm in greatest dimension

T3

Tumor > 5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleura (PL3), chest wall (including superior sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary

TX N0 M0 Stage 0 Tis N0 M0 Stage IA1 T1mi N0 M0 T1a N0 M0 Stage IA2 T1b N0 M0 Stage IA3 T1c N0 M0 Stage IB T2a N0 M0 Stage IIA T2b N0 M0 Stage IIB T1a N1 M0 T1b N1 M0 T1c N1 M0 T2a N1 M0 T2b N1 M0 T3 N0 M0 Stage IIIA T1a N2 M0 T1b N2 M0 T1c N2 M0 T2a N2 M0 T2b N2 M0 T3 N1 M0 T4 N0 M0 T4 N1 M0 T N M Stage IIIB T1a N3 M0 T1b N3 M0 T1c N3 M0 T2a N3 M0 T2b N3 M0 T3 N2 M0 T4 N2 M0 Stage IIIC T3 N3 M0 T4 N3 M0 Stage IVA Any T Any N M1a Any T Any N M1b Stage IVB Any T Any N M1c

CAT-1

NCCN Categories of Evidence and Consensus Category 1

Based upon high-level evidence (≥1 randomized phase 3 trials or high-quality, robust meta-analyses), there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate. Category 2A Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate. Category 2B Based upon lower-level evidence, there is NCCN consensus (≥50%, but < 85% support of the Panel) that the intervention is appropriate.

Category 3

Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Preferred intervention

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.

Other recommended intervention

Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.

Useful in certain circumstances

Other interventions that may be used for selected patient populations (defined with recommendation).

All recommendations are considered appropriate. The overall 5-year relative survival rate among those with adenocarcinoma histology was 32.2%. 3 5] [6] [7] [8] [9] The availability of these new treatments is associated with improved survival rates for patients with NSCLC. From 2015 to 2016, 2-year relative survival for NSCLC was 42% compared with 34% from 2009 to 2010. 10 Patients with NSCLC who are eligible for targeted therapies or immunotherapies are now surviving longer; 5-year survival rates range from 15% to 62.5%, depending on the biomarker. 9,11- 27 Therefore, biomarker testing is critical to guide treatment selection and ensure optimal outcomes in patients with NSCLC, particularly for those with advanced or metastatic disease.

NCCN Guidelines Version 3.2025

Non-Small Cell Lung Cancer MS-3

Guidelines Update Methodology

The complete details of the Development and Update of the NCCN Guidelines are available at www.NCCN.org.

Literature Search Criteria

Prior to the update of the NCCN Guidelines for Non-Small Cell Lung Cancer, an electronic search of the PubMed database was performed to obtain key literature in NSCLC published since the previous Guidelines update, using the search term: non-small cell lung cancer.

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, anti-misogynist, anti-ageist, anti-ableist, and anti-fat-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

Risk Factors

9] [30] [31] [32] Approximately 350 people die every day from lung cancer in the United States; most of these deaths (81%) are caused by cigarette smoking. 33 Cigarette smoke contains many carcinogenic chemicals (eg, nitrosamines, benzo(a)pyrene diol epoxide). 31, 34 The risk for lung cancer increases with the number of packs of cigarettes smoked per day and with the number of years spent smoking (ie, pack-years of smoking history). [36] [37] Other possible risk factors for lung cancer include disease history (eg, COPD), cancer history, family history of lung cancer, and exposure to other carcinogens (see the NCCN Guidelines for Lung Cancer Screening, available at www.NCCN.org). 38, 39 1] [42] Asbestos is a known NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer

MS-4

carcinogen that increases the risk for lung cancer in people exposed to airborne fibers, especially in individuals who smoke cigarettes. It is estimated that about 3% to 4% of lung cancers are caused by asbestos exposure. 43 Asbestos also causes pleural mesothelioma (see the NCCN Guidelines for Mesothelioma: Pleural, available at www.NCCN.org).

Radon gas, a radioactive gas that is produced by the decay of radium 226, also seems to cause lung cancer.

It is not clear whether hormone replacement therapy (HRT) affects the risk for lung cancer in women. More than 20 studies have been published, but the results have been inconsistent. In a large randomized controlled study, no increase in the incidence of lung cancer was found among postmenopausal women treated with estrogen plus progestin HRT; however, the risk of death increased in those with NSCLC. 44 In women who received estrogen alone, the incidence or risk of death from lung cancer did not increase. 45

Smoking Cessation

Approximately 85% to 90% of cases of lung cancer are caused by cigarette smoking. 30 Of patients aged 20 to 49 years who were recently diagnosed with lung cancer, 81% of men and 72% of the women had smoked. 46 Active smoking causes lung cancer; individuals who formerly smoked are at increased risk for lung cancer compared with those who have never smoked. There is a causal relationship between active smoking and lung cancer and also between other cancers (eg, bladder, cervical, colorectal, esophageal, gastric, kidney, laryngeal, oral cavity, ovarian cancer, pancreatic, pharyngeal) and other diseases and conditions. 30 Smoking harms nearly every organ in the body; individuals who smoke have increased mortality compared with those who do not smoke. 47 Those who do not smoke, but live with someone who smokes, have an increased risk for lung cancer due to secondhand smoke. 35 rther complicating this problem, cigarettes also contain nicotine, which is a highly addictive substance.

9] [50] [51] The 5 A's framework is a useful tool (that is, Ask, Advise, Assess, Assist, Arrange). 52 It is in the best interest of patients to quit smoking tobacco. Persistent smoking is associated with second primary cancers, treatment complications, and decreased survival. 53 Some surgeons will not operate on individuals who currently smoke, because active smoking may increase postoperative pulmonary complications. 54 owever, active smoking should not be used to exclude patients with early-stage lung cancer from surgical treatment that will prolong survival. Programs using behavioral counseling combined with medications that promote smoking cessation (approved by the FDA) can be very useful. 55 he American Cancer Society (ACS) has resources on How to Quit Using Tobacco.

Agents that can be used to promote smoking cessation include nicotine replacement (eg, gum, inhaler, lozenge, nasal spray, patch), bupropion sustained release, and varenicline. 56, 57 A study suggests that cytisine is more efficacious than nicotine replacement therapy, although more side effects were reported with cytisine such as nausea, vomiting, and sleep disorders. 58 0] [61] The effectiveness of varenicline for preventing relapse has not been clearly established. 62 The FDA has issued an alert for varenicline regarding neuropsychiatric symptoms. 4] [65] [66] Other side effects of varenicline include nausea, abnormal dreams, insomnia, and headache. 61, 67, 68 Bupropion may also be NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-5 associated with similar serious neuropsychiatric symptoms. Nicotine replacement has fewer adverse effects than varenicline or bupropion. 69 In spite of the potential adverse effects, it is probably more beneficial for motivated patients to use agents to promote smoking cessation. 69

Lung Cancer Screening

Lung cancer is the leading cause of cancer death worldwide in men, and late diagnosis is a major obstacle to improving lung cancer outcomes. 2, 70, 71 he feasibility of lung cancer screening was assessed because localized cancer can be managed with curative intent and because the mortality rate in other solid tumors (eg, cervix, colon) seems to be decreased by screening, early detection, and prompt treatment.

The National Lung Screening Trial (NLST) (ACRIN Protocol A6654), a phase 3 randomized trial, assessed the risks and benefits of low-dose CT scans compared with chest radiographs for detecting lung cancer in more than 53,000 individuals with a long-term history of smoking cigarettesincluding those who currently or previously smoked. 72 The NLST showed that screening individuals with high-risk factors using low-dose CT decreased the mortality rate from lung cancer by 20%. 73 Individuals who currently or previously smoked cigarettes were categorized as high risk for lung cancer if they had a 30 or more pack-year smoking history (individuals who previously smoked had quit smoking up to 15 years before enrollment), were 55 to 74 years of age, and had no evidence of lung cancer.

Classification and Prognostic Factors

2] [83] [84] NSCLC accounts for more than 80% of all lung cancer cases, and it includes two major types: 1) nonsquamous, including adenocarcinoma, large-cell carcinoma, and other subtypes; and 2) squamous cell (epidermoid) carcinoma. 85 Adenocarcinoma is the most common subtype of lung cancer seen in the United States and is also the most frequently occurring histology in individuals who have never smoked cigarettes. 83] [84] 86 All NSCLC should be classified according to subtype using the WHO Guidelines.

Diagnostic Evaluation Incidental Lung Nodules

Lung cancer screening is recommended for early diagnosis in asymptomatic patients at high risk for cancer. 72, 75 Risk assessment is used to determine which individuals are at high risk for lung cancer and thus are candidates for screening with low-dose CT. 88 Clinicians are referred to the NCCN Guidelines for Lung Cancer Screening for risk assessment criteria to determine which patients are eligible for screening and for how to evaluate and follow up on low-dose CT screening findings. 89 The NCCN Guidelines for Lung Cancer Screening have been revised to harmonize with the LungRADs system developed by the American College of Radiology with the goal of decreasing the false-positive low-dose CT screening results reported in the NLST. 90 e diagnostic algorithm for incidental pulmonary nodules in the NCCN Guidelines for NSCLC incorporates information from the NCCN Guidelines for Lung Cancer Screening. 2] [93] [94] [95] Note that the Fleischner Society Guidelines do not specify whether a CT with contrast is necessary for follow-up or whether a low-dose CT is sufficient. Low-dose CT is a preferred recommendation in the NCCN Guidelines unless contrast enhancement is needed for better diagnostic resolution.

Solid and subsolid nodules are the two main types of pulmonary nodules that may be seen on chest CT scans. The Fleischner Society has recommendations for patients with solid and subsolid nodules. 92, 93 0] [101] Data suggest that many nonsolid nodules discovered incidentally on CT imaging will resolve and many of those that persist may not progress to clinically significant cancer. 99, 102, 103 olid and part-solid nodules are more likely to be invasive, faster-growing cancers, factors that are reflected in the increased suspicion and follow-up of these nodules (see the NCCN Guidelines for Lung Cancer Screening, available at www.NCCN.org). 89, 92, 93 l findings and factors for a patient need to be carefully evaluated in a multidisciplinary diagnostic team before establishing a diagnosis of lung cancer and before starting treatment. The NCCN Guidelines recommend biopsy or surgical excision for highly suspicious nodules seen on low-dose CT scans or further surveillance for nodules with a low suspicion of cancer, depending on the type of nodule and a multidisciplinary evaluation of other patient factors (see the NCCN Guidelines for Lung Cancer Screening, available at www.NCCN.org). For patients having repeat scans, the most important radiologic factor is change or stability of a nodule when compared with a previous imaging study. False-positive results (eg, benign intrapulmonary lymph nodes, noncalcified granulomas) frequently occurred with low-dose CT when using the original cutoffs for nodule size deemed suspicious for malignancy from the NLST. 73 The revised cutoff values for suspicious nodules recommended by the American College of Radiology and incorporated into the LungRADs system have been reported to decrease the false-positive rate from low-dose CT. [104] [105] [106] Larger Tumors

The NCCN Guidelines recommend that the diagnostic strategy should be individualized for each patient depending on the size and location of the For example, the NCCN Panel clarified that a preoperative biopsy may be useful for patients with early-stage NSCLC (ie, clinical stage IB or more) who may be candidates for systemic therapy before surgery (also known as neoadjuvant, induction, or preoperative therapy). 107 A preoperative biopsy may be appropriate if an intraoperative diagnosis seems to be difficult or very risky (such as a small and central lesion, where it is difficult to do a wedge or intraoperative core needle biopsy). The preferred biopsy technique depends on the disease site and is described in the NSCLC algorithm. For example, radial endobronchial ultrasound (EBUS; also known as endosonography), navigational bronchoscopy, or transthoracic needle aspiration (TTNA) are recommended for patients with suspected peripheral nodules. 108 T/CT imaging is useful before selecting a biopsy site, because it is better to biopsy the site that will confer the highest stage. For patients with suspected nodal disease, pathologic mediastinal lymph node evaluation is recommended with either noninvasive or invasive staging methods, including endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), EBUS-guided transbronchial needle aspiration (EBUS-TBNA), navigational bronchoscopy, robotic bronchoscopy, or mediastinoscopy (see Principles of Diagnostic Evaluation in the NCCN Guidelines for NSCLC). Clinicians use both noninvasive and invasive methods when staging patients. 109 The panel decided that a preoperative bronchoscopy may also be preferred for tissue diagnosis and/or mediastinal staging (EBUS). EBUS provides access to nodal stations

Pathologic Evaluation of Lung Cancer

Pathologic evaluation is done to determine whether patients have primary lung cancer or metastatic cancer, classify the histologic subtype of the lung cancer, determine the extent of invasion, establish whether the surgical margins contain cancer (ie, positive or negative margins), and conduct biomarker diagnostic studies to assess for certain somatic, disease-associated variants/mutations (eg, EGFR mutations) or immune biomarkers (eg, PD-L1) (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). 110 Targeted therapy is potentially very effective in patients with NSCLC and specific driver mutations, such as EGFR mutations; therefore, tissue needs to be conserved for molecular testing NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-8

2] [113] [114] [115] [116] [117] [118] [119] [120] All specimens should be assessed morphologically, including routine staining approaches such as hematoxylin and eosin (H & E) histology (or relevant stains for cytology specimens). Cytology may be sufficient to distinguish adenocarcinomas from squamous cell carcinomas. 121 Ideally, a diagnosis of NSCLC can be done using H & E findings, clinical findings, imaging studies, and the patient's history, which will conserve tissue for molecular analyses. If necessary, immunohistochemistry (IHC) should be used to distinguish adenocarcinoma, squamous cell carcinoma, metastatic malignancy, and primary pleural mesothelioma (particularly for pleural samplings) (see Immunohistochemistry for Diagnosis of NSCLC in this Discussion). 122 ypically, treatment is not recommended until the patient has been diagnosed with NSCLC.

Preoperative evaluations include examination of the following: bronchial brushings, bronchial washings, sputum, FNA biopsy, core needle biopsy, endobronchial biopsy, and transbronchial biopsy. 108, 123 Minimally invasive techniques can be used to obtain specimens in patients with advanced unresectable NSCLC; 124, 125 however, diagnosis may be more difficult when using small biopsies and cytology. 100 7] [128] [129] [130] The mediastinal lymph nodes are systematically sampled to determine the staging and therapeutic options. 2] [133] Lobectomy or pneumonectomy specimens are evaluated intraoperatively to determine the surgical resection margin status, diagnose incidental nodules discovered at the time of surgery, or evaluate the regional lymph nodes.

Postoperative evaluation provides the pathology characteristics necessary for the classification of tumor type, staging, and prognostic factors. 84] 86 The classification recommends IHC and molecular studies (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). 82, 135 The use of general categories-such as non-small cell carcinoma (NSCC) or NSCC not otherwise specified (NOS)-should be minimized, because more effective treatment can be selected when the histology is known.

Major subtypes of NSCLC include adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, large cell carcinoma, carcinoid tumor, and less common subtypes that are not discussed here (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). All NSCLC should be classified according to subtype using the WHO Guidelines. 82, 84 Ideally, the subtype should be specified. The general terms NSCC or NSCC NOS should be used infrequently and only when a more specific diagnosis cannot be obtained by morphology and/or special staining. The purpose of the pathologic evaluation of NSCLC varies depending on whether the sample is 1) intended for initial diagnosis in a case of suspected NSCLC; 2) a definitive resection sample; or 3) obtained for molecular evaluation in the setting of an established NSCLC diagnosis. Further details are provided in the algorithm.

Adenocarcinomas include AIS, MIA, invasive adenocarcinomas, and invasive adenocarcinoma variants (see Adenocarcinoma in this Discussion and the NCCN Guidelines for NSCLC). Squamous cell carcinoma is a malignant epithelial tumor that 1) shows either keratinization and/or intercellular bridges; or 2) is an undifferentiated The diagnosis of large cell carcinoma requires a thoroughly sampled resected tumor and cannot be made on non-resected or cytology specimens. Large cell carcinoma cannot be accurately identified using small samples because of challenges with complete assessment of the lesion. 86 Immunohistochemical stains that exclude adenocarcinoma (TTF1, Napsin A) and squamous cell carcinoma (p40, p63) need to be used before making a diagnosis of large cell carcinoma; mucin stain is also recommended to assess for occult glandular differentiation. Carcinoid tumors are treated using the neuroendocrine guidelines and not the NSCLC guidelines; however, they are part of the differential diagnosis of pulmonary lesions (see the NCCN Guidelines for Neuroendocrine and Adrenal Tumors, available at www.NCCN.org). Care should be taken to distinguish typical carcinoids from atypical carcinoids by assessing for necrosis (see the NCCN Guidelines for Small Cell Lung Cancer, available at www.NCCN.org.)

The NCCN NSCLC Panel recommends molecular testing for eligible patients with metastatic NSCLC because FDA-approved agents for lung cancer are available for actionable biomarkers (see Testing for Molecular Biomarkers in this Discussion). Molecular testing is recommended for patients with metastatic adenocarcinoma, large cell carcinoma, and NSCLC NOS. Testing may be considered for patients with metastatic squamous cell carcinoma. 136, 137 The NCCN NSCLC Panel also recommends PD-L1 IHC testing (category 1) in all patients with metastatic NSCLC because FDA-approved immunotherapy agents are available for this immune biomarker (see Testing for Immune Biomarkers in this Discussion). 138

Adenocarcinoma

Most lung carcinomas are adenocarcinomas. The categories for adenocarcinoma include: 1) AIS, which is a preinvasive, typically solitary lesion that is usually non-mucinous; 2) MIA, which is a solitary and discrete non-mucinous lesion with a maximum area of invasion no greater than 0.5 cm; and 3) invasive adenocarcinoma variants (see the NCCN Guidelines for NSCLC). Both AIS and MIA are associated with excellent survival if they are resected. The terms AIS and MIA should not be used for small samples because of challenges with complete assessment of the lesion. 86 The categories of BAC or mixed subtype adenocarcinoma are no longer used to classify adenocarcinoma. 86 84] 86 The lung classification recommends that use of general categories-NSCC and NSCC NOS-should be minimized, because more effective treatment can be selected when the specific subtype is known (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). 135

Immunohistochemistry for Diagnosis of NSCLC

174 e presence of EGFR exon 19 deletions or EGFR exon 21 L858R mutations is predictive of treatment benefit from EGFR tyrosine kinase inhibitor (EGFR TKI) therapy, such as osimertinib (see EGFR Mutations in this Discussion). 175, 176 Previously, these mutations were referred to as sensitizing EGFR mutations; however, the specific mutations are now described. The presence of EGFR exon 19 deletions or EGFR exon 21 L858R mutations does not appear to be prognostic of survival for patients with NSCLC, independent of therapy.

Non-Small Cell Lung Cancer

MS-13

Patients with metastatic NSCLC squamous cell carcinoma can also have actionable biomarkers, such as EGFR mutations, although at a lower incidence than those with metastatic NSCLC adenocarcinoma. 136, 137, 184, 185 Molecular testing for actionable alterations can be considered in patients with metastatic squamous cell carcinoma based on the effectiveness of targeted therapies. 184, 185 The NCCN Panel recommends that molecular testing be considered in all patients with metastatic NSCLC squamous cell carcinoma and not just those with certain characteristics, such as those who have never smoked cigarettes, with small biopsy specimens, and with mixed histology.

For patients with metastatic nonsquamous NSCLC, the NCCN NSCLC Panel currently recommends that a minimum of the following biomarkers should be assessed, including ALK rearrangements, BRAF mutations, EGFR mutations, ERBB2 (HER2) mutations, KRAS mutations, METex14 skipping mutations, NTRK1/2/3 fusions, RET rearrangements, ROS1 rearrangements, and PD-L1 expression levels; molecular testing can be considered in those with metastatic squamous cell carcinoma. This list of recommended biomarkers has been revised as new oncogenic driver mutations were identified and new agents were approved. The NCCN NSCLC Panel also recommends molecular testing in eligible patients with metastatic NSCLC for EGFR exon 20 insertion mutations and for less common EGFR mutations, such as EGFR S768I, L861Q, and G719X. 6] [167] [168] [169] [170] In 2020, the NCCN Panel deleted TMB as an emerging immune biomarker based on clinical trial data and other issues (see TMB in this Discussion). 171 The NCCN Guidelines for NSCLC provide recommendations for individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories. 186 Biomarker testing should be done at properly accredited laboratories (minimum of Clinical Laboratory Improvement Amendments [CLIA] accreditation) (see Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC).

ALK, BRAF p.V600E, EGFR, KRAS, METex14 skipping mutations, RET rearrangements, and ROS1 rearrangements do not usually overlap; thus, testing for KRAS mutations may identify patients who will not benefit from further molecular testing (also known as tiered testing approaches). 185,187- 191 The KRAS oncogene is a prognostic biomarker. The presence of KRAS mutations is prognostic of poor survival for patients with NSCLC when compared to the absence of KRAS mutations, independent of therapy (see KRAS Mutations in this Discussion). 192 formation about biomarker testing and plasma circulating tumor DNA (ctDNA) testing (so-called "liquid biopsy") for actionable mutations is included in the algorithm (see Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC). Briefly, the panel feels that plasma ctDNA testing should not be used to diagnose NSCLC; tissue should be used to diagnose NSCLC. Standards and guidelines for plasma ctDNA testing for somatic variants/mutations have not been published, there is up to a 30% false-negative rate, and variants can be detected that are not related to the tumor (eg, clonal hematopoiesis of indeterminate potential [CHIP]). 193, 194 For example, an IDH1 mutation identified by plasma ctDNA testing is likely unrelated to NSCLC, given exceptionally low incidence, and is more likely to represent CHIP. Rare examples of CHIP with KRAS mutations have been described, suggesting caution in the interpretation of ctDNA findings. 195 In addition, CHIP can be identified following prior chemotherapy or radiotherapy, further confounding interpretation of variants such as in TP53. 196 Given the previous caveats, NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-14 careful consideration is required to determine whether ctDNA findings reflect a true oncogenic driver or an unrelated finding. For the 2023 update (Version 1), the NCCN Panel added a caveat that many, but not all, ctDNA tests use next-generation sequencing (NGS)-based technology. 197 wever, plasma ctDNA testing can be used in specific circumstances if 1) the patient is not medically fit for invasive tissue sampling; or 2) there is insufficient tissue for molecular analysis and follow-up tissue-based analysis will be done if an oncogenic driver is not identified. 198, 199 1] [202] Molecular testing of plasma ctDNA should be done using clinically validated tests. 197

Testing for Molecular Biomarkers

Molecular testing is used to test for oncogenic genomic driver events for which targeted therapies are available; these somatic genomic alterations (also known as molecular biomarkers) include gene mutations and fusions. 203 Testing for certain biomarkers is also recommended for eligible patients with resectable early-stage and locally advanced NSCLC (see Surgery Followed by Adjuvant Therapy in this Discussion). The panel defines broad molecular profiling for NSCLC as molecular testing that identifies all of the classic actionable biomarkers described in the algorithm [eg, ALK, BRAF, EGFR, ERBB2 (HER2), KRAS, METex14 skipping, NTRK1/2/3, RET, ROS1]-using either a single assay or a combination of a limited number of assays-and optimally also identifies the emerging biomarkers (eg, high-level MET amplifications) (see Summary of the Guidelines Updates and Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC). Tiered KRAS testing approaches, based on the low prevalence of co-occurring biomarkers, are acceptable (see KRAS Mutations in this Discussion). 173, 204 road genomic profiling may be used to assess for mechanisms of resistance in patients who have had disease progression on targeted therapy. In addition, broad molecular profiling may be used to distinguish separate primary lung cancers from intrapulmonary metastases (see Multiple Lung Cancers in this Discussion). Broad genomic profiling may also help determine eligibility for certain molecularly driven clinical trials.

The various testing methods that may be used to assess for the different biomarkers are described in the algorithm (see Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC). Broad molecular profiling systems may be used to simultaneously test for multiple biomarkers. 6] [207] [208] [209] [210] [211] [212] [213] It is important to recognize that NGS requires quality control as much as any other diagnostic technique; because it is design dependent, the panel of genes and abnormalities detected with NGS will vary depending on the design of the NGS platform. For example, some NGS platforms can detect both mutations and gene fusions, as well as copy number variation, but they are not uniformly present in all NGS assays being conducted either commercially or in institutional laboratories.

Other mutation screening assays are available for detecting multiple biomarkers simultaneously, which can detect more than 50 point mutations; NGS platforms can detect even more biomarkers. However, multiplex PCR systems do not typically detect gene fusions. ROS1 and ALK gene rearrangements can be detected using fluorescence in situ hybridization (FISH), NGS, and other methods (see Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC).

MS-15

To minimize tissue use and potential wastage, the NCCN NSCLC Panel recommends that broad molecular profiling be done as part of biomarker testing using a validated test(s) that assesses a minimum of the following potential genetic variants: ALK rearrangements, BRAF mutations, EGFR mutations, ERBB2 (HER2) mutations, KRAS mutations, METex14 skipping mutations, NTRK1/2/3 gene fusions, RET rearrangements, and ROS1 rearrangements. Both FDA and laboratory-developed test platforms are available that evaluate these and other analytes. Broad molecular profiling is also recommended to identify emerging biomarkers for which effective therapy may be available, such as high-level MET amplifications.

Although clinicopathologic features-such as smoking status, ethnicity, and histology-are associated with specific somatic, disease-associated variants/mutations (eg, EGFR mutations), these features should not be used to select patients for testing. The NCCN Guidelines for NSCLC provide recommendations for individual biomarkers that should be tested and recommend testing techniques, but do not endorse any specific commercially available biomarker assays or commercial laboratories.

Several systems are available to classify the pathogenicity of variants.

One classification system uses 1) variants with strong clinical significance (Tier I); 2) variants with potential clinical significance (Tier II); 3) variants of unknown clinical significance (Tier III); and 4) variants that are benign or likely benign (Tier IV). 111 Another classification system uses pathogenic, likely pathogenic, variants of uncertain significance (VUS), likely not pathogenic (likely benign), and not pathogenic (benign); this schema is most commonly applied to germline alterations, with some adoption in somatic testing interpretation. 214, 215 Laboratories that adopt either approach (or others) typically do not report alterations that are classified as not pathogenic/Tier IV. Certain molecular testing methods-such as NGS or Sanger-can identify VUS alterations, while targeted assays generally do not detect them. The NCCN Guidelines note that any variant that is classified as VUS should not be used to select targeted therapy even if the VUS occurs in a gene in which other variants are clinically actionable (see Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC).

ALK Gene Rearrangements

About 5% of patients with NSCLC have ALK gene rearrangements. 120 atients with ALK rearrangements are resistant to EGFR TKIs but have similar clinical characteristics to those with EGFR mutations, such as adenocarcinoma histology and either a light or never smoking history. 216 8] [219] [220] [221] If patients appear to have squamous cell NSCLC, then ALK testing can be considered because ALK rearrangements also occur in squamous cell NSCLC, although at a lower rate than nonsquamous NSCLC. 136, 137 For the 2023 update (Version 1), the NCCN Panel now recommends testing for ALK rearrangements, in addition to EGFR mutations, in eligible patients with resectable early-stage NSCLC (stages IB-IIIA, stage IIIB [only T3,N2] ) to assess whether adjuvant therapy with atezolizumab or pembrolizumab is an option. PD-L1 inhibitors are less beneficial in patients with some oncogenic drivers (ie, EGFR exon 19 deletions, EGFR exon 21 L858R mutations, or ALK rearrangements). 184 e different testing methods for ALK rearrangements are described in the algorithm (see Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC). A molecular diagnostic FISH test has been approved by the FDA for detecting ALK rearrangements. 3] [224] [225] [226] [227] [228] [229] An IHC assay for ALK rearrangements has also been approved by the FDA. NGS can also be used to assess whether ALK rearrangements are present, if the platform has been appropriately

MS-16

190] [191] 233, 234 Therefore, tiered approaches may identify patients who will not benefit from further molecular testing (see KRAS Mutations in this Discussion).

The

EGFR Mutations

The NCCN NSCLC Panel recommends testing for EGFR mutations, including common and uncommon mutations, in eligible patients with metastatic NSCLC based on clinical trial data as described in the following sections. Molecular testing for EGFR mutations is also recommended for eligible patients with resectable stage IB to IIIA and stage IIIB (only T3,N2) NSCLC to determine whether adjuvant therapy with osimertinib is an option (see Surgery Followed by Adjuvant Therapy: Trial Data and NCCN Recommendations in this Discussion).

EGFR Exon 19 Deletions and EGFR Exon 21 L858R Mutations

In patients with NSCLC, the two most commonly found EGFR gene mutations are deletions in exon 19 (with conserved deletion of the LREA sequence) in 45% of patients with EGFR mutations and a point mutation in exon 21 (L858R in 40%). Both mutations result in activation of the tyrosine kinase domain, and both are associated with sensitivity to the small-molecule EGFR TKIs, such as afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib (see Targeted Therapies in this Discussion). 244 ecause these EGFR mutations are sensitive to the EGFR TKIs, they were previously referred to as sensitizing EGFR mutations; however, the specific mutations are now described. These common EGFR mutations are found in approximately 10% of white patients with NSCLC and up to 50% of Asian patients. 245 Other less common mutations (approximately 10%), which are also sensitive to EGFR TKIs, include exon 20 p.S768I, exon 21 p.L861Q, and/or exon 18 p.G719X (see EGFR S768I, L861Q, and G719X Mutations in this section and Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC). 246, 247 Data suggest that patients harboring tumors without these specific EGFR mutations should not be treated with EGFR TKIs in any line of therapy, although there are exceptions.

Most patients with the common EGFR mutations have adenocarcinoma histology and either have never smoked cigarettes or previously lightly smoked. Data suggest that EGFR mutations can occur in patients with adenosquamous carcinoma, which is harder to discriminate from squamous cell carcinoma in small specimens. 248 Patients with pure squamous cell carcinoma are less likely to have the common EGFR mutations; those with adenosquamous carcinoma may have mutations. 136, 137, 248 However, smoking status, ethnicity, and histology should not be used in selecting patients for testing. The NCCN Panel recommends that molecular testing be considered in all patients with metastatic NSCLC squamous cell carcinoma because these patients may also have actionable biomarkers, such as EGFR mutations, although at a lower incidence than those with metastatic NSCLC adenocarcinoma. 136, 137, 184, 185 e predictive effects of the EGFR exon 19 deletions and EGFR exon 21 L858R mutations are well-defined. Patients with these common EGFR mutations have a significantly better response to afatinib, dacomitinib, erlotinib, gefitinib, or osimertinib. 244 0] [251] [252] [253] [254] Progression-free survival (PFS) is longer with use of EGFR TKI monotherapy in patients with the common EGFR mutations when compared with cytotoxic systemic therapy, although overall survival NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-18

is not statistically different for afatinib, erlotinib, or gefitinib. 249, 250, 255, 256 8] [259] [260] [261] [262] Patients typically have disease progression after first-line EGFR TKI monotherapy; subsequent therapy recommendations are described in the algorithm. The phrase subsequent therapy is used in these NCCN Guidelines instead of second-line or beyond therapy, because the line of therapy may vary depending on previous treatment with targeted agents.

6] [267] [268] [269] [270] [271] Studies suggest T790M may rarely occur in patients who have not previously received afatinib, erlotinib, or gefitinib. 272 4] [275] Therefore, genetic counseling is recommended for patients if p.T790M is identified before treatment. 7] [278] [279] [280] The NCCN NSCLC Panel recommends that a tissue biopsy should be considered at progression to rule out SCLC transformation (approximately 6%) and to evaluate mechanisms of resistance. 277 Acquired resistance can also be mediated by other molecular events, such as acquisition of ALK rearrangement, MET or ERBB2 amplification, and other biomarkers. 281 0] [251] [252] [253] [254] Molecular testing can be considered for EGFR mutations and other biomarkers in patients with squamous cell carcinoma as previously described.

The response rates (0%-25%) to immunotherapy regimens vary, depending on the specific EGFR exon 20 insertion mutation. 179, 302, 303 e

ERBB2 (HER2) Mutations

For the 2023 update (Version 1), the NCCN Panel added content about ERBB2 (HER2) mutations (see Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC). ERBB2 encodes for HER2, which is a receptor tyrosine kinase that is found on the surface of normal epithelial cells that is often overexpressed or mutated in various human malignancies, such as NSCLC. ERBB2 (HER2) alterations are commonly insertion or duplication events in exon 20 but other activating mutations are also observed. The panel added a caveat that while some ERBB2 (HER2) mutations are known to be activating, not all single-or double-nucleotide changes are activating. ERBB2 (HER2) exon 20 mutations occur in approximately 3% of patients (median age, 62 years) with advanced nonsquamous NSCLC. 304 Patients tend to be women who have never smoked cigarettes; they have a higher incidence of brain metastases than those with other actionable mutations. 304, 305 Although

KRAS Mutations

KRAS is a G-protein with GTPase activity that is part of the MAP/ERK pathway; point mutations in KRAS most commonly occur at codon 12. Approximately 25% of patients with adenocarcinomas in a North American population have KRAS mutations; KRAS is the most common mutation in this population. 118, 175, 211, 307, 308 KRAS mutation prevalence is associated with cigarette smoking, unlike many of the other actionable mutations (eg, EGFR mutations, ALK rearrangements). 309 Patients with KRAS mutations appear to have a shorter survival than patients with wild-type KRAS; therefore, KRAS mutations are prognostic biomarkers. 192, 308, 310 90] [191] 311 Therefore, a tiered approach using KRAS testing may identify patients who may not benefit from further molecular biomarker testing. 173, 204 KRAS mutations may infrequently overlap with EGFR mutations or RET rearrangements. 312, 313 In patients with KRAS mutation-positive metastatic NSCLC, data suggest the response rate is about 26% for single-agent ICIs. 184, 314 First-line platinum-based chemotherapy (± immunotherapy) is a recommended option for patients with KRAS mutations (eg, carboplatin plus paclitaxel).

6] [317] Responsiveness to adagrasib or sotorasib has not been assessed for mutations other than KRAS G12C. NGS, real-time PCR, and Sanger sequencing (ideally with tumor enrichment) are the most commonly used methods to assess for KRAS mutations (see Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC).

MET Genomic Alterations

C-MET, the hepatocyte growth factor (HGF) receptor, is a tyrosine kinase receptor that is involved in cell survival and proliferation; oncogenic driver genomic alterations in MET include METex14 skipping mutations, MET gene copy number (GCN) gain or amplification, and MET protein overexpression. 187 MET genomic alterations do not typically overlap with EGFR, ROS1, BRAF, and ALK genetic variants. 318 However, METex14 skipping mutations and MET amplification may occur together. METex14 skipping mutations occur in 3% to 4% of patients with adenocarcinoma NSCLC and 1% to 2% of patients with other NSCLC histologies. 319, 320 ETex14 skipping mutations are more frequent in older women who have never smoked cigarettes. 321 veral different types of METex14 skipping mutations may occur, such as mutations, base substitutions, and deletions, which makes it difficult to test for all of the mutations. NGS is the primary method of detecting METex14 skipping mutations; RNA-based NGS may have improved In patients with METex14 skipping mutation-positive metastatic NSCLC, data suggest the response rate is about 16% for single-agent ICIs, even with high PD-L1 levels. 184, 322 Data suggest that patients with MET amplification respond to immunotherapy. 323 e NCCN NSCLC Panel recommends testing for METex14 skipping mutations in eligible patients with metastatic NSCLC based on data showing the efficacy of several agents for patients with METex14 skipping mutations and on FDA approvals for capmatinib and tepotinib (see NSCLC with MET Exon 14 Skipping Mutations in this Discussion). 324, 325 The NCCN Panel has preference stratified the first-line therapy options for patients with METex14 skipping mutation-positive metastatic NSCLC. The NCCN Panel voted that capmatinib or tepotinib are preferred first-line monotherapy options for patients with METex14 skipping mutationpositive metastatic NSCLC. The panel also voted that crizotinib or systemic therapy options (such as carboplatin plus paclitaxel) are useful in certain circumstances.

NTRK1/2/3 Gene Fusions

NTRK gene fusions encode tropomyosin receptor kinase (TRK) fusion proteins (eg, TRKA, TRKB, TRKC) that act as oncogenic drivers for solid tumors including lung, salivary gland, thyroid, and sarcoma.

RET Rearrangements

RET is a tyrosine kinase receptor that affects cell proliferation and differentiation. Rearrangements may occur in NSCLC between the RET gene and other domains, especially kinesin family 5B (KIF5B) and coiled coil domain containing-6 (CCDC6), which lead to overexpression of the RET protein. 332, 333 3] [334] [335] [336] In European patients, RET rearrangements occur in individuals who currently smoke cigarettes and those who have never nonsmoked. 334 patients with RET-positive metastatic NSCLC, data suggest the response rate is about 6% to single-agent ICIs. 184 8] [339] [340] Previously, the panel deleted vandetanib for patients with RET rearrangements because there are better therapy options. 341, 342 The NCCN Panel has preference stratified the therapy options for patients with RET rearrangement-positive metastatic NSCLC. The NCCN Panel voted that selpercatinib or pralsetinib are preferred monotherapy options for patients with RET rearrangement-positive metastatic NSCLC; cabozantinib is useful in certain circumstances.

ROS1 Rearrangements

Although ROS1 is a distinct receptor tyrosine kinase, it is very similar to ALK and members of the insulin receptor family. 343, 344 5] [346] [347] The NCCN NSCLC Panel recommends ROS1 testing in patients with metastatic nonsquamous NSCLC or NSCLC NOS based on data showing the efficacy of crizotinib, ceritinib, and entrectinib for patients with ROS1 rearrangements. 190, 344, 348, 349 ROS1 testing can be considered in patients with metastatic squamous cell NSCLC because ROS1 rearrangements also occur in metastatic squamous cell NSCLC, although at a lower rate than nonsquamous NSCLC. 136, 137 0] [351] [352] [353] False-negative results may occur with FISH, IHC, PCR and DNA-based NGS. 354 Although entrectinib has better central nervous system (CNS) penetration than crizotinib, it is more toxic. The NCCN NSCLC Panel voted that ceritinib is an "other recommended" first-line therapy option for patients with ROS1-positive metastatic NSCLC. If ROS1 rearrangements are discovered during first-line systemic therapy (eg, carboplatin plus paclitaxel), then the planned therapy may be either completed or interrupted followed by crizotinib (preferred), entrectinib (preferred), or ceritinib.

The NCCN NSCLC Panel recommends lorlatinib as a subsequent therapy option for select patients with ROS1-positive metastatic NSCLC and disease progression after treatment with crizotinib, entrectinib, or ceritinib (see NSCLC with ROS1 Rearrangements in this Discussion). 356 However, the panel clarified that entrectinib is recommended as a subsequent therapy option for patients with symptomatic brain lesions after progression on crizotinib or ceritinib. 357 Initial systemic therapy options that are used for adenocarcinoma or squamous cell carcinoma are also an option in this setting (eg, carboplatin plus paclitaxel). In patients with ROS1-positive metastatic NSCLC, data suggest the response rate is about 17% for single-agent ICIs. 184 Local therapy may be considered for limited progression.

MS-23

Testing for Immune Biomarkers

PD-L1 Expression Levels

9] [360] Cemiplimab-rwlc, nivolumab, and pembrolizumab inhibit PD-1 receptors. 138, 361, 362 Atezolizumab and durvalumab inhibit PD-L1. 363, 364 he NCCN NSCLC Panel recommends IHC testing for PD-L1 expression (category 1) ideally before first-line treatment (if clinically feasible) in all patients with metastatic NSCLC to assess whether the ICI regimens are an option based on clinical data showing the efficacy of these regimens (see Immune Checkpoint Inhibitors in this Discussion). 138, 365 though it is not an optimal biomarker, PD-L1 expression is currently the best available biomarker to assess whether patients are candidates for PD-1 or PD-L1 inhibitors (also known as ICIs, immuno-oncology [IO] agents, immunotherapy). 366, 367 PD-L1 expression is continuously variable and dynamic; thus, a cutoff value for a positive result is artificial. Patients with PD-L1 expression levels just below and just above 50% will probably have similar responses. 366 9] [370] The definition of a positive or negative PD-L1 test result depends on the individual antibody, clone, and platform, which may be unique to each ICI. 370 Extensive effort has been undertaken to examine the cross-comparability of different clones with regard to each other to facilitate adoption of testing. While some clones for PD-L1 are FDA-approved for specific indications, using multiple IHC tests is not necessary if the individual IHC test has been validated against the FDA-approved clone. Testing for PD-L1 is not required for prescribing first-line therapy with certain ICI regimens-such as cemiplimab-rwlc monotherapy or atezolizumab with or without chemotherapy-or for subsequent therapy with single-agent nivolumab or atezolizumab.

The NCCN NSCLC Panel emphasizes that clinicians should obtain molecular testing results for actionable biomarkers before administering first-line ICI therapy, if clinically feasible, including ALK, BRAF, EGFR, ERBB2 (HER2), KRAS, METex14 skipping, NTRK1/2/3, RET, and ROS1 variants. If it is not feasible to do molecular testing, then patients are treated as though they do not have driver oncogenes. Patients with metastatic NSCLC and PD-L1 expression levels of 1% or more-but who also have a targetable driver oncogene molecular variant-should receive first-line targeted therapy for that oncogene and not first-line ICIs, because targeted therapies yield higher response rates (eg, osimertinib, 80%) than ICIs (lower response rates) in the first-line setting, targeted therapy is better tolerated, and these patients are less likely to respond to single-agent ICIs.

TMB

To diagnose NSCLC in small tissue samples, judicious use of IHC is strongly recommended to conserve tumor tissue for molecular studies, especially in patients with advanced disease (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). cell carcinoma, metastatic malignancy, and primary pleural mesothelioma (particularly for pleural samplings). 122 IHC is useful for assessing poorly differentiated NSCLC in small biopsy and/or cytology specimens. 86, 140 enocarcinomas are usually positive for thyroid transcription factor-1 (TTF-1), whereas squamous cell carcinomas are often negative for TTF-1 and positive for p40 (or alternatively p63). 86 Napsin A positivity occurs in more than 80% of lung adenocarcinomas and may also be useful in distinguishing adenocarcinoma from squamous cell carcinoma. 141, 142 Note that p63 can co-stain with TTF-1 or Napsin A in adenocarcinoma. In small biopsy specimens previously classified as NSCC NOS, a panel of TTF-1 (or alternatively Napsin A) and p40 (or alternatively p63) may be sufficient to refine the diagnosis to either adenocarcinoma or squamous cell carcinoma. Thus, two markers may be sufficient to distinguish adenocarcinomas from squamous cell carcinomas. 86, 140 appropriate panel of IHC stains should include those relevant for evaluation of metastatic carcinomas to the lung if the primary origin of the carcinoma is uncertain. It is appropriate to first perform a limited panel of IHC to evaluate for NSCLC and, if negative, then proceed to additional IHC for evaluation of possible metastasis from a distant site. TTF-1 is very useful for distinguishing primary lung adenocarcinoma from metastatic adenocarcinoma, because most (70%-90%) non-mucinous primary adenocarcinomas are TTF-1 positive. TTF-1 is typically negative in squamous cell carcinoma. 140 However, TTF-1 is also positive in tumors such as thyroid cancer and rarely in a few other organ systems. 143 In addition, thyroglobulin and PAX8 are positive in tumors from patients with thyroid cancer, while they are negative in lung cancer. Immunomarkers that may be useful to assess for metastatic carcinoma to the lung include those for breast carcinoma (ERα, PR, GCDFP-15, mammaglobin, GATA-3), renal cell carcinoma (PAX8), papillary serous carcinoma (PAX8, PAX2, ER), and adenocarcinomas of the gastrointestinal tract (CDX2) or prostate gland (NKX3.1). All typical and atypical carcinoid tumors are positive for chromogranin and synaptophysin.

Although the cytologic diagnosis of NSCLC is generally reliable, it is more difficult to diagnose SCLC (see the NCCN Guidelines for Small Cell Lung Cancer, available at www.NCCN.org). 108, 140, 144 Many patients with SCLC have characteristic CT and clinical findings (eg, massive lymphadenopathy, mediastinal invasion). Most SCLCs are immunoreactive for TTF-1; they are typically negative for CK34βE12 and p63. 145, 146 Many SCLCs also stain positively for markers of neuroendocrine differentiation, including insulinoma-associated protein 1 (INSM1), CD56/NCAM, chromogranin, and synaptophysin. IHC should be used to confirm neuroendocrine differentiation only when appropriate morphologic features-speckled chromatin pattern, nuclear molding, and peripheral palisading-are present. CD56/NCAM, INSM1, chromogranin, and synaptophysin are used to identify neuroendocrine tumors if morphologic suspicion of neuroendocrine differentiation exists. 147 One positive marker is sufficient if the staining is not ambiguous in more than 10% of the tumor cells (TCs).

] [150] The NCCN NSCLC Panel feels that malignant mesothelioma and lung adenocarcinoma can be distinguished using clinical impression, imaging, and a limited panel of immunomarkers (if needed) to preserve tissue for molecular testing. Commonly used immunostains sensitive and specific for adenocarcinoma include pCEA, Claudin-4, TTF-1, and Napsin A (negative in mesothelioma). Other potentially useful markers include B72. 9] [150] [151] Broad epithelial markers such as keratin(s), as well as other lineage-specific markers, should be used when the differential diagnosis includes non-pulmonary and non-mesothelial lesions. Other markers can be useful in the differential diagnosis between mesothelioma and metastatic carcinoma to the lung (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC).

Staging

The AJCC Cancer Staging Manual (8th edition) is effective for all cancer cases recorded on or after January 1, 2018. 152, 153 The lung cancer staging system was revised by the International Association for the Study of Lung Cancer (IASLC) [154] [155] [156] and was adopted by the AJCC. 152, 153, 157, 158 he definitions for TNM and the stage grouping for the eighth edition are summarized in Tables 1 and 2 of the staging tables (see Staging in the NCCN Guidelines for NSCLC). The descriptors of the TNM classification scheme are summarized in Table 3 of the staging tables. 159 Early-stage disease is stages I and II with negative nodes (N0), whereas locally advanced disease is stages II and III with positive nodes (N+); 160 advanced or metastatic disease is stage IV. Pathologic staging uses both clinical staging information (which is noninvasive and includes medical history and physical [H & P] examination, and imaging) and other invasive staging procedures (eg, thoracotomy, examination of lymph nodes using mediastinoscopy). 161 om 2012 to 2018, the overall 5-year relative survival rate for adenocarcinoma was 29.6% in the United States; the 5-year survival rate for squamous cell carcinoma was 23%. 162 The corresponding 5-year relative survival rates for adenocarcinoma were 70.1% for localized, 44.7% for regional, 9.6% for distant, and 20% for unstaged. 162 Five-year survival after lobectomy for pathologic stage I NSCLC ranges from 45% to 65%, depending on whether the patient has stage 1A or 1B disease and on the location of the tumor. 163 Another study in patients with stage I disease (n = 19,702) found that 82% had surgical resection and their 5-year overall survival was 54%; for untreated stage I NSCLC, 5-year overall survival was only 6%. 164 Of patients with stage I disease who refused surgery (although it was recommended), 78% died of lung cancer within 5 years.

Predictive and Prognostic Biomarkers

Several biomarkers have emerged as predictive and prognostic markers for NSCLC. A predictive biomarker is indicative of therapeutic efficacy, because there is an interaction between the biomarker and therapy on patient outcome. A prognostic biomarker is indicative of patient survival independent of the treatment received, because the biomarker is an indicator of the innate tumor behavior (see KRAS Mutations in this Discussion). The NSCLC Panel recommends testing for certain molecular and immune biomarkers in all appropriate patients with NSCLC to assess whether patients are eligible for targeted therapies or immunotherapies based on data showing improvement in overall survival for patients receiving targeted therapies or immunotherapies compared with traditional chemotherapy regimens. 6] [167] [168] [169] [170] However, there are less data to support using these agents and they may not be FDA approved for NSCLC; therefore, they are referred to as emerging biomarkers. In 2020, the NCCN Panel deleted tumor mutational burden (TMB) as an emerging immune biomarker based on clinical trial data and other issues (see TMB in this Discussion). 171, 172 e NCCN NSCLC Panel recommends molecular testing based on clinical trial data, but strongly advises broader molecular profiling, to identify these and other rare driver mutations for which targeted therapies may be available to ensure that patients receive the most appropriate treatment; patients may be eligible for clinical trials for some of these targeted agents. 173 Several online resources are available that describe NSCLC driver events, such as My Cancer Genome. Resources are available to assess whether the HER2 mutations are oncogenic or likely to be oncogenic (see oncoKB.org). TMB is an approximate measure of the total number of somatic mutations. 375 Theoretically, high TMB levels will correlate with high neoantigen levels that will activate an antitumor immune response. 376 TMB levels are typically high in patients with NSCLC who currently or previously smoked cigarettes. Low TMB is more commonly detected in individuals who have never smoked cigarettes. 329, 377 Preliminary data for PFS from CHECKMATE 227, a phase 3 randomized trial with a complex design, suggested that TMB might be a useful immune biomarker for deciding whether to use immunotherapy in patients with metastatic NSCLC. 378 owever, updated data from CHECKMATE 227 showed that overall survival was improved with nivolumab plus ipilimumab regardless of TMB or PD-L1 expression levels. 379 In addition, combining TMB with PD-L1 expression level also did not correlate with overall survival. Several trials have shown that high TMB levels do not correlate with PD-L1 expression levels in patients with NSCLC. NSCLC. 382 TMB does not identify patients who will respond to chemotherapy; therefore, TMB has limited value for assessing combination immunotherapy plus chemotherapy regimens. 376 TMB is also not an ideal immune biomarker because some patients with low TMB levels respond to immunotherapy and others with high levels do not respond to immunotherapy. 376 addition to the lack of clinical data to support use of TMB as an immune biomarker, there are technical problems with measuring TMB. 375 These problems include: 1) lack of agreement on the definition of a cut off for designating high TMB levels; and 2) lack of standardization of TMB measurements across laboratories. 375 PD-L1 expression level is a more useful immune biomarker than TMB for deciding how to use immunotherapy, because test results are obtained more quickly, less tissue is needed for testing, and data demonstrate relative reproducibility across platforms and individuals. In 2020, the NCCN Panel removed TMB as an emerging immune biomarker for patients with metastatic NSCLC based on clinical trial data, concerns about variable TMB measurements, and other issues as described here. 171, 375, 379 The NCCN Guidelines do not recommend measurement of TMB levels before deciding whether to use nivolumab plus ipilimumab regimens or to use other ICIs, such as pembrolizumab. 171

Treatment Approaches

Surgery, RT, and systemic therapy are the three modalities most commonly used to treat patients with NSCLC. They can be used either alone or in combination depending on the disease status. In the following sections, the clinical trials are described that have led to the recommended treatments. For tools to aid optimal assessment and care of older adults, see the NCCN Guidelines for Older Adult Oncology (available at www.NCCN.org). Older adults may be at risk for treatment-related adverse events. 383

Surgery

In general, surgery provides the best chance for cure in patients with stage I or II disease. 384 Thoracic surgical oncology consultation should be part of the evaluation of any patient being considered for curative local therapy.

The overall plan of treatment and the necessary imaging studies should be determined before any nonemergency treatment is initiated. [393] The Principles of Surgical Therapy are described in the NSCLC algorithm and are summarized here. Determination of resectability, surgical staging, and pulmonary resection should be performed by thoracic surgeons who should participate in multidisciplinary clinics and/or tumor boards for patients with lung cancer. Surgery may be appropriate for select patients with uncommon types of lung cancer (eg, superior sulcus, chest wall involvement) (see the NCCN Guidelines for NSCLC). 394 Patients with clinical stage IB or greater disease, or high-risk factors, should be referred to a medical oncologist for evaluation. For patients with stage IIIA NSCLC that is deemed resectable, consider referral to a radiation oncologist. Treatment delays, because of poor coordination among specialists, should be avoided. most efficient approach, or to provide consensus that a biopsy is too risky or difficult and that anatomic resection can occur without prior tissue confirmation of lung cancer.

Lung-sparing anatomic resection (sleeve lobectomy [also known as sleeve resection]) is preferred over pneumonectomy, if anatomically appropriate and if margin-negative resection can be achieved; lobectomy or pneumonectomy should be done if physiologically feasible. 384, 395, 396 8] [399] [400] [401] [402] Segmentectomy (preferred) or wedge resection should achieve parenchymal resection margins that are: 1) 2 cm or more; or 2) the size of the nodule or larger. Resection (including wedge resection) is preferred over ablation. 384, 396 Wide wedge resection may improve outcomes. 403 tients with medically inoperable early-stage NSCLC may be candidates for definitive RT, preferably SABR, also known as stereotactic body RT (SBRT). 404, 405 [408] Lymph Node Dissection ACOSOG Z0030, a randomized phase 3 trial, compared systematic mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in patients with NSCLC who had either N0 (no demonstrable metastasis to regional lymph nodes) or N1 (metastasis to lymph nodes in the ipsilateral peribronchial and/or hilar region, including direct extension) disease. In patients with early-stage NSCLC who had negative nodes by systematic lymph node dissection, complete mediastinal lymph node dissection did not improve survival. 409, 410 Thus, systematic lymph node sampling is appropriate during pulmonary resection; one or more nodes should be sampled from all mediastinal stations. For right-sided cancers, an adequate mediastinal lymphadenectomy should include stations 2R, 4R, 7, 8, and 9. For left-sided cancers, stations 4L, 5, 6, 7, 8, and 9 should be sampled. 409 atients should have N1 and N2 node resection and mapping (American Thoracic Society map) with a minimum of three N2 stations sampled or a complete lymph node dissection. 152 The lymph node map from the IASLC may be useful. 411 Formal ipsilateral mediastinal lymph node dissection is indicated for patients undergoing resection for stage IIIA (N2) disease. For patients undergoing sublobar resection, the appropriate N1 and N2 lymph node stations should be sampled unless not technically feasible because sampling would substantially increase the surgical risk.

Thoracoscopic Lobectomy

Video-assisted thoracic surgery (VATS), which is also known as thoracoscopic lobectomy, is a minimally invasive surgical treatment (see Principles of Surgical Therapy in the NCCN Guidelines for NSCLC). 412, 413 5] [416] [417] [418] Acute and chronic pain associated with thoracoscopic lobectomy is minimal; thus, this procedure requires a shorter length of hospitalization. 419, 420 1] [432] [433] [434] Thoracoscopic lobectomy has also been shown to

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improve discharge independence in older populations and patients at high risk. 435, 436 Data show that thoracoscopic lobectomy improves the ability of patients to complete postoperative chemotherapy regimens. 437, 438 0] [441] [442] Robotic VATS seems to be more expensive with longer operating times than conventional VATS. 443, 444 age IIIA N2 Disease

The role of surgery in patients with pathologically documented stage IIIA (N2) disease is described in the NSCLC algorithm (see Principles of Surgical Therapy in the NCCN Guidelines for NSCLC) and summarized here. Before treatment, it is essential to carefully evaluate for N2 disease using radiologic and invasive staging (ie, EBUS-guided procedures, mediastinoscopy, thoracoscopic procedures) and to discuss whether surgery is appropriate in a multidisciplinary team, which should include a thoracic surgeon. 445, 446 Randomized controlled trials suggest that surgery does not increase survival in these patients. 447, 448 However, one of these trials (EORTC) only enrolled patients with unresectable disease. 448 Most clinicians agree that resection is appropriate for patients with negative preoperative mediastinal nodes and with a single positive node ( < 3 cm) found at thoracotomy. 449 Neoadjuvant (also known as preoperative or induction) systemic therapy is recommended for select patients with resectable NSCLC (see Combined Modality Therapy in this Discussion).

1] [452] Adding RT to induction regimens for patients with stage IIIA (N2) disease has been associated with higher pathological response but similar overall survival when compared with using preoperative chemotherapy (generally followed by postoperative RT). 452 or patients with completely resected stage IIIA (N2) NSCLC who received neoadjuvant or adjuvant chemotherapy, data from the LungART and PORT-C trials show that postoperative RT (also known as PORT) did not improve survival compared with no postoperative RT, although locoregional control was significantly improved. 450, 453 Postoperative RT may be considered for select patients with negative margins and high-risk N2 disease (see Chemoradiation in this Discussion and Principles of Radiation Therapy in the algorithm). 5] [456] [457] [458] [459] [460] Clinicians also agree that resection is not appropriate for patients with multiple pathologically proven malignant lymph nodes greater than 3 cm; definitive chemoradiotherapy is recommended for these patients. Patients with resectable stage IIIA (N2) disease should not be excluded from surgery, because some of them may have long-term survival or may be cured. 455, 461 e NCCN NSCLC Panel believes that surgery may be appropriate for select patients with N2 disease. 445, 455, 462 The NCCN Member Institutions were surveyed in 2021 regarding their approach to patients with N2 disease (see Principles of Surgical Therapy in the NCCN Guidelines for NSCLC). For example, more institutions now use neoadjuvant chemotherapy compared with neoadjuvant chemoradiation in patients with N2 disease. Many (66%) of the NCCN Member Institutions use induction chemotherapy, whereas 33% use induction chemoradiation. 463, 464 Before surgery, most institutions require at least stable disease after induction therapy but do not require radiologic or pathologic response. All NCCN institutions consider surgery for single-station non-bulky N2 disease. However, 50% consider surgery for single-station bulky disease, 39% for multi-station non-bulky disease, and 21% for multi-station bulky disease.

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6] [467] [468] [469] [470] [471] [472] [473] [474] [475] These RT principles are summarized in this section. Whole brain RT and SRS for brain metastases are also discussed in this section.

The RT abbreviations are defined in the NSCLC algorithm (see Table 1 in Principles of Radiation Therapy in the NCCN Guidelines for NSCLC). For the 2023 update (Version 1), the NCCN NSCLC Panel revised some of the RT recommendations in the algorithm (see Summary of the Guidelines Updates and Principles of Radiation Therapy in the NCCN Guidelines for NSCLC). [473] [474] [475]

General Principles

Treatment recommendations should be made by a multidisciplinary team.

Because RT has a potential role in all stages of NSCLC, as either definitive or palliative therapy, input from radiation oncologists who perform lung cancer RT as a prominent part of their practice should be part of the multidisciplinary evaluation for all patients with NSCLC. 7] [478] [479] [480] [481] [482] [483] The goals of RT are to maximize tumor control and to minimize treatment toxicity. 5] [486] [487] [488] [489] [490] A secondary analysis of the RTOG 0617 randomized trial reported that 2-year overall survival, PFS, local failure, and distant metastasis-free survival were not significantly different for IMRT when compared with older 3D-conformal RT (3D-CRT) technique despite higher tumor burden in patients treated with IMRT. However, IMRT yielded lower rates of severe pneumonitis compared with 3D-CRT (3.5% vs. 7.9%; P = .039). 491 CT-planned 3D-CRT is now considered to be the minimum technological standard, with IMRT preferred.

Radiation Simulation, Planning, and Delivery

Simulation should be performed using CT scans obtained in the RT treatment position. Intravenous contrast CT scans, with or without oral contrast, are recommended for better target delineation whenever possible, especially in patients with central tumors or nodal involvement. FDG PET/CT can significantly improve target delineation accuracy, especially when there is atelectasis or contraindications to intravenous CT contrast. 492, 493 Ideally, target delineation should be based on PET/CT that is obtained no more than 4 weeks before treatment because of the potential for rapid progression of NSCLC. 494, 495 7] [498] [499] Respiratory motion should be managed. The report from the AAPM Task Group 76 is a useful reference for implementing a broad range of motion management strategies as described in the NSCLC algorithm. 500 486, 509, 510 It is essential to evaluate the dose-volume histogram (DVH) of critical structures and to limit the doses to the organs at risk (such as spinal cord, lungs, heart, esophagus, and brachial plexus) to minimize normal tissue toxicity (see Table 5 in Principles of Radiation Therapy). 511 For patients receiving postoperative RT (also known as PORT), stricter DVH parameters should be considered for the lungs. 4] [525] [526] [527] [528] Therefore, the doses and constraints provided in the tables are not specific prescriptive recommendations; they are useful reference doses that have been commonly used or are from previous clinical trials. A caveat was also added that these constraints represent doses that generally should not be exceeded. Because the risk of toxicity increases progressively with dose to normal tissues, a key principle of radiation treatment planning is to keep normal tissue doses "as low as reasonably achievable" while adequately covering the target. The doses to any given organ at risk should typically be lower than these constraints, approaching them only when there is close proximity to the target volume. After surgery, lung tolerance to RT is much less than for patients with intact lungs; therefore, more conservative constraints should be used for postoperative RT.

Target Volumes, Prescription Doses, and Normal Tissue Dose Constraints

For definitive RT, the commonly prescribed dose is 60 to 70 Gy in 2 Gy fractions over 6 to 7 weeks (see Principles of Radiation Therapy in the NCCN Guidelines for NSCLC). 529, 530 6] [537] [538] [539] [540] [541] Although optimal RT dose intensification remains a valid question, the NCCN Panel does not currently recommend a high dose of 74 Gy for routine use. 532,534,535,537-545

General Treatment Information

The RT recommendations for patients with stages I to IV are described in the NSCLC algorithm (see Principles of Radiation Therapy in the NCCN Guidelines for NSCLC). Definitive RT, preferably SABR, is recommended for patients with early-stage NSCLC (ie, stage I-II, N0) who are medically inoperable or those who refuse surgery (see Stereotactic Ablative Radiotherapy in this Discussion). 404, 405, 408, 483, 546, 547 SABR is also an option for patients at high surgical risk who cannot tolerate a lobectomy because of a major medical comorbidity and/or severely limited lung function. After definitive RT (preferably SABR), adjuvant chemotherapy may be considered in patients with high-risk factors for recurrence (eg, large tumor size), similar to the postoperative setting. (see Principles of Surgical Therapy in the NCCN Guidelines for NSCLC). 558 The indications for using preoperative or postoperative chemoradiation, systemic therapy, or RT alone are described in the NSCLC algorithm (see Principles of Radiation Therapy in the NCCN Guidelines for NSCLC). In patients with clinical stage I or II NSCLC who are upstaged to N2+ after surgery, postoperative chemotherapy can be administered, with concurrent postoperative RT for patients with positive margins, or followed by postoperative RT in selected patients with high-risk features.

Definitive chemoradiation is recommended for patients with stage II to III disease who are not appropriate surgical candidates. 559 For patients with locally advanced NSCLC (stage III), the most commonly prescribed conventionally fractionated doses for definitive RT are 60 to 70 Gy in 2 Gy fractions. Doses of at least 60 Gy should be given. 560 [563] [564] [565] [566] [567] [568] The optimal care of patients with potentially operable stage IIIA (N2) NSCLC is controversial and is discussed in detail in the algorithm (see Principles of Surgical Therapy in the NCCN Guidelines for NSCLC). 445, 447, 452, 459, 569 Before surgical resection of stage IIIA NSCLC, induction systemic therapy or induction chemoradiotherapy is recommended to potentially shrink the tumor(s). 452, 463 Preoperative systemic therapy and postoperative RT is an option for patients with resectable stage IIIA NSCLC with minimal N2 disease who can be treated with lobectomy. 451, 464 Preoperative concurrent chemoradiation is recommended for resectable superior sulcus tumors and is an option for other resectable stage IIA to IIIA NSCLC. 503 In a 2021 survey of the NCCN Member Institutions, we found that 66% use induction chemotherapy, whereas 33% use induction chemoradiation before surgery for patients with stage IIIA N2 disease. 463, 464 The NCCN NSCLC Panel recommends a preoperative RT dose of 45 to 54 Gy in 1.8 to 2 Gy fractions over 5 weeks. 451, 570 Definitive RT doses delivered as preoperative chemo/RT can safely be administered and achieve promising nodal clearance and survival rates; [504] [505] [506] 571 the risk of surgical complications after high-dose RT can be minimized with expert thoracic surgical techniques. Abou 50% of NCCN Member Institutions would consider pneumonectomy after preoperative chemotherapy, whereas only 25% do not consider pneumonectomy absolutely contraindicated after preoperative induction chemoradiation.

Surgery is associated with potentially greater risk of complications, particularly stump breakdown and bronchopleural fistula, in a field that has had high-dose RT (eg, 60 Gy). Thus, surgeons are often wary of resection in areas that have previously received RT doses of more than 45 to 50 Gy, especially in patients who have received definitive doses of preoperative concurrent chemoradiation (ie, ≥60 Gy). 5] [506] When giving preoperative RT to less than definitive doses (eg, 45 Gy), one should be prepared up front to continue to a full definitive dose of RT without interruption if the patient does not proceed to surgery for some reason. For these reasons, when considering trimodality therapy, the treatment plan-including assessment for resectability and the type of resectionshould be decided before initiation of any therapy. In postoperative RT, the clinical target volume (CTV) includes the bronchial stump and high-risk draining lymph node stations. 572 Standard RT doses after complete resection are 50 to 54 Gy in 1.8 to 2 Gy fractions over 5 to 6 weeks, but a boost may be considered to high-risk regions including areas of nodal extracapsular extension or microscopic positive margins. 467, 573, 574 Lung dose constraints should be more conservative, because tolerance appears to be reduced after surgery. The LungART

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and PORT-C trials provide useful guidelines for postoperative RT technique. 450, 453, 575 Highly conformal techniques (such as IMRT or proton therapy) to minimize lung and heart doses are preferred.

0] [581] [582] Higher dose and longer course thoracic RT (eg, ≥30 Gy in 10 fractions) are associated with modestly improved survival and symptoms, especially in patients with good PS. 576, 583 When higher doses ( > 30 Gy) are warranted, technologies to reduce normal tissue irradiation may be used (at least 3D-CRT and including IMRT or proton therapy as appropriate).

Oligometastatic disease is heterogenous and refers to limited metastatic sites or disease burden; management is evolving. Definitive local therapy to oligometastases (including brain and lung) achieves prolonged survival in a small proportion of well-selected patients with PS 0 to 2 who have also received radical therapy to the intrathoracic disease. 584 Definitive RT to oligometastases, particularly SABR, is an appropriate option in such cases if it can be delivered safely to the involved sites. 585, 586 In two randomized phase II trials, significantly longer PFS was found for local consolidative therapy (RT or surgery) to primary and oligometastatic lesions versus maintenance systemic therapy or observation for patients not progressing on systemic therapy. 587, 588 Updated data from one of the trials also show that median overall survival was longer for patients with oligometastatic NSCLC who received local consolidative therapy (median, 41.2 months; 95% CI, 18.9 months-not reached) compared with those receiving maintenance therapy or observation (median, 17.0 months; 95% CI, 10.1-39.8 months; P = .017). 589 A phase 2 trial of consolidative RT for oligometastatic NSCLC (n = 29) reported median overall survival of 28.4 months (95% CI, 14.5-45.8 months). 590 6] [597] [598] [599] With conventionally fractionated RT, 3-year survival is only about 20% to 35% in these patients, with local failure rates of about 40% to 60%. 405 1] [602] [603] [604] [605] A 7-year follow-up of 65 patients with medically inoperable stage I NSCLC reported that overall survival rates were 55.7% at 5 years and 47.5% at 7 years. 546 In 12 patients (18.5%), a second primary lung carcinoma developed after SABR at a median of 35 months (range, 5-67 months); 27% (18/65) had disease recurrence a median of 14.5 months (range, 4.3-71.5 months) after SABR.

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Although SABR is not proven equivalent to lobectomy for patients with operable early-stage NSCLC, some prospective series have shown similar overall survival and cancer-specific survival. 471, 595, 597, 606 A combined analysis of two randomized trials (that individually did not complete accrual) compared SABR to lobectomy, with 3-year overall survival of 95% and 79%, respectively. 606 A single-arm SABR expansion cohort of one of the trials with longer follow-up compared non-randomly to a propensity-matched contemporary cohort treated with VATS lobectomy with mediastinal lymph node dissection and found 5-year overall survival of 87% and 84%, respectively. 471 These analyses do not provide sufficient data to change the standard of care for good surgical candidates but help to confirm the indication for SABR in patients with relative contraindications to surgery or those who refuse surgery. [609] [610] [611] [612] [613] SABR is recommended in the NSCLC algorithm for patients with stage I and II (T1-3,N0,M0) NSCLC who are medically inoperable; SABR is a reasonable alternative to surgery for patients with potentially operable disease who are high risk, older, or refuse surgery after appropriate consultation (see the NCCN Guidelines for NSCLC). 384, 599, 601, 606, 614 If possible, biopsy should confirm NSCLC before use of SABR. 404, 615, 616 ecisions about whether to recommend SABR should be based on multidisciplinary discussion. If therapy is contemplated based on a clinical diagnosis without tissue confirmation of NSCLC, then multidisciplinary evaluation is required to provide consensus on the risk-benefit ratio of biopsy and/or the clinical diagnosis. 617, 618 0] [621] [622] [623] [624] Late recurrences have been reported more than 5 years after SABR, highlighting the need for careful surveillance. 625, 626 After SABR, assessment of recurrences by imaging can be challenging because of benign inflammatory/fibrotic changes that can remain FDG-PET avid for 2 or more years after treatment, emphasizing the importance of follow-up by a team with experience interpreting such post-treatment effects. 627, 628 ] [636] [637] [638] [639] [640] [641] [642] [643] [644] In the United States, only regimens of 5 fractions or less meet the arbitrary billing code definition for SBRT; however, slightly more protracted ablative regimens are also appropriate. 644, 645 Prescription doses do not completely describe the actual delivered doses. 646, 647 These maximum dose constraints are for reference and are not intended to be prescriptive; they are used commonly or have been used in clinical trials. Although none of these dose constraints has been validated as a maximally tolerated dose, outcomes of clinical trials to date suggest that they are safe constraints. The bronchial tree, esophagus, and brachial plexus are critical structures for SABR. 9] [650] The RTOG 0813 trial evaluated 5-fraction regimens and found no high-grade toxicities at 50 Gy in 5 fractions. 651, 652 CCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer

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4] [655] [656] SRS or SABR can be considered for select patients with stage M1c disease who have limited metastases that are amenable to treatment with definitive local therapy; clinical trials have included up to 3 to 5 metastatic sites. 653, 654 ] [663] Nonrandomized clinical data indicate that local tumor control with SABR is higher than with image-guided thermal ablation techniques. Image-guided thermal ablation (ie, cryotherapy, microwave, radiofrequency) may be an option for selected patients who will not be receiving SABR or definitive RT. 384, 408, 557 Whole Brain RT and Stereotactic Radiosurgery Many patients with NSCLC have brain metastases (30%-50%), which substantially affect their quality of life. 664, 665 Control of brain metastases preserves neurocognitive function. 666, 667 9] [670] For limited brain metastases, randomized trials have found that the addition of whole brain RT to SRS decreases intracranial recurrence but does not improve survival and may increase the risk of cognitive decline. 667, 671 Thus, SRS alone is recommended for patients with limited brain metastases. 237 A randomized trial assessed cognitive function in 213 patients with 1 to 3 brain metastases who received SRS alone versus SRS with whole brain RT; most patients had lung cancer. 236 3 months after SRS alone, patients had less cognitive deterioration (40/63 patients [63.5%] ) than those receiving SRS plus whole brain RT (44/48 patients [91.7%]; difference, -28.2%; 90% CI, -41.9% to -14.4%; P < .001). Resection followed by SRS to the cavity (instead of resection followed by whole brain RT) may decrease the risk of neurocognitive impairment. 672, 673 A randomized trial demonstrated that using IMRT to avoid the hippocampus decreases memory impairment after whole brain RT. 674 A phase 3 randomized trial assessed optimal supportive care (including dexamethasone) with whole brain RT versus optimal supportive care alone in patients with NSCLC and brain metastases who were not eligible for brain surgery or SRS. 675 Overall survival was similar between the groups (HR, 1.06; 95% CI, 0.90-1.26). Overall quality of life, use of dexamethasone, and reported adverse events were also similar between the arms. Two retrospective analyses have reported increased survival in patients with brain metastases who received SRS and concurrent ICI therapy. 676, 677 eatment options for limited brain metastases in patients with NSCLC include: 1) SRS alone; and 2) surgical resection for selected patients followed by SRS or whole brain RT (see the NCCN Guidelines for Central Nervous System Cancers, available at www.NCCN.org). 6] [687] Treatment should be individualized for patients with recurrent or progressive brain lesions. 688 ] [239] [240] NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer

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Combined Modality Therapy

As previously mentioned, surgery provides the best chance for cure for patients with stage I or II disease who are medically fit and can tolerate surgery. SABR can be considered for patients with medically inoperable or high-risk stage I or II (T1-3,N0) disease or those who refuse surgery if their disease is node negative (see Stereotactic Ablative Radiotherapy in this Discussion and see the NCCN Guidelines for NSCLC). 4] [695] [696] [697] [698] [699] A randomized trial found no difference in survival with preoperative versus postoperative chemotherapy. 700 The NCCN Guidelines state that patients with stage II or IIIA (T3,N1) disease may be treated with induction systemic therapy before surgery if they would have been candidates for adjuvant chemotherapy after surgery. 384, 701 ] [704] [705] Cytotoxic chemotherapeutic agents can cause hair loss, which is distressing for patients. Hair loss varies depending on the systemic regimen and other factors. 2] [713] [714] [715] [716] [717] [718] Data show that early palliative care combined with systemic therapy improved quality of life, mood, and survival in patients with metastatic NSCLC, even if these patients had less aggressive end-of-life care, when compared with those receiving systemic therapy alone. 719, 720 Patients should receive treatment for debilitating symptoms. 664, 721, 722 A study also suggests that social support, such as being married, is as effective as systemic therapy. 723 5] [726] Surgery is rarely recommended for patients with stage IV disease. However, surgical resection of limited brain progression may improve survival in selected patients with stage IV disease and is recommended for selected patients in the NCCN Guidelines (see the NCCN Guidelines for NSCLC). 727 Definitive local therapy with surgical resection or RT is recommended for limited single-organ progression located in sites other than the brain if definitive thoracic therapy is feasible (see Stage IVA, M1b in the NCCN Guidelines for NSCLC). 394, 584, 587, 589, 599, 653, 654 The trials supporting the recommendations for combined modality therapy are discussed in the following sections.

Surgery Followed by Adjuvant Therapy

Chemotherapy

The International Adjuvant Lung Cancer Trial (IALT) assessed cisplatin-based postoperative therapy in patients with completely resected stage I, II, or III NSCLC. 690 The study included 1867 patients with surgically resected lung cancer who were randomly assigned either to cisplatin-based postoperative chemotherapy or to observation, with a median follow-up duration of 56 months. The survival rate at 5 years was 45% for cisplatin-based therapy versus 40% for observation (HR for death, 0.86; 95% CI, 0.76-0.98; P < .03); the disease-free survival rate was 39% versus 34% at 5 years (HR, 0.83; 95% CI, 0.74-0.94; P < .003). However, after 7.5 years of follow-up, there were more deaths in the chemotherapy group and the benefit of chemotherapy decreased over time. 728 Data show that postoperative chemotherapy prevents recurrences.

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The NCIC CTG JBR.10 trial and the ANITA trial compared the effectiveness of postoperative vinorelbine plus cisplatin versus observation in early-stage NSCLC. In the JBR.10 trial, 482 patients (ECOG PS of 0-1) with completely resected stage IB (T2a,N0) or stage II (T1,N1, or T2,N1) NSCLC were randomly assigned either to vinorelbine plus cisplatin or to observation. 691 Postoperative chemotherapy significantly prolonged overall survival compared with observation alone (94 vs. 73 months; HR for death, 0.69; P = .04) and relapse-free survival (not reached vs. 47 months, HR for recurrence, 0.60; P < .001). The 5-year survival rates were 69% and 54%, respectively (P = .03). When compared with observation alone, postoperative chemotherapy was beneficial for patients with stage II disease but not for stage IB disease as shown by updated data from JBR.10 after 9 years of follow-up. 729 In patients with stage II disease receiving postoperative chemotherapy, median survival was 6.8 versus 3.6 years in those who were only observed. Of note, patients receiving chemotherapy did not have an increased death rate.

In the ANITA trial, 840 patients with stage IB (T2a,N0), II, or IIIA NSCLC were randomly assigned either to postoperative vinorelbine plus cisplatin or to observation. 692 Grade 3 and 4 toxicities were manageable in the chemotherapy group; seven toxic deaths were reported. After a median follow-up of 76 months, median survival was 66 months in the chemotherapy group and 44 months in the observation group. 692 ostoperative chemotherapy significantly improved (8.6%) the 5-year overall survival in patients with completely resected stage II and IIIA disease, although no benefit was observed in stage I. Some clinicians consider vinorelbine plus cisplatin to be the preferred regimen for completely resected early-stage NSCLC based on the number of trials and the amount of use; 730 however, most clinicians in the United States prefer to use regimens with less toxicity. 731, 732 meta-analysis of 4584 patients (LACE) found that postoperative cisplatin-based chemotherapy increased survival over 5 years (absolute benefit of 5.4%); there was no difference among the chemotherapy regimens (vinorelbine, etoposide, and others). 733 A subgroup analysis found that cisplatin plus vinorelbine also increased survival. 730 The benefit was greater in patients with stage II and III disease and with good PS.

Postoperative chemotherapy benefited older patients up to 80 years of age. 389, 734 6] [737] In this trial, 344 patients were randomly assigned either to paclitaxel plus carboplatin or to observation (within 4-8 weeks of resection) with a median follow-up duration of 74 months. Postoperative chemotherapy was well tolerated with no chemotherapy-related toxic deaths. Overall survival at 6 years was not significantly different (however, a subset analysis showed a benefit for tumors ≥4 cm), although 3-year survival was significant (80% vs. 73%, P=.02). 736, 737 Thus, the carboplatin and paclitaxel regimen is only recommended for early-stage disease if patients cannot tolerate cisplatin (see Perioperative Systemic Therapy in the NCCN Guidelines for NSCLC). 738 It is important to note that the CALGB trial was underpowered for patients with stage 1B disease. 739 EAT, a phase 2 randomized study, assessed cisplatin plus pemetrexed versus cisplatin plus vinorelbine as postoperative therapy for patients with completely resected stages IB to III NSCLC. 731 Data showed that cisplatin plus pemetrexed was an effective, less toxic regimen compared with cisplatin plus vinorelbine; in addition, patients were able to receive more cycles of cisplatin plus pemetrexed compared with cisplatin plus vinorelbine. 731 Overall survival at 3 years was similar between the arms (75% vs. 77%; P = .858). 740

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The NCCN NSCLC Panel does not recommend postoperative chemotherapy for resected stage IA disease based on the trials described in the previous paragraphs. 741 Postoperative chemotherapy is recommended for high-risk, margin-negative, stage IB disease. Recommended chemotherapy regimens for preoperative and postoperative (perioperative) chemotherapy for patients with completely resected stages IB to III NSCLC are provided in the NCCN Guidelines; the regimens also include specific dosing (see Perioperative Systemic Therapy in the NCCN Guidelines for NSCLC). 689, 741 e NCCN NSCLC Panel has preference stratified all the systemic therapy regimens and decided that cisplatin plus pemetrexed is the preferred neoadjuvant or adjuvant option for nonsquamous NSCLC if patients are not candidates for ICIs (see Perioperative Systemic Therapy in the NCCN Guidelines for NSCLC). 731, 740 Cisplatin plus gemcitabine or cisplatin plus docetaxel are the preferred perioperative chemotherapy options for patients with squamous cell NSCLC. 742, 743 Other recommended options include cisplatin plus vinorelbine or cisplatin plus etoposide. [690] [691] [692] Perioperative therapy options for patients who are not candidates for cisplatin-based therapy are preference stratified as useful in certain circumstances and include: 1) carboplatin plus paclitaxel; 2) carboplatin plus gemcitabine; and 3) carboplatin plus pemetrexed (but only for nonsquamous NSCLC). [744] [745] [746] [747] Neoadjuvant therapy is also known as preoperative (or induction) therapy; adjuvant therapy is also known as postoperative therapy.

Targeted Therapy ADAURA, a phase 3 randomized trial, assessed adjuvant therapy with osimertinib versus placebo in 682 patients with resected stage IB to IIIA EGFR mutation-positive NSCLC. 748 At 24 months, 89% (95% CI, 85%-92%) of the osimertinib group and 52% (95% CI, 46%-58%) of the placebo group were alive and disease-free (overall HR for disease recurrence or death, 0.20; 99.12% CI, 0.14-0.30; P < .001). At 24 months, 98% (95% CI, 95%-99%) of the osimertinib group and 85% (95% CI, 80%-89%) of the placebo group were alive and did not have CNS disease (overall HR for disease recurrence or death, 0.18; 95% CI, 0.10-0.33). For patients with stage IB NSCLC, 88% (95% CI, 78%-94%) of the osimertinib group and 71% (95% CI, 60%-80%) of the placebo group were alive and disease-free at 24 months (overall HR for disease recurrence or death, 0.39; 95% CI, 0.18-0.76). For patients with stage II NSCLC, 91% (95% CI, 82%-95%) of the osimertinib group and 56% (95% CI, 45%-65%) of the placebo group were alive and disease-free at 24 months (overall HR, 0.17; 95% CI, 0.08-0.31). For those with stage IIIA NSCLC, 88% (95% CI, 79%-94%) of the osimertinib group and 32% (95% CI, 23%-41%) of the placebo group were alive and disease-free at 24 months (overall HR, 0.12; 95% CI, 0.07-0.20). Data were also reported for those who received adjuvant chemotherapy and those who did not; 60% (410/682) of patients received adjuvant chemotherapy. 749 Overall survival data are not yet available. Serious adverse events were reported in 16% (54/339) of patients receiving osimertinib versus 12% (42/343) receiving placebo. Ten patients (3%) receiving osimertinib had interstitial lung disease versus no patients in the placebo group. There were no deaths in the osimertinib group versus one in the placebo group. Panel expanded the criteria to include patients with stage IIIB (only T3,N2) NSCLC based on differences between the AJCC staging systems for the 7 th and 8 Th editions (see Table 3 in the algorithm). 159 Although the 8 th edition of the AJCC staging manual is currently being used, the clinical trial used the 7 th edition.

Immunotherapy

Trial Data IMpower010, a phase 3 randomized trial, assessed adjuvant therapy with atezolizumab versus best supportive care in 1005 patients with resected early-stage NSCLC and various PD-L1 levels who had received adjuvant chemotherapy. 750 In patients with resected stage II to IIIA NSCLC and PD-L1 of 1% or more, disease-free survival was improved in those receiving adjuvant atezolizumab compared with best supportive care (HR, 0.66; 95% CI, 0.5-0.88; P = .0039). Treatment-related grade 3 and 4 adverse events were reported in 11% (53/495) of patients; 4 deaths occurred (1%, 4/495). Atezolizumab is an ICI that inhibits PD-L1 receptors.

PEARLS/KEYNOTE 091, a phase 3 randomized trial, assessed adjuvant therapy with pembrolizumab versus placebo in 1177 patients with completely resected stage IB to IIIA NSCLC (based on AJCC 7 th edition). 751 Most patients (86%) received adjuvant platinum-based chemotherapy after resection but had not received neoadjuvant chemotherapy or radiotherapy. In patients who received adjuvant chemotherapy after resection, the median disease-free survival was 53.6 months (95% CI, 39.2-not reached) in those receiving adjuvant pembrolizumab compared with 42.0 months (95% CI, 31.3-not reached) in those receiving placebo (HR, 0.76; 95% CI, 0.63-0.91). Grade 3 or worse events included hypertension (6%) and pneumonia (2%). In patients receiving pembrolizumab, there were four fatal (1%) treatment-related adverse reactions, including myocarditis and cardiogenic shock, septic shock and myocarditis, pneumonia, and sudden death. Pembrolizumab is an ICI that inhibits PD-1 receptors.

NCCN Recommendations

The 751 The panel added a caveat that the benefit of adjuvant pembrolizumab is unclear for patients with PD-L1 levels less than 1%.

For the 2023 update (Version 1), the NCCN Panel expanded the molecular testing criteria to include ALK rearrangements because patients with ALK rearrangements, EGFR exon 19 deletions, or EGFR exon 21 L858R mutations have less benefit from ICIs. 184 3] [754] [755] [756] [757] [758] The NSCLC Panel also clarified that single-agent therapy with osimertinib is recommended if patients have both EGFR mutations and PD-L1 of 1% or more; the panel does not recommend using single-agent therapy with atezolizumab or combination therapy with osimertinib plus atezolizumab in this setting. The NCCN Panel also added a recommendation that patients should be evaluated for perioperative (neoadjuvant or adjuvant) therapy before surgery. For the 2023 update (Version 1), the NCCN Panel

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expanded the criteria to include patients with stage IIIB (only T3,N2) disease as previously described.

Preoperative Chemotherapy With or Without Immunotherapy Followed by Surgery

Trial Data Data from clinical trials in patients with resected NSCLCs indicate that delivery of chemotherapy is an important problem. In the postoperative setting, significant comorbidities and incomplete recovery after surgery often make it difficult for patients to tolerate systemic therapy. This problem was demonstrated in NATCH, a phase 3 randomized trial-which compared surgery alone to preoperative or postoperative chemotherapy with paclitaxel/carboplatin-because 90% of the preoperative cohort completed 3 cycles of chemotherapy but only 61% of the postoperative cohort completed chemotherapy; however, survival was equivalent among all three arms. 698 IFCT 0002, a randomized trial, found no difference in 3-year overall survival (67.4% vs. 67.7%) with preoperative versus postoperative chemotherapy in patients with early-stage NSCLC; response rate and quality of life were similar in both arms. 700 veral trials suggest that preoperative therapy is beneficial in patients with N2 disease. 445, 452, 697 Other trials suggest that preoperative therapy is beneficial in patients with earlier stage disease. 694, 695, 699 A randomized intergroup trial (SWOG 9900) evaluated preoperative paclitaxel plus carboplatin in 354 patients with stage IB to IIIA (but not N2) disease versus surgery alone. The trial closed prematurely because of practice changes and was therefore not appropriately powered. This SWOG trial did show a trend toward improved PFS (33 vs. 20 months) and overall survival (62 vs. 41 months) with preoperative chemotherapy, and no difference in resection rates between the two arms. 699 agliotti et al published a phase 3 trial of preoperative cisplatin plus gemcitabine versus surgery alone in 270 patients with stage IB to IIIA disease. Although the trial closed early, a significant survival benefit was seen in patients with stages IIB and IIIA disease who received preoperative chemotherapy (HR, 0.63). 694 Song et al published a meta-analysis of 13 randomized clinical trials evaluating preoperative chemotherapy followed by surgery versus surgery alone in resectable NSCLCs (overall survival: HR, 0.84; 95% CI, 0.77-0.92; P = .0001). 693 hese results are similar to those reported in another meta-analysis (HR, 0.89; 95% CI, 0.81-0.98; P = .02). 694 The benefit from preoperative chemotherapy is similar to that attained with postoperative chemotherapy. 694, 698, 700, 733 eckMate 816, a phase 3 randomized trial, assessed neoadjuvant therapy with nivolumab plus platinum-doublet chemotherapy versus chemotherapy alone in 358 patients with resectable (tumors ≥4 cm or node positive) NSCLC (stage IB-IIIA resectable NSCLC using AJCC staging, 7 th edition). None of the adverse events were associated with death or delays in surgery.

Based on clinical trial data, the NCCN Panel recommends that certain patients who are likely to receive adjuvant chemotherapy may instead be treated with preoperative (also known as induction or neoadjuvant) systemic therapy after surgical evaluation. 694, 698, 700, 733 The NCCN Panel recommends nivolumab plus platinum-doublet chemotherapy as a neoadjuvant systemic therapy option for eligible patients with resectable (tumors ≥4 cm or node positive) NSCLC and no contraindications to treatment with PD-1/PD-L1 inhibitors based on clinical trial data and FDA approval. 107, 760 For the 2023 update (Version 1), the panel added a recommendation that all patients should be evaluated for neoadjuvant therapy with strong consideration for those with node-positive disease or tumors 4 cm or more and no contraindications for ICIs. However, neoadjuvant therapy should not be used to attempt to induce resectability in patients who do not already meet criteria for resectability on initial evaluation. Some oncogenic drivers-such as EGFR exon 19 deletions, EGFR exon 21 L858R mutations, or ALK rearrangementshave been shown to be associated with less benefit from PD-1/PD-L1 inhibitors. 184 Testing for PD-L1 status, EGFR mutations, and ALK rearrangements is recommended before administering neoadjuvant nivolumab plus platinum-doublet chemotherapy in eligible patients with stage IB (only tumors = 4 cm) to IIIA, or stage IIIB (only T3, N2) NSCLC.

For the 2023 update (Version 1), the NCCN Panel expanded the criteria to include patients with stage IIIB (only T3,N2) NSCLC as previously described. The chemotherapy regimens that may be used with neoadjuvant nivolumab include: 1) cisplatin plus either pemetrexed (nonsquamous only), gemcitabine (squamous only), or paclitaxel (any histology); or 2) carboplatin plus either pemetrexed (nonsquamous only), gemcitabine (squamous only), or paclitaxel (any histology). 107

Chemoradiation

The major controversies in NSCLC relate to the care of patients with stage IIIA disease (see the Role of Surgery in Patients with Stage IIIA (N2) NSCLC in Principles of Surgical Therapy in the NCCN Guidelines for NSCLC). All three treatment modalities-surgical resection, chemotherapy, and radiation-may be used when treating stage III disease. [763] [764] [765] [766] Two randomized trials assessed postoperative RT in patients with clinical stage I or II disease that was upstaged surgically to N2. 450, 453 LungART, a phase 3 randomized trial, assessed postoperative RT versus no postoperative RT in 501 patients with completely resected stage IIIA (N2) NSCLC who had received either neoadjuvant (14%) or adjuvant chemotherapy (75%). 450 The median disease-free survival was 30.5 months (95% CI, 24-49) Data from the LungART and PORT-C trials show that postoperative RT (also known as PORT) did not improve survival compared with no postoperative RT, although locoregional control was significantly improved. 450, 453 For the 2023 update (Version 1), the NCCN Panel clarified that postoperative RT may be considered for select patients with high-risk N2 disease such as extracapsular extension, multi-station involvement, inadequate lymph node dissection or sampling, and/or refusal of or intolerance to adjuvant systemic therapy. 450, 453, 761, 767 To minimize potential lung and heart toxicities, highly conformal RT techniques such as IMRT or proton therapy are preferred. 466, 530, 768, 769 r patients with unresectable stage IIIA or stage IIIB disease, combined modality therapy (chemoradiation) is more efficacious than RT alone. 762, 763, 765, 766, 770 04] [705] 771 However, concurrent chemoradiation has a higher rate of grade 3 or 4 esophagitis than sequential chemoradiation. Selection of patients should be based not only on the anticipated response to therapy but also on how well the patient is anticipated to tolerate therapy. Accelerated RT regimens may be useful if concurrent chemoradiation would not be tolerated. 772, 773 Sequential chemoradiation or RT alone is recommended for frail patients who cannot tolerate concurrent chemoradiation. 387, 774 OG0301, a phase 3 randomized trial, assessed chemoradiation using low-dose carboplatin versus RT alone in patients ( > 70 years) with unresectable NSCLC. 775 ). In older patients receiving chemoradiation versus RT alone, long-term follow-up data for overall survival continue to support using chemoradiation (HR, 0.74; 95% CI, 0.55-0.99; P = .024). 776 Although the optimal sequence is not established, postoperative RT is generally administered after adjuvant chemotherapy or concurrently for positive resection margins. 466, 468, 469, 768 ncurrent chemoradiation regimens recommended for all histologies for initial treatment include 1) cisplatin plus etoposide; and 2) carboplatin plus paclitaxel (see Concurrent Chemoradiation Regimens in the NCCN Guidelines for NSCLC). 532, 702, 704, [777] [778] [779] [780] [781] [782] For nonsquamous NSCLC, additional recommended concurrent chemoradiation regimens include pemetrexed plus either carboplatin or cisplatin. [783] [784] [785] A weekly paclitaxel plus carboplatin regimen is another chemoradiation option. 532 The different

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options for preoperative, definitive, and postoperative chemotherapy/RT are described in detail in the algorithm. The NCCN NSCLC Panel has preference stratified all the systemic therapy regimens and decided that the following concurrent chemoradiation options are preferred for patients with NSCLC: 1) pemetrexed plus either carboplatin or cisplatin for nonsquamous NSCLC only; 2) carboplatin plus paclitaxel for all histologies; and 3) cisplatin plus etoposide for all histologies. The cisplatin plus vinblastine concurrent regimen is rarely used in the United States; therefore, it is not recommended in the NCCN Guidelines.

The recommended sequential chemoradiation options include cisplatin combined with pemetrexed (nonsquamous only), docetaxel, etoposide, gemcitabine, or vinorelbine. Carboplatin regimens are recommended for patients with comorbidities or those not able to tolerate cisplatin, including 1) carboplatin plus gemcitabine; 2) carboplatin plus paclitaxel; and 3) carboplatin plus pemetrexed (nonsquamous only). The NCCN NSCLC Panel has preference stratified all the systemic therapy regimens and decided that the following sequential chemoradiation options are preferred for patients with NSCLC: 1) pemetrexed plus cisplatin for nonsquamous NSCLC only; 2) cisplatin plus gemcitabine for squamous histology; and 3) cisplatin plus docetaxel for squamous histology.

Durvalumab

60] 363 PACIFIC, a phase 3 randomized trial, compared adjuvant treatment with durvalumab (also known as consolidation immunotherapy in this setting) versus placebo in eligible patients with unresectable stage III NSCLC (PS 0-1) but without disease progression after treatment with 2 or more cycles of definitive concurrent platinum-based chemoradiation. 363, 786 Eligible patients received adjuvant durvalumab after treatment with concurrent chemoradiation (1-42 days).

Most patients either currently or previously smoked cigarettes and did not have EGFR mutations; their PD-L1 status was typically less than 25% or unknown. Grade 3 or 4 adverse events occurred at a similar rate in both groups of patients (durvalumab, 30.5% vs. placebo, 26.1%). Pneumonia was the most common grade 3 or 4 adverse event (durvalumab, 4.4% vs. placebo, 3.8%). Durvalumab did not compromise patient-reported outcomes. 787 An updated analysis of this trial reported that overall survival was increased after durvalumab consolidation (47.5 months; 95% CI, 38.4-52.6) compared with placebo (29.1 months; 95% CI, 22.1-35.1) (stratified HR for death, 0.72; 95% CI, 0.45-0.68). 16, 786 fter 5 years, 42.9% of patients who received durvalumab were alive versus 33.4% of those who received placebo. 13 In addition, 42.9% were alive after 5 years if they had received durvalumab and 33% were alive and free of disease progression compared with 19% of those who received placebo. The subgroup analyses were limited by small sample size and were not powered to assess efficacy. Patients receiving durvalumab received less subsequent immunotherapy (11.6%) compared with those who received placebo (28.3%).

The NCCN NSCLC Panel recommends durvalumab (category 1) as a consolidation immunotherapy option (regardless of PD-L1 status) for eligible patients (PS 0-1) with unresectable stage III NSCLC and without disease progression after treatment with definitive concurrent platinum-based chemoradiation based on this trial and FDA approval. 363, 786 t is important to note that durvalumab is used as an adjuvant treatment option in this setting; it is not used as second-line therapy. Durvalumab may be used as a consolidation immunotherapy option after treatment with any of the concurrent chemoradiation regimens described in the algorithm (eg, cisplatin plus etoposide, carboplatin plus paclitaxel) (see Concurrent Chemoradiation Regimens in the NCCN Guidelines for NSCLC). Ten patients with stage II NSCLC were included in the PACIFIC trial, which used the older AJCC staging criteria (7th edition). Therefore, the NCCN A few of the recommended concurrent chemoradiation regimens have an option for additional cycles (2 or 4) of chemotherapy after radiation, which is termed consolidation chemotherapy (see Concurrent Chemoradiation Regimens in the NCCN Guidelines for NSCLC). 503, 532, 778, 783 If patients will be receiving durvalumab, the NCCN NSCLC Panel does not recommend consolidation chemotherapy based on concerns that adding consolidation chemotherapy will increase the risk of pneumonitis if patients are also receiving durvalumab. Durvalumab should be discontinued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information). If patients will not be receiving durvalumab because of medical contraindications or other reasons, consolidation chemotherapy is an option after concurrent chemoradiation, depending on the initial regimen.

Systemic Therapy

6] [717] If patients are not eligible for the targeted therapy or immunotherapy regimens, then chemotherapy regimens are recommended. 9] [790] However, survival rates are higher for patients with stage IV NSCLC who are eligible for either the newer targeted therapy or immunotherapy regimens. 9,14-27 Phase 3 randomized trials have shown that many of the platinum-doublet combinations yield similar objective response rates and survival. 791, 792 1] [802] [803] The prognosis for stage IV inoperable lung cancer remains poor if patients are not candidates for targeted therapy or immunotherapy regimens.

In the United States, frequently used initial cytotoxic regimens for stage IV nonsquamous NSCLC include: 1) cisplatin (or carboplatin) plus pemetrexed; or 2) carboplatin plus paclitaxel with (or without) bevacizumab. 777, 804, 805 Gemcitabine plus cisplatin (or carboplatin) is often used for patients with stage IV squamous cell NSCLC. 790, 795, 804, 805 These chemotherapy regimens are recommended based on phase 3 randomized trials (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for NSCLC). 790, 806 A phase 3 randomized trial suggests that conventional cytotoxic agents should not be continued beyond 4 to 6 cycles of therapy; however, many patients assigned to a longer duration of therapy did not receive the planned number of cycles (see Maintenance Therapy in this Discussion). 807, 808 phase 3 randomized trial assessed cisplatin plus pemetrexed versus cisplatin plus gemcitabine as first-line therapy in patients with stage IIIB or IV NSCLC. 790 For patients with adenocarcinoma who received cisplatin plus pemetrexed, median overall survival was 12.6 months compared with 10.9 months for those receiving cisplatin plus gemcitabine (HR, 0.84; 95% CI, 0.71-0.99; P = .03). In contrast, for patients with squamous cell NSCLC who received cisplatin plus pemetrexed, overall survival was 9. receiving cisplatin plus pemetrexed had less toxicity when compared with those receiving cisplatin plus gemcitabine. 809 Median overall survival was similar for both regimens when histologies were combined (8.6 vs. 9.2 months, respectively; HR, 1.08; 95% CI, 0.81-1.45; P = .586).

TAX 326, a phase 3 randomized trial, assessed docetaxel plus cisplatin (or carboplatin) versus vinorelbine plus cisplatin as first-line therapy for patients with stage IIIB or IV NSCLC. 743 Docetaxel plus cisplatin was associated with similar overall survival (11.3 vs. 10.1 months; P = .044; HR, 1.183; 97.2% CI, 0.989-1.416) and better response rate (31.6%) when compared with cisplatin plus vinorelbine (24.5%; P = .029); docetaxel plus cisplatin was associated with better quality of life and was better tolerated.

Many oncologists use pemetrexed-based regimens for stage IV adenocarcinomas (if patients are not candidates for targeted therapy or PD-1/PD-L1 inhibitors), because taxane-based regimens are associated with more toxicity (eg, neurotoxicity). 790, 810 There are no agents for the prevention of peripheral neuropathy, and few agents are useful for treatment. 811 The POINTBREAK trial showed that carboplatin plus pemetrexed plus bevacizumab is a reasonable option for patients with metastatic NSCLC and confirmed that taxane-based regimens are more toxic than pemetrexed-based regimens. 812 The POINTBREAK trial also showed that both regimens are similar in regard to overall survival rates; therefore, oncologists may return to using taxane-based regimens, which are well established. A retrospective cohort study suggests that the addition of bevacizumab to carboplatin plus paclitaxel does not increase survival in patients ≥ 65 years with advanced nonsquamous NSCLC. 813 owever, another retrospective cohort study reported increased survival in older patients. 814 A combined analysis of the ECOG 4599 and POINTBREAK trials found a survival benefit with the addition of bevacizumab to carboplatin plus paclitaxel in patients < 75 years but no benefit in those > 75 years. 815 bumin-bound paclitaxel (also known as nab-paclitaxel) can be substituted for paclitaxel or docetaxel for patients: 1) who have experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despite premedication; or 2) in whom premedications (ie, dexamethasone, H2 blockers, H1 blockers) to prevent hypersensitivity are contraindicated. 816, 817 A phase 3 randomized trial in patients with advanced NSCLC reported that an albumin-bound paclitaxel plus carboplatin regimen is associated with less neurotoxicity and improved response rate, when compared with the control arm of paclitaxel plus carboplatin. 818 Based on the trial and FDA approval, the NCCN NSCLC Panel recommends an albumin-bound paclitaxel plus carboplatin regimen as initial cytotoxic therapy for patients with advanced NSCLC and good PS.

Chemotherapy For patients with advanced NSCLC who have a PS of 2, platinum-based combinations and a few single-agent chemotherapy agents are recommended in the NCCN Guidelines; cisplatin-based regimens are not recommended in this setting. 819 1] [822] Patients with a PS of 2 are often just treated with single-agent chemotherapy because of concerns about toxicity. 823 Treatment with carboplatin plus pemetrexed increased median overall survival when compared with pemetrexed alone (9.3 vs. 5.3 months, P = .001) in patients with a PS of 2; however, 4 treatment-related deaths occurred in the carboplatin plus pemetrexed arm. 820, 824 e NCCN NSCLC Panel has preference stratified all the systemic therapy regimens for patients with NSCLC. The newer chemotherapy plus pembrolizumab regimens are preferred for eligible patients with metastatic NSCLC who do not have contraindications to immunotherapy and are not candidates for targeted therapy (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for NSCLC and Immune Checkpoint Inhibitors in this Discussion). For patients with metastatic nonsquamous NSCLC and PS 0 to 1 who have contraindications to immunotherapy, the panel decided that the following chemotherapy regimens are "useful in certain circumstances," including 1) carboplatin with paclitaxel (or albumin-bound paclitaxel), docetaxel, etoposide, gemcitabine, or pemetrexed; all are category 1; 2) cisplatin with paclitaxel (or albumin-bound paclitaxel), docetaxel, etoposide, gemcitabine, or pemetrexed; all are category 1; 3) bevacizumab with carboplatin and either paclitaxel or pemetrexed; and 4) gemcitabine with either docetaxel or vinorelbine. The panel also preference stratified the regimens for patients with metastatic nonsquamous NSCLC and PS 2; carboplatin plus pemetrexed is preferred for patients with adenocarcinoma. The regimens for patients with metastatic squamous cell NSCLC have also been preference stratified.

The initial cytotoxic systemic therapy regimens do not include options that are less effective, more toxic, and/or infrequently used in the United States based on each panel member's experience and data generated by surveying the NCCN NSCLC Panel (see the NCCN Guidelines with Evidence Blocks™ for NSCLC, available at www.NCCN.org). For patients with metastatic nonsquamous NSCLC and NSCLC NOS, the following regimens are not recommended in the NCCN Guidelines: carboplatin plus vinorelbine, cisplatin plus vinorelbine, etoposide, irinotecan, and vinorelbine. For patients with metastatic squamous cell NSCLC, the following regimens are not recommended in the NCCN Guidelines: carboplatin plus vinorelbine, cisplatin plus gemcitabine plus necitumumab, cisplatin plus vinorelbine, etoposide, irinotecan, and vinorelbine.

The NCCN NSCLC Panel voted unanimously to not recommend the necitumumab plus cisplatin plus gemcitabine regimen for patients with metastatic squamous cell NSCLC. The NCCN NSCLC Panel feels the addition of necitumumab to the regimen is not beneficial based on toxicity, cost, and limited improvement in efficacy when compared with cisplatin plus gemcitabine. A phase 3 randomized trial only showed a slight improvement in overall survival (11.5 months; 95% CI, 10.4-12.6; vs. 9.9 months; 95% CI, 8.9-11.1). 825 The stratified HR was 0.84 (95% CI, 0.74-0.96; P = .01). In addition, there were more grade 3 or higher adverse events in patients receiving the necitumumab regimen (388 [72%]

Immune Checkpoint Inhibitors

9] [360] Cemiplimab-rwlc, nivolumab, and pembrolizumab inhibit PD-1 receptors; 361, 362, 138 atezolizumab and durvalumab inhibit PD-L1. 363, 364 The single-agent immunotherapy or combination immunotherapy plus chemotherapy regimens are not recommended if patients have contraindications to immunotherapy, which may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents. PD-L1 inhibitors are less beneficial in patients with some oncogenic drivers (ie, EGFR exon 19 deletions, EGFR exon 21 L858R mutations, ALK rearrangements). 184 Monitoring is recommended during initial therapy with response assessment with CT, with or without contrast, of known or high-risk sites of disease after 2 cycles and then every 2 to 4 cycles. During maintenance or subsequent therapy, monitoring is also recommended with CT, with or without contrast, every 6 to 12 weeks. ICIs (also known as immunotherapy or IO agents) are associated with a delay in benefit when compared with targeted therapy or cytotoxic chemotherapy.

The NCCN NSCLC Panel recommends IHC testing for PD-L1 expression (category 1) before first-line treatment in all patients with metastatic NSCLC, regardless of histology, based on the efficacy of pembrolizumab with or without chemotherapy. 365 Ideally, PD-L1 expression levels are assessed before first-line therapy in patients with metastatic NSCLC, if clinically feasible. Every effort also needs to be made to assess for oncogenic driver variants for which targeted therapies are available (eg, EGFR mutations, ALK rearrangements). Plasma-based ctDNA testing can be used to evaluate for genomic alterations if the assay has been validated and if the patient is unfit for invasive tissue sampling or if there is insufficient tissue for molecular analyses; however, plasma-based ctDNA testing is less sensitive than tissue assays.

It is important to note that targeted therapies are recommended for patients with metastatic NSCLC and specific oncogenic drivers, independent of PD-L1 levels. 73] 827 For patients receiving first-line ICIs with or without chemotherapy, oncologists should be aware of the long half-life of the ICIs and potential adverse effects when using osimertinib in combination with or following ICIs. 828, 829 A few case reports suggest that patients treated with ICIs who have acquired resistance may have transformation to SCLC. 830 2020, the NCCN Panel removed TMB as an emerging immune biomarker for patients with metastatic NSCLC based on clinical trial data, concerns about variable TMB measurements, and other issues as previously described (see TMB in this Discussion). 171, 375, 379 The NCCN Guidelines do not recommend measurement of TMB levels before deciding whether to use nivolumab plus ipilimumab regimens or other ICIs, such as pembrolizumab. 171 e following content briefly summarizes the use of ICIs as first-line or subsequent therapy options in eligible patients with metastatic NSCLC; detailed information, including clinical trial data, is provided in subsequent sections. 831 ICIs may also be used in other settings; clinical trial data and appropriate use are described in greater detail elsewhere. For example,

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adjuvant atezolizumab or pembrolizumab are recommended following adjuvant chemotherapy for eligible patients with completely resected early-stage NSCLC (see Surgery Followed by Adjuvant Therapy: Trial Data and NCCN Recommendations in this Discussion). 750, 751 Durvalumab is recommended as a consolidation immunotherapy option for eligible patients with unresectable stage II or III NSCLC and without disease progression after treatment with definitive concurrent chemoradiation (see Chemoradiation in this Discussion). 363 ngle-agent pembrolizumab, atezolizumab, or cemiplimab-rwlc are recommended (category 1; preferred) as first-line therapy options for eligible patients with metastatic NSCLC regardless of histology, PD-L1 expression levels of 50% or more, and negative test results for actionable driver mutations that have recommended first-line targeted therapies (ie, ALK, BRAF p.V600E, EGFR, METex14 skipping, NTRK1/2/3, RET, ROS1). The NCCN NSCLC Panel recommends single-agent pembrolizumab as a first-line therapy option in eligible patients with metastatic NSCLC regardless of histology, PD-L1 levels of 1% to 49% (category 2B; useful in certain circumstances), and negative test results for actionable driver mutations. 832 mbination therapy with pembrolizumab plus chemotherapy is recommended (category 1; preferred) as a first-line therapy option in eligible patients with metastatic NSCLC and negative test results for actionable driver mutations, regardless of PD-L1 expression levels.

Combination therapy with the ABCP regimen is recommended (category 1; other recommended intervention) as a first-line therapy option for eligible patients with metastatic NSCLC and negative test results for actionable driver mutations, regardless of PD-L1 expression levels.

Combination therapy with pembrolizumab plus chemotherapy or with ABCP may be used as first-line or subsequent therapy options, although they are not preferred options, in eligible patients with actionable driver mutations as shown in the algorithm. Targeted therapy is a preferred first-line therapy option for patients with actionable driver mutations, except for EGFR exon 20 mutations or KRAS mutations. Continuation maintenance immunotherapy is recommended for 2 years, if tolerated, for all first-line immunotherapy (± chemotherapy) regimens.

If patients have disease progression on PD-1/PD-L1 inhibitor therapy (± chemotherapy), then using a PD-1/PD-L1 inhibitor is not recommended for subsequent therapy. 833 Single-agent pembrolizumab is recommended (category 1; preferred) as a subsequent therapy option for select patients with metastatic NSCLC and PD-L1 levels greater than 1%; nivolumab or atezolizumab is recommended (category 1; preferred) as a subsequent monotherapy option for select patients with metastatic NSCLC regardless of PD-L1 levels. Based on data in the second-line setting, PD-1 or PD-L1 inhibitor monotherapy appears to be less effective in patients with EGFR exon 19 deletions, EGFR exon 21 L858R mutations, or ALK rearrangements, regardless of PD-L1 expression levels. 358, 362, 827, 834, 835 A small study suggests that single-agent pembrolizumab is not effective as first-line therapy in patients with metastatic NSCLC and EGFR mutations, even those with PD-L1 levels more than 50%. 372 Patients with ALK-positive NSCLC and very high PD-L1 expression levels do not respond to pembrolizumab. 184, 827 In the trials assessing the efficacy of first-line therapy with pembrolizumab with (or without) chemotherapy, most of the patients were wild type for EGFR or ALK variants. Maintenance immunotherapy is recommended, if tolerated, until progression for all the subsequent therapy regimens.

ICIs are associated with unique immune-mediated adverse events, such as endocrine disorders, that are not seen with traditional cytotoxic chemotherapy; therefore, health care providers should be aware of the spectrum of potential immune-mediated adverse events, know how to manage the adverse events, and educate their patients about possible NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer

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side effects (see the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities, available at www.NCCN.org). 836, 837 tezolizumab, cemiplimab-rwlc, durvalumab, nivolumab, or pembrolizumab should be discontinued for patients with severe or life-threatening pneumonitis or myocarditis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information). [840] Atezolizumab Atezolizumab is a humanized monoclonal immunoglobulin G1 antibody that inhibits PD-L1, which improves antitumor immune response. 364 mmune-mediated adverse events may occur with ICIs, including atezolizumab. 834, 841 For patients with immune-mediated adverse events, intravenous high-dose corticosteroids should be administered based on the severity of the reaction (see the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities, available at www.NCCN.org). Atezolizumab should also be permanently discontinued for patients with severe or life-threatening pneumonitis or myocarditis and should be discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information). The following sections describe the use of atezolizumab in eligible patients with metastatic NSCLC. The use of adjuvant atezolizumab following adjuvant chemotherapy for eligible patients with completely resected early-stage NSCLC is described in a different section (see Surgery Followed by Adjuvant Therapy in this Discussion). It is important to note that a different IHC assay was used to test for PD-L1 levels in IMpower110 (SP142 PD-L1 IHC assay) compared with IHC assays used for pembrolizumab monotherapy in KEYNOTE-024 (PD-L1 IHC 22C3 pharmDx assay); however, the results were similar regardless of which PD-L1 IHC assay was used. 842, 844 Data suggest that different methods of testing for PD-L1 levels are not equivalent. 368, 369 Based on an analysis using the SP142 PD-L1 IHC assay, median OS was 20. 842, 844 There was no survival advantage in the other two subgroups of patients with lower PD-L1 expression (ie, TC ≥ 5% or IC ≥ 5%; TC ≥ 1% or IC ≥ 1%).

The NCCN NSCLC Panel recommends atezolizumab monotherapy (category 1; preferred) as a first-line therapy option for eligible patients with metastatic NSCLC based on clinical trial data and FDA approval. 842, 843 Atezolizumab monotherapy is recommended as a first-line therapy option for patients with metastatic NSCLC, PD-L1 levels of 50% or more, and negative test results for actionable driver mutations, regardless of histology; maintenance therapy with atezolizumab is also recommended in this setting. Cemiplimab-rwlc and pembrolizumab are also recommended first-line therapy options in this setting (category 1; preferred). The NCCN NSCLC Panel has preference stratified the ICI regimens and decided that atezolizumab, cemiplimab-rwlc, and pembrolizumab (all are category 1) are preferred first-line therapy options for eligible patients with metastatic NSCLC based on clinical trial data. 138, 361, 832, 842 power150, a phase 3 randomized trial, compared first-line therapy with the ABCP regimen versus bevacizumab plus chemotherapy for patients with metastatic nonsquamous NSCLC. 841 Median overall survival was 19.2 months (95% CI, 17.0-23.8) in the ABCP arm versus 14.7 months (95% CI, 13.3-16.9) in the carboplatin plus paclitaxel plus bevacizumab arm; the HR for death was 0.78 (95% CI, 0.64-0.96; P = .02). PFS was longer in the ABCP arm versus chemotherapy plus bevacizumab (8.3 vs. 6.8 months; HR, 0.62; 95% CI, 0.52-0.74; P < .001). Some patients with EGFR mutations or ALK rearrangements (n = 108) and disease progression on (or were intolerant of) prior TKI were enrolled in this trial, although most patients (87%) did not have these genetic variants. In these patients with EGFR mutations or ALK rearrangements, PFS was also increased with ABCP compared with chemotherapy plus bevacizumab (9.7 vs. 6.1 months; HR, 0.59; 95% CI, 0.37-0.94). A subgroup analysis of IMpower150 reported that subsequent therapy with the ABCP regimen increased median overall survival in a few patients with EGFR mutationpositive metastatic NSCLC (n = 34) compared with those receiving carboplatin plus paclitaxel plus bevacizumab (n = 45). 845 Therefore, the ABCP regimen may be an option for patients with EGFR mutations or ALK rearrangements and disease progression after initial therapy with TKIs.

The NCCN NSCLC Panel recommends the ABCP regimen (category 1; other recommended intervention) as a first-line therapy option for eligible patients with metastatic nonsquamous NSCLC (including adenocarcinoma) based on clinical trial data and FDA approval. 841 The ABCP regimen (also known as the quadruplicate regimen) is recommended as a first-line therapy option for patients with negative test results for actionable driver mutations (ie, ALK, BRAF p.V600E, EGFR, METex14 skipping, NTRK1/2/3, RET, and ROS1), regardless of PD-L1 expression levels. Combination therapy with the ABCP regimen may be used as a first-line or subsequent therapy option, although it is not a preferred option, in eligible patients with actionable driver mutations as shown in the algorithm. Targeted therapy is a preferred first-line therapy option for patients with actionable driver mutations, except for EGFR exon 20 mutations or KRAS mutations. Maintenance therapy with atezolizumab and bevacizumab is also recommended in this setting (category 1) (see Maintenance Therapy in this Discussion). The NCCN NSCLC Panel has preference stratified the systemic therapy regimens and decided that the ABCP regimen is an other recommended intervention, because the NCCN NSCLC Panel prefers the pembrolizumab plus chemotherapy regimens based on tolerability and experience with these regimens. The NCCN NSCLC Panel recommends that bevacizumab biosimilars may be used in any of the systemic therapy regimens containing bevacizumab, such as NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer

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[848] [849] IMpower130, a phase 3 randomized trial, compared atezolizumab plus carboplatin plus albumin-bound paclitaxel versus chemotherapy alone as first-line therapy in patients with metastatic nonsquamous NSCLC with no EGFR mutations or ALK rearrangements. 850 Median overall survival was 18.6 months (95% CI, 16.0-21.2) in the atezolizumab plus chemotherapy arm versus 13.9 months (95% CI, 12.0-18.7) in carboplatin plus albumin-bound paclitaxel arm (HR, 0.79; 95% CI, 0.64-0.98; P = .033).

Treatment-related deaths were reported in 2% (8/473) of patients in the atezolizumab plus chemotherapy arm and in less than 1% (1/232) of patients in the chemotherapy-only arm.

The NCCN NSCLC Panel recommends atezolizumab plus carboplatin plus albumin-bound paclitaxel (other recommended intervention) as a first-line therapy option for eligible patients with metastatic nonsquamous NSCLC based on clinical trial data. 850 Atezolizumab plus carboplatin plus albumin-bound paclitaxel is recommended as a first-line therapy option for patients with metastatic NSCLC and negative test results for actionable driver mutations, regardless of PD-L1 levels. The atezolizumab plus carboplatin plus albumin-bound paclitaxel regimen may be used as a first-line or subsequent therapy option, although it is not a preferred option, in eligible patients with actionable driver mutations as shown in the algorithm. Maintenance therapy with atezolizumab is also recommended in these settings. Targeted therapy is a preferred first-line therapy option for patients with actionable driver mutations, except for EGFR exon 20 mutations or KRAS mutations.

Subsequent Therapy

OAK, a phase 3 randomized trial, compared atezolizumab versus docetaxel in patients with metastatic NSCLC and disease progression during or after systemic therapy. 834, 851 Most patients either currently or previously smoked cigarettes and had received platinum-based chemotherapy; 10% of patients were not reported because they had EGFR mutations and ALK rearrangements. 834, 851 Patients with nonsquamous NSCLC who received atezolizumab had longer overall survival (15.6 months; 95% CI, 13.3-17.6) when compared with those receiving docetaxel (11.2 months; 95% CI, 9.3-12.6; HR, 0.73; 0.6-0.89; P = .0015). In patients with squamous cell NSCLC, overall survival was 8.9 months (95% CI, 7.4-12.8) in patients receiving atezolizumab versus 7.7 months (95% CI, 6.3-8.9) with docetaxel (HR, 0.73; 0.54-0.98; P = .038). Fewer patients were in the squamous group compared with the nonsquamous group (222 vs. 628). Fewer treatment-related severe adverse events (grades 3-4) were reported for atezolizumab versus docetaxel (15% vs. 43% [90/609 vs. 247/578]).

If patients have not previously received a PD-1/PD-L1 inhibitor, the NCCN NSCLC Panel recommends atezolizumab (category 1; preferred) as a subsequent therapy option for patients with metastatic nonsquamous or squamous cell NSCLC based on clinical trial data and FDA approval. 364, 834, 851 Nivolumab and pembrolizumab are also recommended subsequent therapy options in this setting (category 1; preferred). Testing for PD-L1 expression levels is not required for prescribing subsequent therapy with atezolizumab or nivolumab but may provide useful information. If patients have progressed on a PD-1/PD-L1 inhibitor, then using a PD-1/PD-L1 inhibitor is not recommended.

Cemiplimab-rwlc

Cemiplimab-rwlc is a recombinant human immunoglobulin G4 monoclonal antibody that inhibits PD-1 receptors, which improves antitumor immune response. 361 Immune-mediated adverse events may occur with ICIs, including cemiplimab-rwlc. 361 For patients with immune-mediated adverse events, intravenous high-dose corticosteroids should be administered

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based on the severity of the reaction. Cemiplimab-rwlc should also be permanently discontinued for patients with grades 2, 3, or 4 myocarditis and should be discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information).

EMPOWER-Lung 1, a phase 3 randomized trial, compared first-line therapy with single-agent cemiplimab versus platinum-based chemotherapy for patients with metastatic squamous or nonsquamous NSCLC, PD-L1 levels of 50% or more, and negative test results for EGFR mutations, ALK rearrangements, or ROS1 rearrangements. 361 Patients receiving first-line cemiplimab also received maintenance therapy with cemiplimab. Median overall survival was not reached for patients receiving cemiplimab (95% CI, 17.9-not evaluable) versus 14.2 months (95% CI, 11.2-17.5) for chemotherapy (HR, 0.57; 95% CI, 0.42-0.77; P=.0002).

The response rate was 39% (95% CI, 34%-45%) for those receiving cemiplimab versus 20% (95% CI, 16%-26%) for chemotherapy. Of patients treated with cemiplimab, 28% (98/355) had grade 3 to 4 adverse events compared with 39% (135/342) for those treated with chemotherapy. Treated-related deaths occurred in 2.5% (9/355) of patients receiving cemiplimab versus 2.0% (7/342) with chemotherapy. The cemiplimab-related deaths were due to autoimmune myocarditis, cardiac failure, cardiopulmonary failure, cardiorespiratory arrest, nephritis, respiratory failure, septic shock, tumor hyperprogression, and unknown reasons.

The NCCN NSCLC Panel recommends cemiplimab-rwlc monotherapy (category 1; preferred) as a first-line therapy option for eligible patients with metastatic NSCLC regardless of histology, PD-L1 levels of 50% or more, and negative test results for actionable driver mutations based on clinical trial data and FDA approval; maintenance therapy with cemiplimab-rwlc is also recommended. 361 Atezolizumab and pembrolizumab are also recommended first-line therapy options in this setting (category 1; preferred). The NCCN NSCLC Panel has preference stratified the ICI regimens and decided that atezolizumab, cemiplimab-rwlc, and pembrolizumab (all are category 1) are preferred first-line therapy options for eligible patients with metastatic NSCLC based on clinical trial data. 138, 361, 832, 842 POWER-Lung 3, a randomized phase 3 trial, assessed first-line therapy with cemiplimab plus platinum-based chemotherapy versus platinum-based chemotherapy alone in 466 patients with advanced NSCLC, regardless of PD-L1 levels or histology. The chemotherapy regimens included 1) cemiplimab plus paclitaxel plus either cisplatin or carboplatin for either nonsquamous NSCLC or squamous cell histology; or 2) cemiplimab plus pemetrexed plus either cisplatin or carboplatin for nonsquamous NSCLC. 852 Patients received maintenance therapy if indicated. Most patients (85%) had stage IV NSCLC and 57% had nonsquamous NSCLC. Most patients either currently smoked cigarettes (55%) or had previously smoked (31%). Patients did not have EGFR, ALK, or ROS1 mutations. The median overall survival was 21.9 months (95% CI, 15.5-not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9-16.1) with chemotherapy alone (HR, 0.71; 95% CI, 0.53-0.93; P = .01). Subgroup analysis showed that overall survival was similar between the groups for PD-L1 levels less than 1%, nonsquamous NSCLC, and other subgroups; however, the trial was not powered to detect differences in efficacy within the subgroups. Grade 3 or higher treatment-related adverse events occurred in 44% (136/312) of patients receiving cemiplimab plus chemotherapy, and 31% (48/153) of patients receiving chemotherapy alone. Immune-related adverse events occurred in 19% of patients receiving cemiplimab plus chemotherapy. Death occurred in 6.1% (19/312) of patients receiving cemiplimab plus chemotherapy versus 7.8% (12/153) of patients receiving chemotherapy alone. One patient died from immune-mediated pneumonitis.

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Switch Maintenance Therapy

Issues have been raised about switch maintenance therapy, including the design of the trials, modest survival benefits, quality of life, and toxicity. 810, 889 Two phase 3 randomized trials reported a benefit in PFS and overall survival with the initiation of pemetrexed after first-line chemotherapy (4-6 cycles) in patients with nonsquamous NSCLC and no apparent disease progression. 890, 891 The NCCN NSCLC Panel recommends switch maintenance therapy with pemetrexed in eligible patients with nonsquamous cell carcinoma; negative test results for actionable driver mutations, and PD-L1 expression less than 1% based on clinical trial data and FDA approval. 891, 892 e NCCN NSCLC Panel does not recommend erlotinib as switch maintenance therapy (or as subsequent therapy) for patients with nonsquamous NSCLC, good PS, and negative test results for actionable driver mutations based on results from IUNO, a randomized trial, and a revised indication from the FDA. 893 The NCCN NSCLC Panel also does not recommend switch maintenance therapy with erlotinib in patients with squamous cell NSCLC, because overall survival and quality of life were not improved. 742, 894 A phase 3 trial assessed switch maintenance therapy with docetaxel given either immediately after gemcitabine plus carboplatin or delayed until progression in patients with advanced NSCLC; however, many patients in the delayed chemotherapy arm did not receive docetaxel. 895 Previously, the panel deleted the recommendation for switch maintenance therapy with docetaxel for patients with squamous cell NSCLC because there are better options. 895, 896 CCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer

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Targeted Therapy Targeted therapies are available for the treatment of eligible patients with NSCLC. 182, 897, 898 For information about the use of targeted therapy in early-stage resectable NSCLC, see the Surgery Followed by Adjuvant Therapy and the Neoadjuvant and Adjuvant Therapy sections in this Discussion.

For information about targeted therapies for advanced or metastatic NSCLC with clinically actionable biomarkers, see the Systemic Therapy for Advanced or Metastatic NSCLC section in this Discussion.

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Clinical Evaluation

The workup and evaluation of incidental lung nodules-that are detected on imaging for other conditions-are described in the NSCLC algorithm (see Incidental Lung Nodules in this Discussion and the NCCN Guidelines for NSCLC). 2] [93] [94] [95] As previously described, low-dose CT screening is recommended for asymptomatic select patients who are at high risk for lung cancer and management of any nodules detected in these patients is described elsewhere (see the NCCN Guidelines for Lung Cancer Screening, available at www.NCCN.org).

After patients are confirmed to have NSCLC based on a pathologic diagnosis, a clinical evaluation needs to be done (see the NCCN Guidelines for NSCLC). In patients with symptoms, the clinical stage is initially determined from disease history (ie, cough, dyspnea, chest pain, weight loss) and physical examination together with a limited battery of tests (see Initial Evaluation and Clinical Stage in the NCCN Guidelines for NSCLC). 0] [901] After the clinical stage is determined, the patient is assigned to one of the pathways that are defined by the stage, specific subdivision of the particular stage, and location of the tumor. Note that for some patients, diagnosis, staging, and surgical resection are done during the same operative procedure. A multidisciplinary evaluation should be done before treatment.

Additional Pretreatment Evaluation

As previously noted, evaluation of the mediastinal nodes is a key step in further staging of the patient. 3] [904] When compared with noninvasive staging methods (EBUS, EUS), surgical staging with mediastinoscopy is more appropriate for certain settings when evaluating mediastinal nodes; however, clinicians use both methods when staging patients. 109 Thus, mediastinoscopy is encouraged as part of the initial evaluation, particularly if the results of imaging are not conclusive and the probability of mediastinal involvement is high (based on tumor size and location). Therefore, mediastinoscopy is appropriate for patients with T2 to T3 lesions even if the FDG PET/CT scan does not suggest mediastinal node involvement.

Mediastinoscopy may also be appropriate to confirm mediastinal node involvement in patients with a positive FDG PET/CT scan. Although mediastinal biopsy is generally preferred, the risks in selected patients may outweigh the benefits, such as patients who are medically inoperable.

In patients with peripheral tumors (outer one third of the lung) less than 3 cm, pathologic mediastinal lymph node evaluation is optional if the nodes are FDG PET/CT negative because there is a low likelihood of positive mediastinal nodes. 905 Invasive mediastinal staging is recommended for central tumors. Mediastinal evaluation can be considered in patients with clinical stage IA disease (T1abc,N0). In patients with peripheral T2a, central T1abc, or T2a lesions with negative FDG PET/CT scans, the risk for mediastinal lymph node involvement is higher and mediastinoscopy and/or EUS-FNA and EBUS-TBNA are recommended. Dillemans et al have reported a selective mediastinoscopy strategy, proceeding straight to thoracotomy without mediastinoscopy for T1 peripheral tumors without enlarged mediastinal lymph nodes on preoperative CT. 906 This strategy For identifying N2 disease, chest CT scans had sensitivity and specificity rates of 69% and 71%, respectively. Using a chest CT scan plus mediastinoscopy was significantly more accurate (89% vs. 71%) than using a chest CT scan alone for identifying N2 disease. When using CT scans, node positivity is based on the size of the lymph nodes. Therefore, a CT scan will miss small metastases that do not result in node enlargement. To address this issue, Arita et al specifically examined lung cancer metastases in normal size mediastinal lymph nodes in 90 patients and found an incidence of 16% (14/90) false-negative chest CT scans with histologic identification of occult N2 or N3 disease. 907 Bronchoscopy is used in diagnosis and local staging of both central and peripheral lung lesions and is recommended for pretreatment evaluation of stage I to IIIA tumors. In patients who present with a solitary pulmonary nodule where the suspicion of malignancy is high, surgical resection without prior invasive testing may be reasonable.

As previously mentioned, CT scans have known limitations for evaluating the extent of lymph node involvement in lung cancer. 902 PET scans have been used to help evaluate the extent of disease and to provide more accurate staging. The NCCN NSCLC Panel reviewed the diagnostic performance of CT and PET scans. The panel assessed studies that examined the sensitivity and specificity of chest CT scans for mediastinal lymph node staging. 908 Depending on the clinical scenario, a sensitivity of 40% to 65% and a specificity of 45% to 90% were reported. 909 Because they detect tumor physiology, as opposed to anatomy, PET scans may be more sensitive than CT scans. Moreover, if postobstructive pneumonitis is present, there is little correlation between the size of the mediastinal lymph nodes and tumor involvement. 910 Chin et al found that PET, when used to stage the mediastinal nodes, was 78% sensitive and 81% specific with a negative predictive value of 89%. 911 Kernstine et al compared PET scan to CT scan for identifying N2 and N3 disease in NSCLC. 912 The PET scan was found to be more sensitive than the CT scan in identifying mediastinal node disease (70% vs. 65%). FDG PET/CT has been shown to be useful in restaging patients after adjuvant therapy. 913, 914 When patients with early-stage disease are accurately staged using FDG PET/CT, inappropriate surgery is avoided. 915 e NCCN NSCLC Panel believes that PET scans can play a role in the evaluation and more accurate staging of NSCLC, for example, in identifying stage I (peripheral and central T1-2,N0), stage II, stage III, and stage IV diseases. 109, 916, 917 However, FDG PET/CT is even more sensitive and is recommended by the panel. 915, 918, 919 PET/CT is typically done from the skull base to the knees; whole body PET/CT may also be done.

Positive FDG PET/CT scan findings for distant disease need pathologic or other radiologic confirmation (eg, MRI of bone). If the FDG PET/CT scan is positive in the mediastinum, the lymph node status needs pathologic confirmation. 109, 920 2] [923] [924] When compared with CT and PET, EBUS-TBNA has a high sensitivity and specificity for staging mediastinal and hilar lymph nodes in patients with lung cancer. 925 In patients with positive nodes on CT or PET, EBUS-TNBA can be used to clarify the results. 926, 927 8] [929] Note that EBUS is also known as endosonography.

The routine use of bone scans (to exclude bone metastases) is not recommended. 2] [553] [554] [555] [556] [557] In some instances, positive mediastinal nodes (N2) are discovered at surgery; in this setting, an additional assessment of staging and tumor resectability must be made, and the treatment (ie, inclusion of systematic mediastinal lymph node dissection) must be modified accordingly. Therefore, the NCCN Guidelines include two different tracks for T1-2,N2 disease (ie, stage IIIA disease): 1) T1-2,N2 disease discovered unexpectedly at surgical exploration; and 2) T1-2,N2 disease confirmed before thoracotomy. In the second case, an initial brain MRI with contrast and FDG PET/CT scan (if not previously done) are recommended to rule out metastatic disease. options are organized according to the location of the tumor, such as the superior sulcus, chest wall, proximal airway, or mediastinum. 394 For each location, a thoracic surgeon needs to determine whether the tumor is resectable (see Principles of Surgical Therapy in the NCCN Guidelines for NSCLC). 3] [934] The overall 5-year survival rate is approximately 40%. 503 For patients with resectable tumors (T3 invasion,N0-1) in the superior sulcus, the NCCN NSCLC Panel recommends preoperative concurrent chemoradiation followed by surgical resection and adjuvant chemotherapy plus either atezolizumab, pembrolizumab, or osimertinib, if patients have certain EGFR mutations or PD-L1 levels of 1% or more (see Initial Treatment for Superior Sulcus Tumors in the NCCN Guidelines for NSCLC). Patients with possibly resectable superior sulcus tumors should undergo preoperative concurrent chemoradiation before surgical re-evaluation (including CT with or without contrast ± PET/CT). For patients with unresectable tumors (T4 extension,N0-1) in the superior sulcus, definitive concurrent chemoradiation is recommended followed by durvalumab (category 1). 781, 935 finitive concurrent chemoradiation is recommended for patients with medically inoperable stage II or III NSCLC. The NCCN NSCLC Panel recommends durvalumab (category 1) as a consolidation immunotherapy option for eligible patients with unresectable stage III NSCLC and without disease progression after treatment with definitive concurrent chemoradiation based on clinical trial data and FDA approval (see Chemoradiation in this Discussion and the NCCN Guidelines for NSCLC). 16, 363, 786 The panel also recommends durvalumab as a consolidation immunotherapy option (regardless of PD-L1 status) for eligible patients (PS 0-1) with unresectable stage II NSCLC but without disease progression after definitive concurrent platinum-based chemoradiation. The recommendation for consolidation immunotherapy with durvalumab occurs in multiple places in the NCCN Guidelines.

Surgical resection is the preferred treatment option for patients with tumors of the chest wall, proximal airway, or mediastinum (T3-4,N0-1).

Other treatment options include preoperative systemic therapy or concurrent chemoradiation before surgical resection. For unresectable tumors (T4,N0-1) without pleural effusion, definitive concurrent chemoradiation (category 1) is recommended followed by consolidation immunotherapy with durvalumab (category 1). 16, 447, 702, 786 Additional chemotherapy (ie, consolidation chemotherapy) is an option if patients will not be receiving durvalumab. 532, 778 However, consolidation chemotherapy is not recommended if patients will be receiving durvalumab, based on concerns that consolidation chemotherapy will increase the risk of pneumonitis if patients are also receiving durvalumab.

Multimodality therapy is recommended for most patients with stage III NSCLC. 774 For patients with stage IIIA disease and positive mediastinal nodes (T1-2,N2), treatment is based on the findings of pathologic mediastinal lymph node evaluation (see the NCCN Guidelines for NSCLC). Patients with negative mediastinal biopsy findings are candidates for surgery. For those patients with resectable lesions, mediastinal lymph node dissection or lymph node sampling should be performed during the operation. Those individuals who are medically inoperable should be treated according to their clinical stage. For patients with (T1-2) N2 node-positive disease, a brain MRI with contrast and FDG PET/CT scan (if not done previously) are recommended to search for distant metastases. When distant metastases are not present, the NCCN NSCLC Panel recommends that the patient be treated with definitive concurrent chemoradiation therapy. 482, 703 Recommended therapy for NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-66 metastatic disease depends on whether disease is in a solitary site or is widespread.

When a lung metastasis is present, it usually occurs in a patient with other systemic metastases; the prognosis is poor. Therefore, many of these patients are not candidates for surgery; however, systemic therapy is recommended. Although uncommon, patients with lung metastases but without systemic metastases have a better prognosis and are candidates for surgery (see Multiple Lung Cancers in this Discussion). 936 Patients with separate pulmonary nodule(s) in the same lobe (T3,N0-1) or ipsilateral non-primary lobe (T4,N0-1), without other systemic metastases, are potentially curable by surgery; 5-year survival rates are about 30%. 937 For those with N2 nodes after surgery, concurrent chemoradiation is recommended for those with positive margins and an R2 resection; either sequential or concurrent chemoradiation is recommended after an R1 resection. Most NCCN Member Institutions favor concurrent chemoradiation for positive margins, but sequential chemoradiation is reasonable in frailer patients. 768 For those with N2 nodes and negative margins, l chemotherapy (category 1) or sequential chemotherapy with RT is recommended. Adjuvant chemotherapy followed by adjuvant atezolizumab, pembrolizumab, or osimertinib is recommended for those with N0-1, depending on EGFR mutation levels and PD-L1 levels (see the NCCN Guidelines for NSCLC). In patients with synchronous solitary nodules (contralateral lung), the NCCN NSCLC Panel recommends treating them as two primary lung tumors if both are curable, even if the histology of the two tumors is similar. 938

Multiple Lung Cancers

Patients with a history of lung cancer or those with biopsy-proven synchronous lesions may be suspected of or confirmed with having multiple lung cancers. 939, 940 It is important to determine whether the multiple lung cancers are metastases or separate lung primaries (synchronous or metachronous); most multiple lung tumors are metastases. 86, 394, 941, 942 Lesions with different cell types, such as squamous cell or adenocarcinoma, are usually different primary tumors. However, lesions of the same cell type may not be metastases. Therefore, it is essential to determine the histology of the lung tumor (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC). Infection and other benign diseases also need to be ruled out (eg, inflammatory granulomas). 943, 944 5] [946] [947] The Martini and Melamed criteria are often used to diagnose multiple lung cancers as follows: 1) the histologies are different; or 2) the histologies are the same, but there is no lymph node involvement and no extrathoracic metastases. 947 [950] Broad molecular profiling can be used to assess multiple lung lesions (see Summary of the Guidelines Updates in the NCCN Guidelines for NSCLC). For example, tumors with non-overlapping, unique mutations are considered to be clonally unrelated, separate primary lung cancers even if they are histologically similar. Therefore, these tumors can be treated with local therapy (see Multiple Lung Cancers in the NCCN Guidelines for NSCLC). 2] [953] Patients should be evaluated in a multidisciplinary setting by thoracic surgeons, pulmonary medicine, radiation oncologists, and medical oncologists. In patients eligible for definitive local therapy, parenchymal-sparing resection is preferred (see the Principles of Surgical Therapy in the NCCN Guidelines for NSCLC). 940, 941 VATS or SABR are reasonable options depending on the number and distribution of the tumors requiring local treatment. 954 Multiple lung nodules (eg, solid, subsolid nodules) may also be detected on CT scans; some of these NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-67

nodules can be followed with imaging, whereas others need to be biopsied or excised (see Incidental Lung Nodules in this Discussion and the NCCN Guidelines for Lung Cancer Screening, available at www.NCCN.org). 955 r the 2023 update (Version 1), the NCCN NSCLC Panel revised the algorithm for multiple lung cancers. For example, the NCCN Panel added an initial recommendation for multidisciplinary evaluation for patients suspected of or confirmed with having multiple lung cancers. One of the goals during multidisciplinary evaluation for multiple lung cancers is to assess whether patients have lung nodules that can be observed instead of erroneously assuming that patients have stage IV NSCLC. The panel added the following caveats: lesions at low risk of becoming symptomatic can be observed, such as small subsolid nodules with slow growth. However, treatment should be considered if the lesion(s) show accelerating growth, increasing solid component, or increasing FDG uptake, even if the lesions are small.

Stage IIIB and IIIC NSCLC

Stage IIIB NSCLC comprises two unresectable groups, including: 1) T1-2,N3 tumors; and 2) T3-4,N2 tumors; stage IIIC NSCLC includes T3,N3 and contralateral mediastinal nodes (T4,N3), which are also unresectable. Surgical resection is not recommended in patients with T1-2,N3 disease. However, in patients with suspected N3 disease, the NCCN Guidelines recommend pathologic confirmation of nodal status (see Pretreatment Evaluation in the NCCN Guidelines for NSCLC). 956, 957 In addition, FDG PET/CT scans (if not previously done) and brain MRI with contrast should also be included in the pretreatment evaluation. If these imaging tests are negative, then treatment options for the appropriate nodal status should be followed (see the NCCN Guidelines for NSCLC). [960] Durvalumab is recommended (category 1) as a consolidation immunotherapy option for eligible patients with unresectable stage III NSCLC and without disease progression after treatment with definitive concurrent chemoradiation (see Chemoradiation in this Discussion and the NCCN Guidelines for NSCLC). 16, 363, 786 If patients will be receiving durvalumab, additional f chemotherapy (ie, consolidation chemotherapy) is not recommended based on concerns that adding consolidation chemotherapy will increase the risk of pneumonitis if patients are also receiving durvalumab. If patients will not be receiving durvalumab because of medical contraindications or other reasons, consolidation chemotherapy is an option after concurrent chemoradiation. 532, 778 For metastatic disease that is confirmed by FDG PET/CT scan and brain MRI with contrast, treatment is described in the NCCN Guidelines for limited or metastatic disease.

For patients with T4,N2-3 disease (stages IIIB and IIIC), surgical resection is not recommended. The initial workup includes biopsies of the N3 and N2 nodes. If these biopsies are negative, the same treatment options may be used as for stage IIIA (T4,N0-1) disease (see the NCCN Guidelines for NSCLC). 9] [960] [961] Again, durvalumab is recommended (category 1) as a consolidation immunotherapy option for eligible patients with unresectable stage III NSCLC and without disease progression after treatment with definitive concurrent chemoradiation. 16, 363, 786 Consolidation chemotherapy is an option for eligible patients. 532, 778 However, consolidation chemotherapy is not recommended if patients will be receiving durvalumab. Pleural or pericardial effusion is a criterion for stage IV, M1a disease. T4 with pleural effusion is classified as stage IV, M1a (see Table 3 in Staging in the NCCN Guidelines for NSCLC). 158 Pleural or pericardial effusions are malignant in 90% to 95% of patients; however, they may be related to obstructive pneumonitis, atelectasis, lymphatic or venous obstruction, or a pulmonary embolus. Therefore, pathologic confirmation of a malignant effusion by using thoracentesis or pericardiocentesis is recommended. In certain cases where thoracentesis is inconclusive, thoracoscopy may be performed. In the absence of nonmalignant causes (eg, obstructive pneumonia), an exudate or sanguineous effusion is considered malignant regardless of the results of cytologic examination. If the pleural or pericardial effusion is considered negative for malignancy (M0), recommended treatment is based on the confirmed T and N stage (see the NCCN Guidelines for NSCLC). Data suggest that most pleural or pericardial effusions are associated with unresectable disease in 95% of cases. 963 In patients with effusions that are positive for malignancy, the tumor is defined as M1a and is treated with local therapy (ie, ambulatory small catheter drainage, pleurodesis, and pericardial window) in addition to treatment as for stage IV disease. 964, 965 re of patients with distant metastases in limited sites (ie, stage IVA,M1b) and good PS depends on the location and number of the metastases; the diagnosis is aided by mediastinoscopy, bronchoscopy, FDG PET/CT scan, and brain MRI with contrast. The increased sensitivity of FDG PET/CT scans, compared with other imaging methods, may identify additional metastases and, thus, spare some patients from unnecessary futile surgery. Positive FDG PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If the FDG PET/CT scan is positive in the mediastinum, the lymph node status needs pathologic confirmation. Patients with oligometastatic disease (eg, brain metastases) and otherwise limited disease in the chest may benefit from aggressive local therapy to both the primary chest and metastatic sites. 584, 966 Aggressive local therapy may comprise surgery and/or definitive RT, including SRS and SABR, and may be preceded or followed by chemotherapy. After progression on TKIs, patients with EGFR mutation-positive metastatic NSCLC may be able to continue with their current TKIs; local therapy can be considered to treat their limited progression (eg, SRS to brain metastases or other sites, SABR for limited thoracic or other metastatic disease; surgery). 967, 968 oadjuvant or Adjuvant Therapy pemetrexed is a preferred neoadjuvant or adjuvant therapy option (also known as preoperative and postoperative therapy) for nonsquamous NSCLC, whereas cisplatin plus either gemcitabine or docetaxel is preferred for squamous cell NSCLC (see Perioperative Systemic Therapy in the NCCN Guidelines for NSCLC). 738, 743, 790 Cisplatin combined with either vinorelbine or etoposide are "other recommended" options. For patients with comorbidities or those who cannot tolerate cisplatin, carboplatin may be combined with pemetrexed (nonsquamous only), paclitaxel, or gemcitabine; thus, these regimens are useful in certain circumstances. 738, 969 [746] [747] Because patients with stage III disease have both local and distant failures, theoretically, the use of chemotherapy may eradicate micrometastatic disease obviously present but undetectable at diagnosis. The timing of this chemotherapy varies (see the NCCN Guidelines for NSCLC). Such chemotherapy may be given alone, sequentially, or concurrently with RT. In addition, chemotherapy could be given preoperatively or postoperatively in appropriate patients. ] [972] All three studies showed a survival advantage for patients who received preoperative chemotherapy. SWOG S9900-one of the largest randomized trials examining preoperative chemotherapy in early-stage NSCLC-assessed surgery alone compared with surgery plus preoperative paclitaxel plus carboplatin in patients with stage IB/IIA and stage IIB/IIIA NSCLC (excluding superior sulcus tumors). PFS and overall survival were improved with preoperative chemotherapy. 971, 972 The two earlier phase 3 studies had a small number of patients, while the SWOG study was stopped early because of the positive results of the IALT study. [975] Post-surgical treatment options for patients with stage IA tumors (T1abc,N0) and with positive surgical margins (R1, R2) include re-resection (preferred) or RT (category 2B); observation is recommended for patients with negative surgical margins (R0). Postoperative chemotherapy is a recommended option for patients with T2ab,N0 tumors and negative surgical margins who have high-risk features, including poorly differentiated tumors, vascular invasion, wedge resection, visceral pleural involvement, and unknown lymph node status (Nx) (see the NCCN Guidelines for NSCLC). 737, 976 If the surgical margins are positive in patients with T2ab,N0 tumors, options include: 1) re-resection (preferred) with (or without) chemotherapy; or 2) RT with (or without) chemotherapy (chemotherapy is an option for T2b,N0). 467, 737 e NCCN NSCLC Panel recommends atezolizumab as an adjuvant therapy option for eligible patients with completely resected (R0) stage IIB to IIIA, stage IIIB (only T3,N2), or high-risk stage IIA NSCLC and PD-L1 of 1% or more, and negative for EGFR exon 19 deletions, EGFR L858R mutations, or ALK rearrangements, who have previously received adjuvant chemotherapy based on clinical trial data and FDA approval (see Surgery Followed by Adjuvant Therapy: Trial Data and NCCN Recommendations in this Discussion). 750 For the 2023 update (Version 2), the NCCN Panel also recommends pembrolizumab as an adjuvant therapy option following adjuvant chemotherapy for eligible patients with completely resected early-stage NSCLC based on clinical trial data and FDA approval. 751 The panel recommends osimertinib as an adjuvant therapy option for eligible patients with completely resected (R0) stage IB to IIIA or stage IIIB (only T3,N2) NSCLC and EGFR exon 19 deletions or EGFR L858R mutations who have previously received adjuvant chemotherapy or are ineligible to receive platinum-based chemotherapy based on clinical trial data and FDA approval. 748 For patients who have these EGFR mutations and PD-L1 levels of 1% or more, the panel only recommends osimertinib; the panel does not recommend using 1)

MS-70

single-agent therapy with either atezolizumab or pembrolizumab; or 2) combination therapy with osimertinib plus atezolizumab or pembrolizumab.

The NCCN NSCLC Panel recommends adjuvant chemotherapy (category 1) followed by atezolizumab, pembrolizumab, or osimertinib for eligible patients with the appropriate biomarkers, negative surgical margins, and stage IIB disease, including 1) T1abc-T2a,N1; 2) T2b,N1; or 3) T3,N0 disease. 733, 977 If surgical margins are positive in these patients, options after an R1 resection include: 1) re-resection and chemotherapy; or 2) chemoradiation (either sequential or concurrent). After an R2 resection, options include: 1) re-resection and chemotherapy; or 2) concurrent chemoradiation. Most NCCN Member Institutions favor concurrent chemoradiation for positive margins, but sequential chemoradiation is reasonable in frailer patients. 768 Postoperative chemotherapy or chemoradiation can also be used in patients with stage III NSCLC who have had surgery (see the NCCN Guidelines for NSCLC). Patients with T1-3,N2 or T3,N1 disease (discovered only at surgical exploration and mediastinal lymph node dissection) and positive margins may be treated with chemoradiation; either sequential or concurrent chemoradiation is recommended for an R1 resection, whereas concurrent chemoradiation is recommended for an R2 resection. For patients with negative margins (R0), treatment options include either 1) chemotherapy (category 1) followed by atezolizumab, pembrolizumab, or osimertinib for eligible patients with the appropriate biomarkers; or 2) sequential chemotherapy and consider RT. 733 For stage IIIA superior sulcus tumors (T4 extension,N0-1) that become resectable after preoperative concurrent chemoradiation, resection followed by chemotherapy is recommended and then atezolizumab, pembrolizumab, or osimertinib, depending on biomarker status (see the NCCN Guidelines for NSCLC). Surgical reevaluation (including chest CT with or without contrast and with or without PET/CT) is done to determine whether the tumor is resectable after treatment. If the lesion remains unresectable after preoperative concurrent chemoradiation, then completion of definitive dose chemoradiation without interruption, followed by consolidation immunotherapy with durvalumab (category 1) is recommended for eligible patients. Among patients with chest wall lesions with T3 invasion-T4 extension, N0-1 disease, those who are initially treated with surgery (preferred) may receive chemotherapy and then either atezolizumab, pembrolizumab, or osimertinib depending on biomarker status, if the surgical margins are negative. For patients with positive margins, options include either 1) sequential or concurrent chemoradiation; or 2) re-resection and chemotherapy. As previously mentioned, most NCCN Member Institutions favor concurrent chemoradiation for positive margins, but sequential is reasonable in frailer patients. 768 Similar treatment plans are recommended for resectable tumors of the proximal airway or mediastinum (T3-4,N0-1).

For patients with stage III disease and positive mediastinal nodes (T1-3,N2) and no apparent disease progression after initial treatment with induction systemic therapy with or without RT, surgery is recommended (see the NCCN Guidelines for NSCLC). 450 Alternatively, if the disease progresses, treatment options include either 1) local therapy using RT (if feasible) with (or without) chemotherapy; or 2) systemic therapy. In patients with separate pulmonary nodules in the same lobe (T3,N0-1) or ipsilateral non-primary lobe (T4,N0-1), surgery is recommended; neoadjuvant systemic therapy with nivolumab plus chemotherapy is an option before surgery. In patients with N2 disease and negative margins, options include 1) chemotherapy (category 1); or 2) sequential chemotherapy with radiation. If the resection margins are positive in patients with N2 disease, concurrent chemoradiation is recommended for an R2 resection, whereas either concurrent or sequential chemoradiation

is recommended for an R1 resection. Concurrent chemoradiation is often used for positive margins, but sequential is reasonable in frailer patients.

Radiation Therapy

After complete resection of clinical early-stage NSCLC, postoperative RT has been found to be detrimental for pathologic N0 or N1 stage disease in a meta-analysis (population-based analysis of data from SEER) of small randomized trials using older techniques and dosing regimens. 978 Data from two randomized phase 3 trials, the LungART and PORT-C trials, show that postoperative RT (also known as PORT) did not improve survival compared with no postoperative RT, although locoregional control was significantly improved in patients with completely resected stage IIIA (N2) NSCLC who received neoadjuvant or adjuvant chemotherapy. 450, 453 Postoperative RT may be considered for select patients with negative margins and high-risk N2 disease (see Chemoradiation in this Discussion and Principles of Radiation Therapy in the algorithm). Previous trials and meta-analyses had suggested that there was an apparent survival benefit of postoperative RT in patients with N2 nodal stage diagnosed surgically. 467, 574, 977, 979, 980 OCLAIM, a phase 3 randomized trial, assessed concurrent thoracic RT with cisplatin plus pemetrexed versus cisplatin plus etoposide followed by consolidation chemotherapy in patients with unresectable stage III nonsquamous NSCLC. 778 Both regimens were equivalent in terms of survival, but the cisplatin plus pemetrexed regimen was associated with less neutropenia (24.4% vs. 44.5%; P < .001) and fewer grade 3 to 4 adverse events (64.0% vs. 76.8%; P = .001). The NCCN Panel has preference stratified the concurrent chemoradiation regimens and decided that pemetrexed with either carboplatin or cisplatin are preferred concurrent chemoradiation regimens for eligible patients with nonsquamous NSCLC. 783, 981, 982 Other preferred concurrent chemoradiation regimens include 1) paclitaxel plus carboplatin; and 2) cisplatin plus etoposide;, these regimens may be used regardless of histology. 532, 780 The NCCN NSCLC Panel deleted the cisplatin plus etoposide consolidation regimen based on the PROCLAIM trial. 778 Other consolidation chemotherapy regimens are an option for eligible patients receiving definitive chemoradiation; however, consolidation chemotherapy is not recommended if the patient will be receiving durvalumab.

Postoperative chemotherapy (category 1) followed by adjuvant atezolizumab, pembrolizumab, or osimertinib, depending on the biomarker status, is recommended for patients with T1-3, N2 disease and negative margins (see the NCCN Guidelines for NSCLC). Postoperative sequential chemotherapy with consideration of postoperative RT is recommended for select patients with negative margins and high-risk N2 disease such as extracapsular extension, multistation involvement, inadequate lymph node dissection or sampling, and/or refusal or intolerance of adjuvant systemic therapy. 450, 453, 767 Either concurrent or sequential chemoradiation may be used for postoperative therapy and positive margins, depending on the type of resection and the setting (eg, N2 disease). Concurrent chemoradiation is recommended for R2 resections, whereas either sequential or concurrent chemoradiation is recommended for R1 resections. Concurrent chemoradiation is often used for positive margins, but sequential is reasonable in frailer patients. 768 Cisplatin plus etoposide and carboplatin plus paclitaxel are chemoradiation regimens recommended by the NCCN NSCLC Panel for all histologies (see Concurrent Chemoradiation Regimens in the NCCN Guidelines for NSCLC). 780 When chemoradiation is recommended in the NCCN Guidelines, these regimens may be used for stage II to III disease. 468, 469, 702, 703, 781, 784, 785

Surveillance

0] [991] [992] Patients treated with chemotherapy with (or without) RT who have residual abnormalities may require more frequent imaging. FDG PET/CT or brain MRI is not routinely recommended for routine surveillance in patients without symptoms. 983 But, PET may be useful for assessing CT scans that appear to show malignant neoplasms but may be radiation fibrosis, atelectasis, or other benign conditions. Areas previously treated with RT may remain FDG avid for up to 2 years; therefore, histologic confirmation of suspicious areas with apparent "recurrent" disease is needed. 993 The NCCN NSCLC Panel recommends assessing patients with recurrences using PET/CT and brain MRI with contrast; if brain MRI is not possible, then CT with contrast of the head is recommended. Information about smoking cessation (eg, advice, counseling, therapy) should be provided for patients undergoing surveillance to improve their quality of life.

Treatment of Recurrences and Distant Metastases

Recurrences are subdivided into locoregional recurrences and distant metastases. Management of locoregional recurrences or symptomatic local disease-endobronchial obstruction, mediastinal lymph node recurrence, superior vena cava (SVC) obstruction, and severe hemoptysis-is described in the NCCN Guidelines (see Therapy for Recurrence and Metastasis in the NCCN Guidelines for NSCLC). 664 An NCCN

SVC stent may be used with either concurrent chemoradiation or RT to treat SVC obstruction. For patients with endobronchial obstruction, relieving airway obstruction may increase survival, especially in patients who are severely compromised, and may improve their quality of life. 995 fter treatment for locoregional recurrence, observation or systemic therapy (category 2B for systemic therapy) is recommended if disseminated disease is not evident. Systemic therapy is recommended for disseminated disease. The type of systemic therapy depends on the histologic type, whether somatic genomic alterations are present that can be treated with targeted therapy, and PS (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for NSCLC).

Management of distant metastases-localized symptoms; bone; and limited, diffuse brain, or disseminated metastases-is described in the NCCN Guidelines (see Therapy for Recurrence and Metastasis in the NCCN Guidelines for NSCLC). Palliation of symptoms throughout the disease course can be achieved with external-beam RT for distant metastases with localized symptoms, diffuse brain metastases, or bone metastases (bisphosphonate or denosumab therapy can be considered). 480, 579, 996 For patients at risk of fracture in weight-bearing bone, orthopedic stabilization and palliative RT are recommended.

Of note, recurrent and metastatic disease have historically been regarded as incurable. However, select limited locoregional recurrences may be treated with curative intent therapy (re-resection preferred or RT or SABR) (see Therapy for Recurrence and Metastasis in the NCCN Guidelines for NSCLC). ] [1002] [1003] [1004] In patients with NSCLC who have bone metastases, data suggest that denosumab increases median overall survival when compared with zoledronic acid (9.5 vs. 8 months). 1005 The FDA has approved the use of zoledronic acid and denosumab in patients with bone metastases from solid tumors.

Systemic Therapy for Advanced or Metastatic NSCLC

For patients with advanced or metastatic NSCLC, the NCCN Guidelines recommend that histologic subtype should be determined before therapy so that an appropriate treatment can be selected. Smoking cessation counseling (if necessary) and palliative care should also be integrated into the disease management strategy. Data suggest that early palliative care is associated with higher quality of life in patients with metastatic NSCLC. 720 lecular testing for somatic, disease-associated oncogenic driver mutations or alterations should be conducted as part of broad molecular profiling, which is strongly recommended by the panel. Broad molecular profiling is defined as molecular testing that identifies all actionable molecular biomarkers specified in the NCCN Guidelines for NSCLC in either a single assay or a combination of a limited number of assays, and optimally also identifies emerging biomarkers. Tiered approaches based on low prevalence of co-occurring biomarkers are acceptable. The goal of broad molecular profiling is to identify driver alterations that can guide use of available targeted therapies or to appropriately counsel patients regarding potential clinical trials that may be available. Therefore, broad molecular profiling is considered a key component of improving care for patients with NSCLC.

Molecular testing via biopsy and/or plasma testing is recommended; combinations of tissue and plasma testing, either concurrently or in sequence, are acceptable. 3] [1014] [1015] [1016] [1017] Negative results (defined as the absence of a definitive driver mutation) by one method suggest that a complementary method may be used.

Molecular testing for EGFR, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, METex14 skipping, RET, and ERBB2 (HER2) alterations is recommended in all patients with advanced or metastatic nonsquamous NSCLC (ie, adenocarcinoma, large cell carcinoma) and NSCLC not otherwise specified (NOS); EGFR mutation and ALK rearrangement testing are category 1 recommendations for patients with nonsquamous NSCLC or NSCLC NOS based on the data available to recommend targeted therapies for these biomarkers. As the cumulative incidence of targetable molecular alterations in squamous cell carcinoma across all alterations ranges from 2% to 10%, 136, 137, 184, 185 the same molecular testing should be considered in all patients with advanced or metastatic NSCLC squamous cell carcinoma, and not just those with certain clinical characteristics, such as never smoking status and mixed histology.

If a clinically actionable biomarker is found, the NCCN Guidelines for NSCLC provide appropriate therapy recommendations. If results are unknown or pending, patients can be treated as if they do not have driver oncogenes. However, retrospective data indicate that the availability of molecular testing prior to treatment initiation is associated with longer overall survival (OS) in patients with advanced nonsquamous NSCLC. 1018 If patients require an urgent start to therapy, clinicians should consider holding immunotherapy for one cycle (ie, just use platinum-based chemotherapy regimens). Clinicians need to be aware of the long half-life of immune checkpoint inhibitors and the potential for higher rates of side effects when using certain targeted therapies, (such as osimertinib) in combination with or following checkpoint inhibitors. 828, 829, 1019, 1020 a clinical actionable biomarker is discovered during first-line systemic therapy, then the planned systemic therapy (including maintenance therapy) can be either interrupted or completed before switching to the appropriate targeted therapy. Factors that can be considered to guide

this decision include the level of toxicity that the patient is experiencing and whether a clinical or radiographic response has been observed.

Upfront programmed death ligand 1 (PD-L1) expression testing before first-line therapy is also a category 1 recommendation (regardless of histology) in patients with advanced or metastatic NSCLC to assess how immune checkpoint inhibitors (ICIs) could be used if no actionable molecular biomarkers are identified. Treatment options for advanced or metastatic NSCLC without actionable molecular biomarkers are stratified by PD-L1 level and include systemic therapy options such as immunotherapy with or without chemotherapy (see NSCL-37 and NSCL-38 in the NCCN Guidelines for NSCLC). Refer to the full Guidelines at www.NCCN.org for complete treatment recommendations for advanced or metastatic NSCLC based on PD-L1 levels in the absence of a clinically actionable marker.

In the NCCN Guidelines, targeted therapies with a first-line indication are recommended as initial therapy (rather than first-line ICIs) for patients with advanced or metastatic NSCLC and some (but not all) oncogenic drivers, regardless of PD-L1 levels. The rationale is that targeted therapies typically yield higher response rates (eg, osimertinib, 80%) than ICIs (poor response rates) in the first-line setting, and targeted therapy is better tolerated. 184, 371, 372, 827, 1021 It should be noted that targeted therapies are not available or recommended for NSCLC with certain actionable biomarkers in the first-line setting. For instance, patients with NSCLC with KRAS G12C mutations are likely to benefit from immunotherapy (with or without chemotherapy) in the first-line setting. 184, 1022, 1023 Targeted therapies are recommended only in the second-line setting or later for those with KRAS G12C mutations.

Monitoring is recommended during initial therapy with response assessment with CT (with or without contrast) of known or high-risk sites of disease (such as chest, abdomen, and pelvis) after 2 cycles and then every 2 to 4 cycles. Likewise, monitoring of known or high-risk sites of disease is also recommended during maintenance or subsequent therapy with CT (with or without contrast) every 6 to 12 weeks.

For complete treatment recommendations for advanced or metastatic NSCLC, see NSCL-19.

NSCLC with EGFR Alterations

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is altered in a subset of patients with NSCLC. The two most common EGFR alterations in NSCLC are deletions in exon 19 (with conserved deletion of the LREA sequence) and a point mutation in exon 21 (L858R); these represent approximately 85% to 90% of all EGFR alterations in NSCLC. 246 Both result in activation of the tyrosine kinase domain and are associated with sensitivity to small-molecule EGFR tyrosine kinase inhibitors (TKIs). 244 These EGFR alterations are found in approximately 10% of white patients with NSCLC and up to 19% of Black and 50% of Asian patients. 245, 1024, 1025 her less common EGFR mutations (approximately 10%) include exon 20 S768I, exon 21 L861Q, and/or exon 18 G719X. 246, 247 The median progression-free survival (PFS) was longer with osimertinib compared with either erlotinib or gefitinib (18.9 months vs. 10.2 months; hazard ratio [HR], 0.46; P < .001). 371 The median duration of response was longer with osimertinib compared with erlotinib or gefitinib (median response, 17.2 vs. 8.5 months). 371 Only 6% of patients receiving osimertinib had central nervous system (CNS) progression events when compared with 15% of those receiving erlotinib or gefitinib. 371 Grade 3 or higher adverse events (AEs) were reported in 34% of patients receiving osimertinib and 45% of those receiving erlotinib or gefitinib. 371 An updated analysis showed that median overall survival (OS) was 38.6 months with osimertinib compared with 31.8 months for either erlotinib or gefitinib (HR, 0.8; P = .046). Amivantamab-vmjw is a bispecific human antibody to EGFR and MET that has been studied in a variety of contexts of NSCLC with EGFR mutations. 178 For patients with advanced NSCLC and EGFR exon 19 deletion or L858R mutation whose disease progressed on or after osimertinib monotherapy, MARIPOSA-2, a phase 3 randomized trial, evaluated the efficacy of amivantamab-vmjw in combination with chemotherapy (carboplatin and pemetrexed) as subsequent therapy compared with chemotherapy. 1033 The median PFS was longer for the amivantamab-vmjw plus chemotherapy group than the chemotherapy group (6. The following combination regimens are also included in the NCCN Guidelines for NSCLC as "other recommended" options for advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R mutations in the first-line setting: osimertinib in combination with pemetrexed and either cisplatin or carboplatin (category 1; nonsquamous), erlotinib in combination with bevacizumab (nonsquamous and no recent history of hemoptysis), or erlotinib in combination with ramucirumab. An FDA-approved biosimilar is an appropriate substitute for bevacizumab.

Targeted therapies are also recommended as an option if an EGFR exon 19 deletion or EGFR exon 21 L858R mutation is discovered during first-line systemic therapy. For patients receiving first-line ICIs with or without chemotherapy, oncologists should be aware of the long half-life of the ICI and potential AEs when using osimertinib (or other TKIs) in combination with or following ICIs. 828, 829, 1019, 1020 For example, the rate of AEs, such as pneumonitis, is higher when osimertinib is initiated within 3 months of treatment with certain ICIs. 828 patients who experience disease progression after receiving first-line osimertinib, decisions about subsequent therapies are guided by disease symptoms as well as sites of progression. Changes in systemic therapy are generally recommended if patients have symptomatic systemic progression and/or multiple lesions. When considering second-line systemic therapy, ideally patients should be re-biopsied to rule out transformation to small cell histology, a phenomenon that occurs in approximately 5% EGFR TKI-resistant tumors. 265, 278 Amivantamab-vmjw in combination with carboplatin and pemetrexed is a category 1 and preferred treatment option for patients with multiple lesions (if nonsquamous). The NCCN NSCLC Panel recommends cemiplimab-rwlc plus platinum-based chemotherapy regimens as first-line therapy options (category 1; other recommended) for eligible patients with metastatic NSCLC-regardless of histology or PD-L1 levels and with negative test results for actionable driver mutations-based on clinical trial data and FDA approval; maintenance therapy with cemiplimab-rwlc with or without pemetrexed is also recommended. 852 Combination therapy with cemiplimab-rwlc plus platinum-based chemotherapy may be used as a first-line or subsequent therapy option, although it is not a preferred option, in eligible patients with actionable driver mutations as shown in the algorithm. Targeted therapy is a preferred first-line therapy option for patients with actionable driver mutations, except for EGFR exon 20 mutations or KRAS mutations. The NCCN Panel has preference stratified the cemiplimab-rwlc plus chemotherapy regimens and decided that they are other recommended first-line therapy options for eligible patients with metastatic NSCLC based on clinical trial data. 852 volumab with or Without Ipilimumab Nivolumab and ipilimumab are ICIs that have complementary mechanisms of action on T cells; nivolumab is used either with or without ipilimumab, depending on the setting. Nivolumab is a human immunoglobulin G4 monoclonal antibody that inhibits PD-1 receptors, which improves antitumor immune response. 358, 362, 138 PD-1 receptors are expressed on activated cytotoxic T cells. [358] [359] [360] Ipilimumab is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody that binds to CTLA-4 and prevents the interactions with CD80/CD86, which induces de novo T-cell responses against tumors; CTLA-4 inhibits T-cell activation. 853 Immune-mediated adverse events may occur with ICIs, including nivolumab or nivolumab plus ipilimumab. 379 For patients with immune-mediated adverse events, intravenous high-dose corticosteroids should be administered based on the severity of the reaction (see the NCCN Guidelines for the Management of Immunotherapy-Related

Toxicities, available at www.NCCN.org). Nivolumab either with or without ipilimumab should also be permanently discontinued for patients with severe or life-threatening pneumonitis or myocarditis and should be discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information). If patients are receiving nivolumab plus ipilimumab and have treatment-related adverse events, it may be reasonable to discontinue ipilimumab and continue nivolumab. 379

First-Line Therapy CheckMate 227, a phase 3 randomized trial with a complex design, compared first-line therapy with nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy for patients with metastatic nonsquamous or squamous NSCLC who had PD-L1 expression levels of 1% or more, PS 0 to 1, and no EGFR mutations or ALK rearrangements. First-line therapy with nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone was also compared for patients with PD-L1 expression levels less than 1%. In addition, first-line therapy with nivolumab plus ipilimumab or chemotherapy was compared as one of the co-primary analyses in patients who had high TMB levels (≥10 mutations/megabase). 378 Preliminary data for PFS from CHECKMATE 227 suggested that TMB might be a useful immune biomarker for deciding whether to use immunotherapy in patients with metastatic NSCLC. 378 owever, updated data from CHECKMATE 227 showed that overall survival was improved with nivolumab plus ipilimumab regardless of TMB or PD-L1 expression levels. 379 e PFS rate at 1 year was 42.6% for nivolumab plus ipilimumab versus 13.2% for chemotherapy alone. The median PFS for nivolumab plus ipilimumab was 7.2 months (95% CI, 5.5-13.2) compared with 5. for nivolumab plus ipilimumab was 45.3% versus 26.9% with chemotherapy alone; nivolumab plus ipilimumab was beneficial regardless of PD-L1 expression levels or histology. The rate of grade 3 or 4 adverse events was similar for nivolumab plus ipilimumab versus chemotherapy alone (31% vs. 36%). The median PFS was not significantly different when comparing nivolumab monotherapy (N = 71) (4.2 months; 95% CI, 2.7-8.3) versus chemotherapy (N = 79) (5.6 months; 95% CI, 4.5-7.0). Updated results from CheckMate 227 for patients with PD-L1 expression of 1% or more, reported that the median overall survival was 17.1 months (95% CI, 15.0-20.1) for nivolumab plus ipilimumab versus 14.9 months (95% CI, 12.7-16.7) for chemotherapy (HR, 0.79; 95% CI, 0.65-0.96; P = .007). 379 For patients with PD-L1 levels of 1% or more, the 4-year overall survival rate was 29% with nivolumab plus ipilimumab versus 18% for those receiving chemotherapy (HR, 0.76; 95% CI, 0.65-0.90). 854 For patients with PD-L1 levels less than 1%, the 4-year overall survival rate was 24% with nivolumab plus ipilimumab versus 10% for those receiving chemotherapy (HR, 0.64; 95% CI, 0.51-0.81).

The NCCN NSCLC Panel recommends nivolumab plus ipilimumab as a first-line therapy option for eligible patients with metastatic NSCLC based on clinical trial data and FDA approval. 378, 379, 381 Nivolumab plus ipilimumab is recommended for patients with metastatic NSCLC, regardless of PD-L1 levels or histology, negative test results for actionable driver mutations (ie, ALK, BRAF p.V600E, EGFR, METex14 skipping, NTRK1/2/3, RET, ROS1), and no contraindications to immunotherapy. For patients with PD-L1 levels of 1% or more, the NCCN recommendation is category 1 for nivolumab plus ipilimumab. Nivolumab plus ipilimumab is also a recommended option for patients with PD-L1 levels less than 1%. Maintenance therapy with nivolumab plus ipilimumab is also recommended. Combination therapy with nivolumab plus ipilimumab may be used as a first-line or subsequent therapy option, although it is not a preferred option, in eligible patients with actionable driver mutations as shown in the algorithm. Targeted therapy is a preferred first-line therapy option for patients with actionable driver mutations, except for EGFR exon 20 mutations or KRAS mutations.

The NCCN NSCLC Panel has preference stratified the systemic therapy regimens and decided that first-line therapy with nivolumab plus ipilimumab is "useful in certain circumstances" (eg, renal impairment) for patients with PD-L1 levels of 50% or more and is an "other recommended" first-line therapy option for patients with PD-L1 levels less than 50%. For the 2023 update (Version 1), the NCCN Panel revised the preference stratification for first-line therapy with nivolumab plus ipilimumab to an "other recommended" option from useful in certain circumstances in patients with PD-L1 levels of 1% to 49%. Previously, the NCCN Panel deleted TMB as an emerging immune biomarker based on clinical trial data and other issues (see TMB in this Discussion). 171 The NCCN Guidelines do not recommend measurement of TMB levels before deciding whether to use nivolumab plus ipilimumab regimens or to use other ICIs, such as pembrolizumab. 171 eckMate 9LA, a phase 3 randomized trial, compared first-line nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic nonsquamous or squamous NSCLC, regardless of PD-L1 expression levels, who had PS 0 to 1 and no EGFR mutations or ALK rearrangements. 855 For metastatic nonsquamous NSCLC, the chemotherapy was pemetrexed with either cisplatin or carboplatin; for metastatic squamous NSCLC, the chemotherapy was paclitaxel with carboplatin. Updated data show that the median overall survival with nivolumab plus ipilimumab plus chemotherapy was 15.8 months (95% CI, 13.9-19.7) versus 11.0 months (95% CI, 9.5-12.7) with chemotherapy alone regardless of histology or PD-L1 expression levels (HR, 0.72; 95% CI, 0.61-0.86). 856 In patients receiving nivolumab plus ipilimumab plus NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-52 chemotherapy, the 2-year overall survival rate was 38% versus 26% in those receiving chemotherapy alone. Based on histology or PD-1 levels, overall survival was also significantly different in patients receiving nivolumab plus chemotherapy compared with chemotherapy alone. The overall response rate was 38% with nivolumab plus ipilimumab plus chemotherapy versus 25% with chemotherapy alone.

Serious grade 3 or 4 adverse events occurred in 25.4% of patients receiving nivolumab plus ipilimumab plus chemotherapy versus 15% in those receiving chemotherapy alone. The death rate was 2% in each arm (nivolumab plus ipilimumab plus chemotherapy: 7/358; chemotherapy alone: 6/349). In the nivolumab plus ipilimumab plus chemotherapy arm, treatment-related deaths were from acute renal failure due to chemotherapy, thrombocytopenia, pneumonitis, hepatic toxicity, hepatitis, diarrhea, sepsis, and acute renal insufficiency; treatment-related deaths in the chemotherapy arm were from anemia, pancytopenia, febrile neutropenia, respiratory failure, pulmonary sepsis, and sepsis. The most common treatment-related adverse events (≥15%) were nausea, anemia, asthenia, and diarrhea.

The NCCN NSCLC Panel recommends nivolumab plus ipilimumab plus chemotherapy (category 1; other recommended) as first-line therapy options for eligible patients with metastatic NSCLC based on clinical trial data and FDA approval. 855, 857 For metastatic nonsquamous NSCLC, the recommended chemotherapy is pemetrexed with either cisplatin or carboplatin; for metastatic squamous NSCLC, the recommended chemotherapy is paclitaxel with carboplatin. Nivolumab plus ipilimumab plus chemotherapy is recommended for patients with metastatic NSCLC, regardless of PD-L1 levels; negative test results for actionable driver mutations; and no contraindications to PD-1/PD-L1 inhibitors. Maintenance therapy with nivolumab plus ipilimumab is also recommended. Combination therapy with nivolumab plus ipilimumab may be used as a first-line or subsequent therapy option, although it is not a preferred option, in eligible patients with actionable driver mutations as shown in the algorithm. Targeted therapy is a preferred first-line therapy option for patients with actionable driver mutations, except for EGFR exon 20 mutations or KRAS mutations. The panel has preference stratified the systemic therapy regimens and voted that first-line therapy with nivolumab plus ipilimumab plus chemotherapy is an "other recommended" first-line therapy option for eligible patients with metastatic NSCLC regardless of PD-L1 expression levels or histology.

CheckMate-057, a phase 3 randomized trial, compared nivolumab versus docetaxel as subsequent therapy for patients with metastatic nonsquamous NSCLC and disease progression on or after first-line chemotherapy. 358 Median overall survival was 12.2 months (95% CI, 9.7-15.0) for patients receiving nivolumab compared with 9.4 months (95% CI, 8.1-10.7) for docetaxel (HR, 0.73; 95% CI, 0.59-0.89; P = .002). 358 The median duration of response was 17.2 months with nivolumab compared with 5.6 months for docetaxel. At 18 months, the overall survival rate was 39% (95% CI, 34%-45%) with nivolumab compared with 23% (95% CI, 19%-28%) for docetaxel. Fewer grade 3 to 5 adverse events were reported for nivolumab (10%) when compared with docetaxel (54%). Although many patients with metastatic nonsquamous NSCLC benefit from nivolumab, those whose tumors have PD-L1 staining of 1% to 10% or more have an overall survival of 17 to 19 months compared with 8 to 9 months for docetaxel. For patients who did not have PD-L1 expression, there was no difference in overall survival for nivolumab versus docetaxel; however, nivolumab was associated with a longer duration of response and fewer side effects.

CheckMate-017, a phase 3 randomized trial, compared nivolumab versus docetaxel as subsequent therapy for patients with metastatic NSCLC NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer

MS-53

squamous cell and disease progression on or after first-line chemotherapy. 362 Median overall survival was 9.2 months (95% CI, 7.3-13.3) for nivolumab compared with 6.0 months (95% CI, 5.1-7.3) for docetaxel (HR, 0.59; 95% CI, 0.44-0.79; P < .001). 362 Patients had a response rate of 20% with nivolumab compared with 9% for docetaxel (P = .008). PD-L1 expression was not associated with response to nivolumab in patients with squamous cell NSCLC. Fewer grade 3 to 4 adverse events were reported with nivolumab (7%) compared with docetaxel (55%). No patients died in the nivolumab arm versus three deaths in the docetaxel arm.

In a long-term analysis of CheckMate-057 and CheckMate-017, 2-year survival and durable responses were increased in patients with advanced NSCLC receiving nivolumab when compared with docetaxel. 858 For patients with nonsquamous NSCLC, 2-year survival was 29% (95% CI, 24%-34%) with nivolumab versus 16% (95% CI, 12%-20%) with docetaxel. For those with squamous NSCLC, 2-year survival was 23% (95% CI, 16%-30%) with nivolumab versus 8% (95% CI, 4%-13%) with docetaxel. Fewer severe treatment-related adverse events were reported with nivolumab compared with docetaxel (grade 3-4, 10% vs. 55%). At 5 years, overall survival was 13.4% for patients receiving nivolumab versus 2.6% for those receiving docetaxel. 17

If patients have not previously received a PD-1/PD-L1 inhibitor, the NCCN NSCLC Panel recommends single-agent nivolumab (category 1; preferred) as a subsequent therapy option for patients with metastatic nonsquamous or squamous NSCLC and disease progression on or after first-line chemotherapy based on clinical trial data and FDA approval. 358, 362, 858, 859 Testing for PD-L1 is not required for prescribing nivolumab but may provide useful information. 370 The NCCN NSCLC Panel recommends nivolumab, atezolizumab, or pembrolizumab as preferred subsequent therapy options (category 1 for all) based on improved overall survival rates, longer duration of response, and fewer adverse events when compared with cytotoxic chemotherapy. 358, 362, 835, 860 If patients have progressed on a PD-1/PD-L1 inhibitor, then using a PD-1/PD-L1 inhibitor is not recommended.

2] [863] [864] [865] [866] [867] Intravenous high-dose corticosteroids should be administered for patients with immune-mediated adverse events based on the severity of the reaction (see the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities, available at www.NCCN.org).

Nivolumab should be discontinued for patients with severe or life-threatening pneumonitis or myocarditis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information).

Pembrolizumab

Pembrolizumab is a humanized immunoglobulin G4 monoclonal antibody that inhibits PD-1 receptors, which improves antitumor immune response. 362, 138 The FDA has approved a companion diagnostic biomarker test for assessing PD-L1 expression and determining which patients are eligible for pembrolizumab therapy. Although it is not an optimal biomarker, PD-L1 expression is currently the best available biomarker to assess whether patients are candidates for pembrolizumab. 366, 367 PD-L1 expression is continuously variable and dynamic; thus, a cutoff value for a positive result is artificial. Patients with PD-L1 expression levels just below and just above 50% will probably have similar responses. 366 Unique anti-PD-L1 IHC assays have been developed for each one of the different ICIs currently available. 366, 370 The definition of a positive PD-L1 test result varies depending on which biomarker assay is used. 370 mune-mediated adverse events may occur with ICIs, including pembrolizumab. 861, 863, 868 For patients with immune-mediated adverse NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-54 events, intravenous high-dose corticosteroids should be administered based on the severity of the reaction (see the NCCN Guidelines for the Management of Immunotherapy-Related Toxicities, available at www.NCCN.org). Pembrolizumab should also be discontinued for patients with severe or life-threatening pneumonitis or myocarditis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information). The following sections describe the use of pembrolizumab in eligible patients with metastatic NSCLC. The use of adjuvant pembrolizumab following adjuvant chemotherapy in eligible patients with completely resected NSCLC is described in a different section (see Surgery Followed by Adjuvant Therapy in this Discussion). 751

First-Line Monotherapy KEYNOTE-024, a phase 3 randomized trial, compared single-agent pembrolizumab versus platinum-based chemotherapy as first-line therapy for patients with advanced nonsquamous or squamous NSCLC and PD-L1 expression levels of 50% or more, but without EGFR mutations or ALK rearrangements. 9, 12, 138 At 6 months, the rate of overall survival was 80.2% with pembrolizumab monotherapy versus 72.4% with chemotherapy (HR for death, 0.60; 95% CI, 0.41-0.89; P = .005). Reponses were higher for pembrolizumab than for chemotherapy (44.8% vs. 27.8%). 138 An updated analysis of KEYNOTE-024 showed that median overall survival was 26.3 months (95% CI, 18.3 months-40.4) with pembrolizumab monotherapy compared with 13.4 months (95% CI, 9.4-18.3 months) with chemotherapy (HR, 0.62; 95% CI, 0.48-0.81). 12 The 5-year overall survival rate was 31.9% for pembrolizumab and 16.3% for chemotherapy. Fewer severe treatment-related adverse events (grades 3-5) were reported in patients receiving pembrolizumab monotherapy compared with those receiving chemotherapy (31.2% vs. 53.3%). 9 reatment-related deaths occurred in 1.3% (2/154) of patients receiving pembrolizumab monotherapy versus 2% (3/150) of patients receiving chemotherapy alone.

KEYNOTE-042, a phase 3 randomized trial, compared single-agent pembrolizumab versus platinum-based chemotherapy as first-line therapy for patients with advanced nonsquamous or squamous NSCLC and PD-L1 expression levels of 1% or more, but without EGFR mutations or ALK rearrangements. 832 Overall survival was 20.0 months (95% CI, 15.4-24.9) in patients with PD-L1 levels of 50% or more who received single-agent pembrolizumab compared with 12.2 months (95% CI, 10.4-14.2) with chemotherapy (HR, 0.69; 95% CI, 0.56-0.85; P = .0003). In a subgroup analysis, overall survival was similar in patients with PD-L1 levels of 1% to 49% who received single-agent pembrolizumab (13.4 months; 95% CI, 10.7-18.2) compared with chemotherapy (12.1 months; 95% CI, 11.0-14.0) (HR, 0.92; 95% CI, 0.77-1.11).

Long-term data from KEYNOTE-001 show that 5-year survival for patients with metastatic NSCLC is approximately 23% for patients who received first-line pembrolizumab monotherapy; for patients with PD-L1 levels of 50% or more, 5-year overall survival is about 29.6%. 19 Median overall survival was 22.3 months (95% CI, 17.1-32.3) for treatment-naïve patients. For patients with metastatic NSCLC receiving chemotherapy alone, 5-year overall survival is approximately 6%. 19 The NCCN NSCLC Panel recommends IHC testing for PD-L1 expression (category 1) before first-line treatment in all patients with metastatic NSCLC based on the efficacy of pembrolizumab (see Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC). 365 he panel recommends single-agent pembrolizumab (category 1; preferred) as a first-line therapy option for eligible patients with advanced nonsquamous or squamous NSCLC, PD-L1 expression levels of 50% or more, no contraindications to PD-1 or PD-L1 inhibitors, and negative test results for actionable driver mutations based on clinical trial data and FDA NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-55 approval. 138, 832, 869 Maintenance therapy with pembrolizumab is also a recommended option in this setting (category 1). The NCCN NSCLC Panel has preference stratified the ICI regimens and decided that pembrolizumab, atezolizumab, and cemiplimab-rwlc (all are category 1) are all preferred single-agent options for eligible patients with metastatic NSCLC. 138, 361, 832, 842 For patients who have disease progression on first-line therapy with single-agent pembrolizumab, subsequent therapy with initial cytotoxic systemic therapy regimens (eg, carboplatin plus paclitaxel) is recommended by the NCCN NSCLC Panel.

The NCCN NSCLC Panel also recommends single-agent pembrolizumab as a first-line therapy option (category 2B; useful in certain circumstances) for eligible patients with metastatic NSCLC, PD-L1 expression levels of 1% to 49%, no contraindications to PD-1 or PD-L1 inhibitors, and negative test results for actionable driver mutations based on clinical trial data and FDA approval. 832, 869 The NCCN NSCLC Panel decided that single-agent pembrolizumab is a useful intervention in patients with PD-L1 levels of 1% to 49% when there are contradictions to combination chemotherapy (category 2B; useful in certain circumstances). In patients with PD-L1 levels of 1% to 49%, the HR of 0.92 is not statistically or clinically significant for pembrolizumab monotherapy versus chemotherapy; therefore, pembrolizumab plus chemotherapy is recommended (category 1; preferred) if patients can tolerate the therapy.

First-Line Combination Therapy

KEYNOTE-189, a phase 3 randomized trial, compared pembrolizumab added to carboplatin (or cisplatin) plus pemetrexed versus chemotherapy in patients with metastatic nonsquamous NSCLC. 711 Most patients received pembrolizumab plus carboplatin plus pemetrexed (72% [445/616]) in this trial, but some received pembrolizumab plus cisplatin plus pemetrexed (28% [171/616] ); patients did not have EGFR mutations or ALK rearrangements. The estimated rate of overall survival at one year was 69.2% (95% CI, 64.1%-73.8%) in patients receiving pembrolizumab plus chemotherapy versus 49.4% (95% CI, 42.1%-56.2%) for chemotherapy alone (HR for death, 0.49; 95% CI, 0.38-0.64; P < .001) after a median follow-up of 10.5 months. Overall survival was improved regardless of PD-L1 expression levels; TMB did not predict for response. 870 For the pembrolizumab plus chemotherapy group, median PFS was 8.8 months (95% CI, 7.6-9.2) compared with 4.9 months (95% CI, 4.7-5.5) for chemotherapy alone (HR for disease progression or death, 0.52; 95% CI, 0.43-0.64; P < .001). Grade 3 or higher adverse events occurred at a similar rate in both arms (pembrolizumab plus chemotherapy, 67.2% vs. chemotherapy, 65.8%).

The NCCN NSCLC Panel recommends pembrolizumab plus pemetrexed and either carboplatin or cisplatin (category 1; preferred) as a first-line therapy option for eligible patients with metastatic nonsquamous NSCLC (ie, adenocarcinoma, large cell carcinoma) or NSCLC NOS based on clinical trial data and FDA approval. 711, 712 The NCCN NSCLC Panel has preference stratified the systemic therapy regimens and decided that these pembrolizumab plus chemotherapy regimens are preferred first-line options for eligible patients with metastatic nonsquamous NSCLC. These pembrolizumab plus chemotherapy regimens are recommended (category 1; preferred) as first-line therapy options for patients with metastatic nonsquamous NSCLC, no contraindications to PD-1 or PD-L1 inhibitors, and negative test results for actionable driver mutations, regardless of their PD-L1 expression levels. Maintenance therapy with pembrolizumab plus pemetrexed is also a recommended option (category 1) in this setting.

Combination therapy with pembrolizumab plus pemetrexed and either carboplatin or cisplatin may be used as a first-line or subsequent therapy option in eligible patients with actionable driver mutations as shown in the algorithm. However, targeted therapy is a preferred first-line therapy option for patients with actionable driver mutations, except for EGFR exon 20

NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-56 mutations or KRAS mutations. For patients with metastatic NSCLC and disease progression on combination therapy with PD-1/PD-L1 inhibitors plus chemotherapy, subsequent therapy with docetaxel (with or without ramucirumab), pemetrexed (nonsquamous only), albumin-bound paclitaxel, or gemcitabine is recommended if not previously given.

KEYNOTE-407, a phase 3 randomized trial, compared pembrolizumab added to carboplatin and either paclitaxel or albumin-bound paclitaxel in patients with metastatic squamous cell NSCLC; 32% of patients received albumin-bound paclitaxel (also known as nab-paclitaxel). 871 Median overall survival was 15.9 months (95% CI, 13.2-not reached) with pembrolizumab plus chemotherapy versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR for death, 0.64; 95% CI, 0.49-0.85; P < .001). Patients receiving pembrolizumab plus chemotherapy had an overall response rate of 57.9% compared to 38.4% for those receiving chemotherapy alone. Only 38% of patients had a PD-L1 tumor proportion score (TPS) less than 1%. Grade 3 or higher adverse events were similar in both groups (pembrolizumab plus chemotherapy, 69.8% vs. chemotherapy alone, 68.2%). Because of adverse events, more patients discontinued treatment with pembrolizumab plus chemotherapy than with chemotherapy (13.3% vs. 6.4%, respectively). A pooled analysis of three randomized trials (ie, KEYNOTE-189, KEYNOTE-407, KEYNOTE-021) in patients with metastatic NSCLC and PD-L1 levels less than 1% showed that overall survival was improved in those receiving pembrolizumab plus chemotherapy versus chemotherapy alone (HR, 0.63; 95% CI, 0.50-0.79). 872 e NCCN NSCLC Panel recommends pembrolizumab plus carboplatin and either paclitaxel or albumin-bound paclitaxel (category 1; preferred) as a first-line therapy option for patients with metastatic squamous cell NSCLC based on clinical trial data and FDA approval. 871, 873 Maintenance therapy with pembrolizumab is also a recommended option in this setting (category 1). The NCCN NSCLC Panel has preference stratified the systemic therapy regimens and decided that these pembrolizumab plus chemotherapy regimens are preferred for eligible patients with metastatic squamous cell NSCLC. These pembrolizumab plus chemotherapy regimens are recommended (category 1; preferred) as first-line therapy options for patients with metastatic squamous cell NSCLC, no contraindications to PD-1 or PD-L1 inhibitors, and negative test results for actionable driver mutations, regardless of their PD-L1 expression levels. The panel does not recommend pembrolizumab plus cisplatin with either paclitaxel or albumin-bound paclitaxel, because there are fewer data for this regimen. Combination therapy with pembrolizumab plus carboplatin and either paclitaxel or albumin-bound paclitaxel may be used as a first-line or subsequent therapy option in eligible patients with actionable driver mutations as shown in the algorithm. However, targeted therapy is a preferred first-line therapy option for patients with actionable driver mutations, except for EGFR exon 20 mutations or KRAS mutations.

Subsequent Therapy KEYNOTE-010, a phase 3 randomized trial, assessed single-agent pembrolizumab in patients with previously treated advanced nonsquamous and squamous NSCLC who were PD-L1 positive (≥1%); most patients either currently or previously smoked cigarettes. 835 There were three arms in this trial: pembrolizumab at 2 mg/kg, pembrolizumab at 10 mg/kg, and docetaxel at 75 mg/m² every 3 weeks. The median overall survival was 10.4 months for the lower dose of pembrolizumab, 12.7 months for the higher dose, and 8.5 months for docetaxel. Overall survival was significantly longer for both doses of pembrolizumab versus docetaxel (pembrolizumab 2 mg/kg: HR, 0.71; 95% CI, 0.58-0.88; P = .0008) (pembrolizumab 10 mg/kg: HR, 0.61; CI, 0.49-0.75; P < .0001). For those patients with at least 50% PD-L1 expression in tumor cells, overall survival was also significantly longer at either dose of pembrolizumab when compared with docetaxel (pembrolizumab 2 mg/kg: 14.9 vs. 8. Long-term data from KEYNOTE-010 show that 5-year survival for patients with metastatic NSCLC is approximately 15.6% for patients who received subsequent pembrolizumab monotherapy versus 6.5% for those receiving docetaxel. For patients with PD-L1 levels of 50% or more, 5-year overall survival was about 25% for patients receiving pembrolizumab versus 8.2% for those receiving docetaxel, respectively. 11

If patients have not previously received a PD-1/PD-L1 inhibitor, the NCCN NSCLC Panel recommends single-agent pembrolizumab (category 1; preferred) as a subsequent therapy option for patients with metastatic nonsquamous or squamous NSCLC and PD-L1 expression levels of 1% or more based on clinical trial data and FDA approval. 835, 874, 875 Nivolumab and atezolizumab are also recommended subsequent therapy options in this setting (category 1; preferred). Testing for PD-L1 expression levels is recommended before prescribing pembrolizumab monotherapy (see Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC).

Tremelimumab-actl and Durvalumab

Tremelimumab-actl is a monoclonal IgG2 antibody that enhances immune function by inhibiting CTLA-4 and preventing interactions with CD80/CD86; CTLA-4 inhibits T-cell activation. 876 Durvalumab is a human immunoglobulin G1 monoclonal antibody that inhibits PD-L1 binding to PD-1 and CD80, thus increasing immune function (see Durvalumab in this Discussion). Immune-mediated adverse events may occur with ICIs, including tremelimumab-actl and durvalumab. 876 For patients with immune-mediated adverse events, intravenous high-dose corticosteroids should be administered based on the severity of the reaction.

Tremelimumab-actl and durvalumab should be permanently discontinued for patients with grades 2, 3, or 4 myocarditis and should be discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information).

POSEIDON, a phase 3 randomized trial, assessed three different first-line treatment arms in 1013 patients with metastatic NSCLC who did not have EGFR or ALK mutations. 877 The treatment arms included 1) tremelimumab plus durvalumab plus platinum-based chemotherapy; 2) durvalumab plus platinum-based chemotherapy; and 3) platinum-based chemotherapy alone; there were 675 patients in arms 1 and 3. The chemotherapy regimens included 1) tremelimumab plus durvalumab plus albumin-bound paclitaxel plus carboplatin for either nonsquamous NSCLC or squamous cell histology; 2) tremelimumab plus durvalumab plus pemetrexed plus either cisplatin or carboplatin for nonsquamous NSCLC; or 3) tremelimumab plus durvalumab plus gemcitabine plus either cisplatin or carboplatin for squamous cell histology. Most patients received the pemetrexed regimen. Most patients either currently smoked cigarettes (25%) or had previously smoked (57%). The median overall survival was 14 months (95% CI, 11.7-16.1) in patients receiving tremelimumab plus durvalumab plus chemotherapy versus 11.7 months (95% CI, 10.5-13.1) in patients receiving chemotherapy alone (HR, 0.77; 95% CI, 0.65-0.92; P=.003). Subgroup analysis showed that overall survival was similar between the groups for squamous cell histology and other subgroups.

In patients receiving tremelimumab plus durvalumab plus chemotherapy, grade 3 or 4 adverse events included neutropenia, anemia, leukopenia, NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-58 lymphocytopenia, increased lipase levels, hyponatremia, and thrombocytopenia. 877 Common serious adverse events in patients receiving tremelimumab plus durvalumab plus chemotherapy included pneumonia (11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%), pyrexia (2.4%), and febrile neutropenia (2.1%). Grade 3 to 4 immune-related adverse events occurred in 10% of patients receiving tremelimumab plus durvalumab plus chemotherapy versus 1.5% of those receiving chemotherapy alone. Treatment-related deaths occurred in 3.3% (11/330) of patients receiving tremelimumab plus durvalumab plus chemotherapy and 2.4% (8/333) receiving chemotherapy alone. An exploratory analysis suggests that tremelimumab plus durvalumab plus chemotherapy may be beneficial in patients with metastatic NSCLC who have STK11, KEAP1, or KRAS mutations; however, the sample size was too small to yield definitive conclusions. 878 e NCCN NSCLC Panel recommends tremelimumab-actl plus durvalumab plus platinum-based chemotherapy regimens as first-line therapy options for eligible patients with metastatic NSCLC-regardless of histology or PD-L1 levels, and with negative test results for actionable driver mutations-based on clinical trial data and FDA approval; maintenance therapy with durvalumab with or without pemetrexed is also recommended. 877 Combination therapy with tremelimumab-actl plus durvalumab plus platinum-based chemotherapy may be used as a first-line or subsequent therapy option, although it is not a preferred option, in eligible patients with actionable driver mutations as shown in the algorithm. Targeted therapy is a preferred first-line therapy option for patients with actionable driver mutations, except for EGFR exon 20 mutations or KRAS mutations. The category assignment (ie, category 1, 2A, or 2B) for the tremelimumab-actl plus durvalumab plus platinum-based chemotherapy regimens varies depending on the histology, chemotherapy, and PD-L1 levels. The NCCN Panel has preference stratified the tremelimumab-actl plus durvalumab plus chemotherapy regimens and decided that they are other recommended first-line therapy options for eligible patients with metastatic NSCLC based on clinical trial data. 877

Maintenance Therapy

Maintenance therapy refers to therapy given for patients with advanced NSCLC after 4 to 6 cycles of first-line therapy. 879 Patients are only candidates for maintenance therapy if their tumors have responded to their previous treatment or they have stable disease and their tumors have not progressed. Continuation maintenance therapy refers to the use of at least one of the agents that was given in the first-line regimen. Switch maintenance therapy refers to the initiation of a different agent that was not included as part of the first-line regimen. Selection of appropriate maintenance therapy depends on several factors, such as histologic type, presence of mutations or gene fusions, and PS. Maintenance therapy is recommended in the NCCN Guidelines for select patients with tumor response or stable disease and is not recommended for all patients; it is not recommended for patients with PS 3 to 4 or those with progression (see the NCCN Guidelines for NSCLC). 880 Monitoring is recommended during maintenance therapy with response assessment with CT, with or without contrast, of known or high-risk sites of disease every 6 to 12 weeks.

Continuation Maintenance Therapy

For continuation maintenance therapy, select agents (which were initially given with first-line therapy) may be continued until evidence of disease progression or unacceptable toxicity based on the design of the clinical trials that led to their approval. This section mainly discusses continuation maintenance with chemotherapy; continuation maintenance with ICIs is discussed in another section (see Immune Checkpoint Inhibitors in this Discussion). Use of continuation maintenance therapy depends on several factors, such as whether the patient had minimal toxicity during treatment.

NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-59

A drug vacation may be more appropriate for some patients. 810 Some clinicians feel that continuation maintenance therapy is only appropriate for select patients, because it has only been shown to improve overall survival or quality of life for a few agents and not all agents, although it has been shown to improve PFS. 808, 810 In addition, maintenance therapy has not been shown to be superior to subsequent therapy, which is initiated at disease progression. A phase 3 randomized trial suggests that conventional cytotoxic agents should not be continued beyond 4 to 6 cycles of therapy; however, many patients assigned to a longer duration of therapy did not receive the planned number of cycles (see Maintenance Therapy in this Discussion). 807, 808 RAMOUNT, a phase 3 randomized trial, reported that continuation maintenance therapy with pemetrexed slightly increased PFS when compared with placebo (4.1 vs. 2.8 months). 881 Updated results from PARAMOUNT reported that continuation maintenance therapy with pemetrexed also improves overall survival (13.9 vs. 11.0 months). 882 [883] POINTBREAK, a phase 3 randomized trial, assessed bevacizumab plus carboplatin plus pemetrexed compared with bevacizumab plus carboplatin plus paclitaxel in patients with metastatic NSCLC; patients received maintenance therapy with either bevacizumab plus pemetrexed or bevacizumab alone. 812 PFS was 6 months with pemetrexed plus carboplatin plus bevacizumab versus 5.6 months with paclitaxel plus carboplatin plus bevacizumab. 812 It is important to note that the pemetrexed-based arm was associated with less toxicity (eg, less neurotoxicity, less neutropenia, less hair loss) than the paclitaxel-based arm. AVAPERL, a phase 3 randomized trial, assessed maintenance therapy with bevacizumab plus pemetrexed versus bevacizumab alone in patients with advanced nonsquamous NSCLC; the initial regimen was bevacizumab plus cisplatin plus pemetrexed. 884, 885 An updated analysis reported that overall survival was 17.1 months with bevacizumab plus pemetrexed maintenance versus 13.2 months with bevacizumab alone (HR, 0.87; 95% CI, 0.63-1.21; P = .29). 884 e NCCN NSCLC Panel recommends continuation maintenance therapy with bevacizumab plus pemetrexed in patients with nonsquamous NSCLC who initially received bevacizumab plus pemetrexed plus platinum regimen based on clinical trial data. 884, 885 Single-agent bevacizumab (category 1) may be continued beyond 4 to 6 cycles of initial therapy (ie, platinum-doublet chemotherapy given with bevacizumab) in patients with nonsquamous NSCLC. 806, 883, 886 7] [848] [849] Therefore, if a bevacizumab biosimilar was initially used as part of first-line combination therapy, the biosimilar should be continued as maintenance therapy in eligible patients.

IFCT-GFPC 0502, a phase 3 randomized trial, compared using maintenance therapy with either gemcitabine or erlotinib after first-line therapy with cisplatin-gemcitabine in patients with advanced NSCLC. Continuation maintenance therapy with single-agent gemcitabine was reported to increase PFS to a greater extent (3.8 months) than switch maintenance therapy with erlotinib (2.9 months) when compared with observation (1.9 months). 742, 887 A phase 3 randomized trial from the CECOG assessed continuation maintenance therapy with gemcitabine versus best supportive care after an initial regimen of cisplatin plus gemcitabine. 888 The data showed a slight difference in PFS but no difference in overall survival (13 vs. 11 months, respectively; P = .195).

MS-60

The NCCN NSCLC Panel recommends gemcitabine (category 2B) as continuation maintenance therapy regardless of histology in patients with metastatic NSCLC, negative test results for actionable driver mutations, and PD-L1 expression less than 1%.

Switch Maintenance Therapy

265, 278 Amivantamab-vmjw in combination with carboplatin and pemetrexed is a category 1 and preferred treatment option for patients with multiple lesions (if nonsquamous). Systemic therapy options such as chemotherapy (NSCL-K 1 of 5 or NSCL-K 2 of 5 in the NCCN Guidelines for NSCLC) are also recommended for patients with symptomatic systemic progression. Data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is less effective in EGFR exon 19 deletion or exon 21 L858R NSCLC, irrespective of PD-L1 expression. 358, 827, 834, 835 finitive local therapy has a role in the treatment of metastatic EGFRpositive NSCLC. For patients with a limited number of initial sites of metastasis (oligometastasis; limited number is not universally defined, If the patient experiences disease progression after treatment with osimertinib as well as chemotherapy with pemetrexed and either cisplatin or carboplatin then the subsequent therapy options listed on NSCL-K 4 of 5 in the NCCN Guidelines for NSCLC (such as chemotherapy) can be considered.

Clinical Data: NSCLC with EGFR S768I, L861Q, and/or G719X Mutations

For patients with the less common EGFR S768I, L861Q, and/or G719X mutations, treatment recommendations are based on non-randomized studies. Afatinib is a second-generation oral TKI that irreversibly inhibits the ErbB/HER family of receptors including EGFR and HER2. 1043, 1044 atinib is approved by the FDA for the first-line treatment of metastatic NSCLC whose tumors have some EFGR mutations. Retrospective data suggest that the clinical response to osimertinib versus afatinib may differ, depending on the exact EGFR mutation identified; for example, NSCLC with EGFR L861Q may be more likely to respond to osimertinib than afatinib.

Clinical Data: NSCLC with EGFR Exon 20 Insertion Mutation

For patients with NSCLC and EGFR exon 20 insertions, treatment with early-generation EGFR TKIs has generally not been associated with disease response. 178, 179, 257 Patients with EGFR exon 20 insertion-positive metastatic NSCLC have frequently been treated with first-line platinum-based chemotherapy. 297, 299 The response rates (0%-25%) to immunotherapy regimens vary, depending on the specific EGFR exon 20 insertion mutation. 179, 302 Mobocertinib, an EGFR TKI developed specifically for patients with EGFR exon 20 insertions, was previously granted accelerated approval by the FDA in the United States. However, mobocertinib was withdrawn from the U.S. market in 2023 and is no longer recommended as a subsequent treatment option by the panel based on data from the phase 3 EXCLAIM-2 trial, which compared firstline mobocertinib to platinum-based chemotherapy, as the primary endpoint was not met. 1048,1049

Single-agent amivantamab-vmjw is FDA-approved for the treatment of adults with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, whose disease has progressed on or after platinumbased chemotherapy. 1050 CHRYSALIS, a phase 1 study, assessed subsequent therapy with amivantamab-vmjw in 81 patients with EGFR exon 20 insertion-positive metastatic NSCLC who had received one or more previous lines of therapy. 178 The overall response rate was 40%, with 3 complete responses. The median PFS was 8.3 months. Common treatment-related AEs included cutaneous reactions, infusion-related reactions, and paronychia. The most common grade 3 to 4 AEs included hypokalemia as well as pulmonary embolism, neutropenia, diarrhea, and rash. Eight deaths were reported in the safety assessment (7%).

Amivantamab-vmjw in combination with carboplatin and pemetrexed is also approved by the FDA for the treatment of adults with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. 1050 PAPILLON, a phase 3 randomized trial, assessed the efficacy and safety of first-line amivantamab-vmjw plus chemotherapy (pemetrexed and carboplatin) versus chemotherapy alone in 308 patients with advanced NSCLC with EGFR exon 20 insertions who had not previously received systemic therapy. 1051 The median PFS was longer in the amivantamab-vmjw plus chemotherapy group than in the chemotherapy alone group (11.4 months vs. 6.7 months; HR, 0.40; P < .001). Based on the interim OS analysis, the HR for amivantamab-vmjw plus chemotherapy versus chemotherapy alone was 0.67 (P = .11). The most common AEs reported with amivantamab-vmjw plus chemotherapy were hematologic effects and skin-related EGFR-related toxic events (eg, rash, paronychia, dermatitis acneiform).

NCCN Recommendations: Advanced or Metastatic NSCLC with EGFR Exon 20 Insertion Mutation (NSCL-25)

The monotherapy is associated with low activity in NSCLC with EGFR alterations. 184, 1052 e NCCN NSCLC Panel recommends amivantamab-vmjw as a subsequent therapy option for patients with EGFR exon 20 insertion mutation-positive advanced or metastatic NSCLC and disease progression who were not previously treated with amivantamab-vmjw.

For patients whose disease progressed after first-line treatment with amivantamab-vmjw in combination with chemotherapy, subsequent therapy options listed on NSCL-K 4 of 5 in the NCCN Guidelines for NSCLC are recommended.

NSCLC with KRAS G12C Mutation

KRAS is a protein with intrinsic GTPase activity that is commonly mutated in lung cancers; these mutations can result in unregulated signaling through the MAP/ERK pathway. 1053, 1054 KRAS G12C is an activating mutation that results in increased activation of downstream oncogenic pathways. 317 Data suggest that approximately 25% of patients with adenocarcinomas in a North American population have a KRAS mutation, the most common mutation in this population. 118, 175, 211, 307, 308 ome, but not all, KRAS mutations are associated with cigarette smoking, unlike many of the other actionable mutations (eg, EGFR mutations, ALK rearrangements). 309, 1055 inical Data

Targeted therapies are not recommended as first-line treatment options for advanced or metastatic NSCLC with a KRAS G12C mutation, unlike most other actionable alterations. Data indicate that patients with advanced or metastatic NSCLC and KRAS mutations are likely to derive benefit from immunotherapy-based regimens in the first-line setting. 1022,1023 Additionally, one study reported a positive association between PFS and PD-L1 expression in patients with advanced NSCLC and KRAS mutations who received ICI monotherapy. 184 o targeted therapies are available as subsequent therapy options for NSCLC with KRAS G12C mutations. Adagrasib and sotorasib are oral small molecules that target KRAS G12C and have both been granted accelerated approval by the FDA for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic NSCLC who received at least one prior systemic therapy. 315, 1056, 1057 phase 2 study assessed sotorasib as subsequent therapy in 126 patients with KRAS G12C mutation-positive advanced NSCLC who had previously received platinum-based chemotherapy (± PD-1 or PD-L1 immunotherapy). 317 The median OS was 12.5 months and the objective response rate was 37.1%; a complete response was reported in 4 patients. Treatment-related grade 3 AEs occurred in 19.8% of patients, including diarrhea, and increased alanine transaminase (ALT) and aspartate transferase (AST) levels; one treatment-related grade 4 event occurred (dyspnea and pneumonitis).

A phase 2 study evaluated adagrasib as subsequent therapy in 116 patients with KRAS G12C mutation-positive advanced NSCLC who had previously received at least one platinum-based chemotherapy and immunotherapy. 315 The median OS was 12.6 months and the objective response rate was 42.9%. The intracranial response rate was 33.3%. Grade 3 or higher AEs occurred in 44.8% of patients, including anemia, pneumonia, dyspnea, acute kidney injury, hyponatremia, fatigue, nausea, and increased ALT and AST levels. There were two deaths (cardiac failure and pulmonary hemorrhage).

A randomized phase 3 trial compared subsequent therapy with sotorasib to treatment with docetaxel in 345 patients with KRAS G12C mutation-positive advanced NSCLC who had previously received

platinum-based chemotherapy plus a PD-1 or PD-L1 inhibitor. 316 Median PFS was 5.6 months in patients receiving sotorasib compared with 4.5 months in those receiving docetaxel (HR, 0.66; P = .0017). There was no reported difference in OS.

NCCN Recommendations (NSCL-26)

The NCCN NSCLC Panel recommends using PD-L1 level to determine the appropriate first-line systemic therapy regimen (such as immunotherapy and/or chemotherapy) for patients with advanced or metastatic NSCLC with KRAS G12C mutations. See NSCL-37 and NSCL-38 in the full NCCN Guidelines for NSCLC at www.NCCN.org for treatment recommendations based on PD-L1 level.

The panel recommends sotorasib or adagrasib as subsequent therapy options for patients who experience disease progression after treatment with first-line systemic therapy. Sotorasib or adagrasib may also be used as third-line therapy or beyond if the patient has not previously received a KRAS G12C-targeted therapy. The panel notes that switching between agents with a similar mechanism of action at the time of progression is not recommended.

NSCLC with ALK Rearrangement

About 5% of patients with NSCLC have ALK gene rearrangements leading to gene fusions. 120 These events can result in dysregulation and inappropriate ALK signaling. 1058

Clinical Data

0] 1059 Both crizotinib and ceritinib are FDA-approved for the treatment of adults with ALKpositive metastatic NSCLC. 1060,1061 Subsequent trials have compared newer agents to crizotinib.

Alectinib is an ALK inhibitor that is approved by the FDA for the treatment of patients with ALK-positive metastatic NSCLC. Brigatinib is an ALK inhibitor that is approved by the FDA for the treatment of adults with ALK-positive metastatic NSCLC. ALTA-1L, a phase 3 randomized trial, assessed brigatinib versus crizotinib as first-line therapy in 275 patients with ALK-positive metastatic NSCLC. 221 At the first interim analysis, PFS rate was higher in patients receiving brigatinib (67%) than in those receiving crizotinib (43%) (HR, 0.49; P < .001). The rate of intracranial response was also higher with brigatinib (78%) versus crizotinib (29%). 221 At the second interim analysis (24.9 months of median follow-up), brigatinib continued to show improved blinded independent review committee (BIRC)-assessed PFS when compared with crizotinib (48% vs. 26%; HR, 0.49; P < .0001). 1067 After 3 years, the PFS was 43% for brigatinib versus 19% for crizotinib (HR, 0.48). The median OS was not reached in either arm; however, a post-hoc analysis suggested a survival benefit for patients with intracranial metastasis (HR, 0.43; 95% CI, 0.21-0.89). 1068 rlatinib is an ALK inhibitor that is approved by the FDA for the treatment of adults with ALK-positive metastatic NSCLC. 1069 CROWN, a phase 3 randomized trial, assessed lorlatinib versus crizotinib as first-line therapy in 296 patients with ALK-positive advanced NSCLC. 217 At 12 months, 78% of patients were alive without disease progression in the lorlatinib group versus 39% in the crizotinib group (HR, 0.28; P < .001). The objective response rate was 76% for patients receiving lorlatinib and 58% for those receiving crizotinib. For patients with measurable brain metastases, an intracranial response was reported in 82% of those receiving lorlatinib and 23% of those receiving crizotinib. A complete intracranial response was achieved in 71% of those who received lorlatinib. Hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects were the most common AEs seen with lorlatinib. More grade 3 or 4 AEs (mainly altered lipid levels) occurred with lorlatinib than with crizotinib (72% vs. 56%, respectively). A post hoc analysis of the CROWN study showed that in patients with brain metastases at baseline, the 12-month cumulative incidence of CNS progression was 7% with lorlatinib compared with 72% with crizotinib; the 12-month PFS rates were 78% versus 22%, respectively. 1070 In patients without brain metastases at baseline, the 12-month cumulative incidence of CNS progression was 1% with lorlatinib compared with 18% with crizotinib; the 12-month PFS rates were 78% versus 45%, respectively. 1070 Updated data from the CROWN trial demonstrated that the 3-year PFS rate was 64% with lorlatinib and 19% with crizotinib. 1071 dditionally, the HR for time to intracranial progression for lorlatinib in comparison to crizotinib was 0.10 among those with baseline brain metastases and 0.02 among those without brain metastases at baseline.

Data have suggested that lorlatinib can be used as subsequent therapy in patients with disease progression after treatment with other ALK inhibitors, including those with CNS metastases. Data from this trial also showed that lorlatinib is effective as subsequent therapy in patients with the resistance mutation ALK G1202R, which is often detected after progression on second-generation ALK TKIs such as brigatinib, alectinib, or ceritinib. 1074 The objective response rate with lorlatinib was 62% when using plasma ctDNA (and 69% when using

tissue) for patients with ALK resistance mutations and disease progression on second-generation ALK TKIs compared with 32% (plasma) and 27% (tissue) in patients without ALK mutations. [1076]

NCCN Recommendations (NSCL-27, NSCL-28, and NSCL-29)

The NCCN NSCLC Panel recommends alectinib, brigatinib, or lorlatinib as preferred first-line therapy options for patients with advanced or metastatic NSCLC and ALK rearrangements. Ceritinib is an "other recommended" first-line option, whereas crizotinib is considered useful in certain circumstances. All these options are appropriate for patients with performance status 0-4 and are category 1 recommendations if an ALK rearrangement is discovered prior to first-line systemic therapy.

Upon disease progression, the NCCN Panel recommends considering plasma and/or tissue-based testing using broad molecular profiling to determine genomic resistance mechanisms and to guide use of subsequent therapy options. 1074 ter progression on alectinib, brigatinib, or ceritinib, the NCCN Panel recommends a switch in treatment to lorlatinib. Continuing lorlatinib is an option for those who experienced disease progression on or after lorlatinib given in the first-line setting. Lorlatinib can be used for NSCLC with resistant mutations such as ALK G1202R or L1196M, but not if compound resistant mutations are detected (ie, both L1196M and G1202R). Continuing the same TKI that was used in the first-line setting is another option, except for those with symptomatic systemic progression and multiple lesions.

NSCLC with ROS1 Rearrangement

It is estimated that ROS1 gene rearrangements occur in about 1% to 2% of patients with NSCLC. distinct receptor tyrosine kinase, it is similar to ALK and members of the insulin receptor family. 343, 344 Several (but not all) targeted therapies recommended for the treatment of ALK-positive metastatic NSCLC are also recommended for the treatment of ROS1-positive metastatic disease (ie, ceritinib, crizotinib, lorlatinib).

9] [1080] [1081] [1082] Crizotinib is approved for the treatment of adults with ROS1-positive and ALK-positive metastatic NSCLC. 1060 Crizotinib yielded an objective response rate of 72%; there were 3 complete responses and 33 partial responses. 344 The median duration of response was 17.6 months, and the median PFS was 19.2 months. Updated results from PROFILE 1001 reported an objective response rate of 72% with crizotinib including 6 confirmed complete responses in 53 patients with ROS1-positive advanced NSCLC. 22 The median OS was 51.4 months.

No grade 4 or higher treatment-related AEs were reported.

The phase 2 single-arm EUCROSS study reported that crizotinib yielded an objective response rate of 70% and a median PFS of 20 months in 30 patients with ROS1-positive advanced NSCLC. 1083 AEs related to treatment occurred in 97% of patients. A retrospective study based on data from Europe in patients (n = 30 evaluable) with stage IV lung adenocarcinoma and ROS1 rearrangements also assessed crizotinib. 190 here were 5 complete responses (overall response rate, 80%; disease control rate, 86.7%). The median PFS was 9.1 months. Many patients (n = 26) received pemetrexed (either alone or in combination with platinum and either before or after crizotinib) and had a response rate of 57.7%; the median PFS was 7.2 months.

Entrectinib is an oral TKI that inhibits several kinases (including ROS1, ALK, and TRK) and is approved by the FDA for the treatment of ROS1positive metastatic NSCLC. 330, 1085, 1086 Entrectinib has been assessed in several phase 1 and 2 trials in patients with ROS1-positive metastatic NSCLC (ie, phase 2 STARTRK-2 trial, phase 1 STARTRK-1 trial, phase 1 ALKA-372-001 trial). 348, 1087 Pooled data from these 3 trials in 53 patients with ROS1-positive metastatic NSCLC receiving first-line entrectinib showed an objective response rate of 77% (3 complete responses). 348, 357 The intracranial overall response rate was 55% (4 complete responses, 7 partial responses) among the 20 patients with baseline CNS metastases. 348, 1087 In the larger ROS1 population (n = 134), grade 3 to 4 AEs were seen in 34% of patients. Fifteen patients had serious AEs such as nervous system disorders and cardiac disorders. Although entrectinib has better CNS penetration than crizotinib, it is more toxic. 357 potrectinib is a next-generation ROS1, TRK, and ALK TKI that is approved by the FDA for the treatment of adults with locally advanced or metastatic ROS1-positive NSCLC. Lorlatinib is an oral TKI that is active against both ALK and ROS1 and can penetrate the blood-brain barrier. 1069,1091 A phase 1 to 2 trial assessed lorlatinib in 69 patients with ROS1-positive metastatic NSCLC. 356 Many patients (58%) had previously received crizotinib; some patients were TKI naïve (30%). Objective responses were achieved in 35% (14/40) of patients who previously received crizotinib and 62% (13/21) of those who were TKI-naïve. An intracranial response was observed in 50% (12/24) of patients who previously received crizotinib and 64% (7/11) of those who were TKI-naïve. Serious treatment-related AEs occurred in 7% of patients.

Data suggest that ceritinib, an oral TKI that has activity against both ALK and ROS1, can also be considered as a treatment option for patients with NSCLC and ROS1 rearrangements. 1061,1091,1092

NCCN Recommendations (NSCL-30 and NSCL-31)

The NCCN NSCLC Panel recommends entrectinib, crizotinib, or repotrectinib as preferred first-line treatment options for patients with ROS1-positive advanced or metastatic NSCLC, while ceritinib is considered an "other recommended" first-line treatment option. All are appropriate for patients with performance status 0-4; however, entrectinib or repotrectinib may be better for patients with brain metastases.

Upon disease progression, plasma or tissue-based testing via broad molecular profiling should be considered to identify genomic resistance mechanisms. If plasma-based testing is negative, the panel strongly recommends tissue-based testing with rebiopsy material.

For asymptomatic progression on entrectinib, crizotinib, repotrectinib, or ceritinib, the NCCN NSCLC Panel recommends repotrectinib (if not previously given) or lorlatinib as subsequent therapy options. For patients with CNS progression, entrectinib (if previously treated with crizotinib or ceritinib), repotrectinib (if previously treated with crizotinib, ceritinib, or entrectinib), or lorlatinib are recommended options. See also the NCCN Guidelines for CNS Cancers on www.NCCN.org for additional recommendations. For symptomatic systemic progression with multiple systemic lesions, repotrectinib (if not previously given) or lorlatinib are recommended targeted therapy options. Systemic therapies (such as chemotherapy with or without immunotherapy) can be considered in this setting as well (see NSCL-K 1 of 5 and NSCL-K 2 of 5 in the NCCN Guidelines for NSCLC). Data indicate that ICI monotherapy is less effective in NSCLC with ROS1 alterations. 184, 1052 ntinuation of entrectinib, crizotinib, repotrectinib, or ceritinib is also an option for certain patients with disease progression; continuation of these therapies is not recommended for those with symptomatic systemic progression and either multiple lesions or brain metastases.

Definitive local therapy has a role in the treatment of metastatic ROS1positive NSCLC. For patients with a limited number of initial sites of metastasis (oligometastasis; limited number is not universally defined,

NSCLC with BRAF V600E Mutation

The BRAF V600E mutation occurs in 1% to 2% of patients with lung adenocarcinoma; it is the most common of the BRAF point mutations when considered across all tumor types. 188, 241 Rare BRAF mutations include V600K and V600D. The BRAF gene encodes for BRAF, a serine/threonine kinase; activating mutations in BRAF result in unregulated signaling through the MAP/ERK pathway. 1093

nocarcinoma (NSCL-K 1 of 5) or Squamous Cell Carcinoma (NSCL-K|

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|BRAF V600E MUTATION nn|||||

|||FIRST-LINE THERAPY rr||SUBSEQUENT THERAPY rr|

|mutation BRAF V600E|BRAF V600E mutation systemic therapy prior to first-line discovered|Preferred Dabrafenib + trametinib ss or Encorafenib + binimetinib ss Useful in Certain Circumstances Dabrafenib ss,qqq or Vemurafenib ss,qqq Adenocarcinoma (NSCL-K 1 of 5) or Squamous Cell Carcinoma (NSCL-K 2 of 5) Systemic Therapy, Other Recommended|Progression Progression Progression|Encorafenib + binimetinib or Dabrafenib + trametinib qqq Systemic Therapy, Adenocarcinoma (NSCL-K 1 of 5) or Squamous Cell Carcinoma (NSCL-K 2 of 5)|

||BRAF V600E mutation discovered during first-line systemic therapy|Interrupt current therapy and start Dabrafenib + (preferred) Encorafenib + binimetinib trametinib qqq (preferred) or maintenance therapy, or systemic therapy, including Complete planned|Progression|(NSCL-K 2 of 5) Squamous Cell Carcinoma (NSCL-K 1 of 5) or Systemic Therapy, Adenocarcinoma Systemic Therapy, Subsequent (NSCL-|

Dabrafenib and encorafenib are both oral BRAF kinase inhibitors. 188, 189, 1094, 1095 Dabrafenib, in combination with MEK1/2 inhibitor trametinib, is approved by the FDA for the treatment of metastatic NSCLC with BRAF V600E mutation. 1096 Encorafenib, in combination with MEK1/2 inhibitor binimetinib, is FDA-approved for the treatment of metastatic NSCLC with a BRAF V600E mutation. 1097

A phase 2 trial assessed dabrafenib in combination with trametinib as first-line therapy in 36 patients with metastatic NSCLC and BRAF V600E mutations. 15, 1098 The overall response rate was 63.9%; there were 2 complete responses. 15 The median PFS was 10.8 months. 15 Many patients (69%) had one or more grade 3 or 4 AEs. 1098 Serious AEs included increased ALT, increased AST, pyrexia, and decreased ejection fraction. 1098 An updated analysis reported that patients receiving dabrafenib plus trametinib had a median OS of 17.3 months. 15 After 5 years, the OS rate was 22%.

The same trial also assessed the dabrafenib plus trametinib regimen as subsequent therapy in 57 patients with advanced NSCLC and BRAF V600E mutations and disease progression on chemotherapy. 15, 188 The overall response rate was 68.4% and the median PFS was 10.2 months. 15 Serious AEs occurred in 56% of patients, including pyrexia, anemia, confused state, hemoptysis, hypercalcemia, and cutaneous squamous cell carcinoma. 188 Grade 3 to 4 AEs included neutropenia, hyponatremia, and anemia. 188 An updated analysis reported that the median OS was 18.2 months. 15 After 5 years, the OS rate was 19%.

A phase 2, open-label, single-arm study evaluated encorafenib in combination with binimetinib in patients with BRAF V600E-positive metastatic NSCLC in both the first-line and subsequent therapy settings. 1095 The objective response rate was 75% in treatment-naïve patients and 46% in previously treated patients. The median PFS was not estimable for the treatment-naïve patients and 9.3 months in those who were previously treated. The most common treatment-related AEs were nausea, diarrhea, and fatigue. One Grade 5 treatment-related AE (intracranial hemorrhage) was reported.

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Data suggest that treatment with a single-agent BRAF inhibitor, such as vemurafenib, can also be used to treat patients with metastatic NSCLC and BRAF V600E. 243 Results from retrospective studies indicate that patients with advanced NSCLC and BRAF mutations may also derive benefit from PD-1/PD-L1 inhibitors. 184, 1099 Therefore, first-line treatment with an ICI-based regimen can be considered, particularly for those with a minimal burden of disease and/or high PD-L1 levels.

NCCN Recommendations (NSCL-32)

The NCCN NSCLC Panel recommends dabrafenib plus trametinib or encorafenib plus binimetinib as preferred first-line therapy options for patients with BRAF V600E mutation-positive advanced or metastatic NSCLC. The panel also recommends dabrafenib plus trametinib or encorafenib plus binimetinib as subsequent therapy options if the patient with BRAF V600E mutation did not previously receive a BRAF inhibitor. Single-agent therapy with dabrafenib or vemurafenib can be considered for those who do not tolerate dabrafenib plus trametinib. These options are all appropriate for patients with performance status 0-4.

Other first-line therapy options include systemic therapy regimens (such as chemotherapy with or without immunotherapy) listed on NSCL-K 1 of 5 and NSCL-K 2 of 5 in the NCCN Guidelines for NSCLC; these are designated as "other recommended" options. These regimens can also be used as subsequent therapy options for patients whose disease progressed after receiving a first-line therapy that included a BRAF inhibitor.

NSCLC with NTRK Gene Fusion

NTRK1/2/3 gene fusions encode TRK fusion proteins that act as oncogenic drivers for various solid tumors, including lung, salivary gland, thyroid, and sarcoma. 328, 1100 It is estimated that NTRK1/2/3 fusions occur in 0.2% of patients with NSCLC and do not typically overlap with other oncogenic drivers such as EGFR, ALK, or ROS1. 327

Entrectinib and larotrectinib are oral TRK inhibitors and both were granted accelerated approval by the FDA for the treatment of patients with solid tumors that have an NTRK gene fusion. 1086, 1100, 1101 Entrectinib is also approved for the treatment of ROS1-positive metastatic NSCLC (see above for more information). 1086

Entrectinib has been assessed in several phase 1 and 2 trials in patients with NTRK gene fusion-positive metastatic NSCLC (phase 2 STARTRK-2 trial, phase 1 STARTRK-1 trial, and phase 1 ALKA-372-001 trial). 331 Pooled data from these 3 trials in 10 patients with NTRK gene fusion-positive NSCLC showed that entrectinib yielded an overall response rate of 70% (7/10). 331 Updated data in 22 patients with NTRKpositive locally advanced or metastatic NSCLC found that the objective response rate was 64.5%; a complete response was observed in 16.1% of patients. 1102 Among the 15 patients with CNS metastases at baseline, the intracranial objective response rate was 60%. Most treatment-related AEs were grade 1 or 2.

A study in 55 patients with NTRK gene fusion-positive disease across a range of solid tumors showed that larotrectinib yielded an overall response rate (by independent review) of 75%. 328 In an analysis of 15 patients with NTRK fusion-positive lung cancer, the objective response rate by investigator assessment was 73%; 1 patient had a complete response and 10 had a partial response. 1103 The median OS was 40.7 months, and the median PFS was 35.4 months. Among those with CNS metastases at baseline, the objective response rate was 63%. Most of the reported AEs were grade 1 or 2.

NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-88

NCCN Recommendations (NSCL-33)

The NCCN NSCLC Panel recommends larotrectinib or entrectinib as preferred first-line therapy options for patients with NTRK1/2/3 gene fusion-positive advanced or metastatic NSCLC (performance status 0-4).

Either may be used as a subsequent therapy option for NTRK1/2/3 gene fusion-positive metastatic NSCLC if larotrectinib or entrectinib was not previously given as first-line therapy.

Other systemic therapies (such as chemotherapy with or without immunotherapy) on NSCL-K 1 of 5 and NSCL-K 2 of 5 in the NCCN Guidelines for NSCLC are categorized as first-line treatment options that may be useful in certain circumstances for NTRK-positive advanced or metastatic NSCLC; these are also recommended as subsequent therapy options for patients whose disease progressed after treatment with larotrectinib or entrectinib. Data indicate that ICI monotherapy may be less effective in NSCLC with NTRK mutations. 184, 1052

NSCLC with MET Exon 14 Skipping Mutation

METex14 skipping mutations occur in 3% to 4% of patients with adenocarcinoma NSCLC and 1% to 2% of patients with other NSCLC histologies. 319, 320 METex14 skipping mutations lead to dysregulation of the MET receptor tyrosine kinase and inappropriate signaling. The presence of this type of mutation is associated with responsiveness to oral MET TKIs. The NCCN Guidelines recommend testing for METex14 skipping mutations as part of broad molecular profiling, due to the availability of FDA-approved targeted therapies for this biomarker.

In contrast, high-level MET amplification is designated as an emerging biomarker in the NCCN Guidelines because there is less evidence for using targeted agents for this biomarker. In addition, no therapies have been approved by the FDA for the treatment of metastatic NSCLC with MET amplification.

[1106] GEOMETRY, a phase 2 study, assessed capmatinib in different cohorts of patients with MET genomic alterations, including those with METex14 skipping mutations; patients had stage IIIB or IV NSCLC and were wild-type for EGFR and ALK genomic alterations. 170, 324 Updated data from GEOMETRY showed that first-line therapy with capmatinib resulted in an overall response rate of 68% in 28 patients with METex14 skipping mutations; the median PFS was 12.4 months for first-line therapy. 170 ubsequent therapy with capmatinib yielded an overall response rate of 41% in 69 patients with METex14 skipping mutations; the median PFS was 5.4 months for subsequent therapy. 170 The data from GEOMETRY also suggest that capmatinib is effective for patients with brain metastases. 170, 1107 Among patients with brain metastases, a response to capmatinib was reported in 54%; 4 patients had a complete response in the brain. However, 43% of patients whose disease responded had previously received RT. 170 Common AEs for patients with METex14 skipping mutations across all cohorts included peripheral edema, nausea, and vomiting, but most of these events were grades 1 to 2. 170 One treatment-related death occurred.

VISION, a phase 2 study, assessed tepotinib in patients with METex14 skipping mutations; patients mainly had stage IV NSCLC and were wild-type (negative) for EGFR and ALK genomic alteration. 167, 1108, 1109 The response rate to tepotinib was 46%; PFS was 8.5 months in the combined biopsy group (tissue biopsy plus plasma ctDNA). 1109 tepotinib because of peripheral edema, pleural effusion, or dyspnea. 1109 ne treatment-related death occurred. 1109 The 18-month follow-up analysis of VISION confirmed the efficacy of tepotinib in patients with METex14-positive advanced/metastatic NSCLC. 1110 Among treatmentnaïve patients, the objective response rate with tepotinib was 57.3% and the median duration of response was 46.6 months. Among previously treated patients, the objective response rate was 45% and the median duration of response was 12.6 months.

Data suggest that crizotinib, an oral TKI that inhibits multiple kinases, including ALK, ROS1, and MET, is also a viable option for patients with advanced NSCLC and METex14 skipping mutations. 325

NCCN Recommendations (NSCL-34)

The NCCN NSCLC Panel recommends capmatinib, tepotinib, or crizotinib as first-line treatment options for patients with advanced or metastatic NSCLC and METex14 skipping mutation. These are also recommended as subsequent therapy options, if the patient was not previously treated with capmatinib, tepotinib, or crizotinib. Capmatinib and tepotinib are categorized as preferred, while crizotinib is considered useful in certain circumstances. The panel notes that switching between agents with a similar mechanism of action at the time of progression is not recommended.

Other systemic therapy regimens (such as chemotherapy with or without immunotherapy) listed on NSCL-K 1 of 5 and NSCL-K 2 of 5 in the NCCN Guidelines for NSCLC are recommended as useful in certain circumstances for first-line therapy. These are also recommended as subsequent therapy options in patients whose disease progressed following treatment with capmatinib, tepotinib, or crizotinib. Data indicate that ICI monotherapy may be less effective in NSCLC with MET alterations. 184, 1052 CLC with RET Rearrangement RET rearrangements occur in about 1% to 2% of patients with NSCLC and are more frequent in patients with adenocarcinoma histology. [332] [333] [334] [335] [336] Rearrangements may occur between RET and other genes, including KIF5B and CCDC6, which can lead to overexpression and dysregulation of RET kinase and inappropriate signaling. 332, 333 Clinical Data

[1113] Libretto-001, a phase 1/2 study, assessed selpercatinib in patients with NSCLC and RET rearrangements. 338, 1114 Updated results from the trial showed that first-line therapy with selpercatinib yielded an objective response rate of 85%. 338 Second-line therapy with selpercatinib yielded an objective response rate of 64%; the median PFS was 18.4 months. Of patients with brain metastases, a response to selpercatinib was reported in 91% (10/11). Common grade 3 or more AEs with selpercatinib included hypertension, increased liver enzyme levels, hyponatremia, and lymphopenia.

Libretto-431, a randomized phase 3 trial, evaluated selpercatinib versus control (platinum-based chemotherapy with or without pembrolizumab) as first-line therapy in 212 patients with advanced NSCLC and RET gene fusion. 1115 Based on the interim analysis, the median PFS was longer with selpercatinib than with the control treatment (24.8 months vs. 11.2 months; HR, 0.46; P < .001). The HR for time to CNS progression was 0.28. Among those with brain metastases at baseline, a higher proportion of patients in the selpercatinib group experienced an intracranial response compared with those in the control group (82% versus 58%).

NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-90 ARROW, a phase 1/2 study, assessed pralsetinib in 233 patients with metastatic NSCLC and RET rearrangements. 337 First-line therapy with pralsetinib resulted in an overall response rate of 70%; 3 patients (11%) had a complete response. Second-line therapy with pralsetinib resulted in an overall response rate of 61% (53/87); 5 patients (6%) had a complete response. Among the nine patients with measurable brain metastases, a response to pralsetinib was reported in 56%; 3 patients had an intracranial complete response. Grade 3 or more AEs with pralsetinib include anemia, neutropenia, and hypertension. Common AEs with pralsetinib included increased AST levels, increased ALT levels, anemia, hypertension, constipation, and neutropenia. Updated data from the ARROW trial showed that the overall response rate with pralsetinib was 72% for those who were treatment-naïve and 59% for those who previously received platinum-based chemotherapy. 1116 Among the 10 patients with intracranial metastases (all who previously received systemic therapy), the intracranial response rate was 70%.

Data suggest that cabozantinib, an oral kinase inhibitor active against multiple receptor tyrosine kinases, including RET, MET, VEGFR2, and others, 1111 is another viable treatment option for patients with RETpositive metastatic NSCLC. 339, 340, 1117

NCCN Recommendations (NSCL-35)

The NCCN NSCLC Panel recommends selpercatinib or pralsetinib as preferred first-line therapy options for patients with advanced or metastatic NSCLC and RET rearrangements. Cabozantinib is recommended by the panel as a first-line therapy option that may be useful in certain circumstances. All are appropriate for performance status 0-4. These agents are also recommended as subsequent therapy options for patients with RET rearrangement-positive metastatic NSCLC if selpercatinib, pralsetinib, or cabozantinib were not previously given as first-line therapy. The panel notes that switching between agents with a similar mechanism of action at the time of progression is not recommended.

Other systemic therapies (such as chemotherapy with or without immunotherapy) on NSCL-K 1 of 5 and NSCL-K 2 of 5 in the NCCN Guidelines for NSCLC are categorized as "other recommended" first-line treatment options for RET-positive advanced or metastatic NSCLC; these are also recommended as subsequent therapy options in patients whose disease progressed after treatment with selpercatinib, pralsetinib, or cabozantinib. Data indicate that ICI monotherapy may be less effective in NSCLC with RET rearrangements. 184, 1052 CLC with ERBB2 (HER2) Mutation ERBB2 encodes for HER2, a receptor tyrosine kinase found on the surface of normal epithelial cells that is often overexpressed or mutated in a variety of human malignancies. 1118 Approximately 3% of advanced NSCLC (adenocarcinoma) have a mutation in ERBB2 (HER2). 169 esources are available to assess whether a specific ERBB2 (HER2) mutation is oncogenic or likely to be oncogenic (such as oncoKB.org).

Fam-trastuzumab deruxtecan-nxki was granted accelerated approval by the FDA for the treatment of adults with unresectable or metastatic NSCLC tumors that have activating ERBB2 (HER2) mutations, and who received a prior systemic therapy. 1119 Fam-trastuzumab deruxtecan-nxki is a humanized monoclonal antibody drug conjugate consisting of trastuzumab, an antibody targeting HER2, linked to deruxtecan, a topoisomerase I inhibitor; the agent remains stable until it is cleaved by peptides in cancer cells. 169 STINY-Lung01, a phase 2 study, assessed fam-trastuzumab deruxtecan-nxki in 91 patients with metastatic nonsquamous NSCLC and ERBB2 mutations (not ERBB2 amplification). 169, 1120, 1121 Most patients had ERBB2 (HER2) exon 20 insertion mutations (86%); 66% were female, 57% had never smoked cigarettes, 36% had CNS metastases at baseline, and all had nonsquamous NSCLC. 169 The objective response rate with fam-trastuzumab deruxtecan-nxki was 55%; most patients had received prior treatment. 169 Median OS was 17.8 months. 169 Grade 3 or higher AEs occurred in 46% of patients including neutropenia (19%). Two patients died from drug-related interstitial lung disease.

Data have shown that ado-trastuzumab emtansine (also known as T-DM1), a humanized antibody-drug conjugate consisting of trastuzumab and microtubule inhibitor emtansine, also has efficacy in patients with metastatic or recurrent NSCLC and ERBB2 (HER2) mutations. 168, 1122

NCCN Recommendations (NSCL-36)

The NCCN NSCLC Panel recommends the systemic therapy regimens (such as chemotherapy with or without immunotherapy) listed on NSCL-K 1 of 5 or NSCL-K 2 of 5 in the NCCN Guidelines for NSCLC for the first-line treatment of advanced or metastatic NSCLC with ERBB2 (HER2) mutations. Data indicate that ICI monotherapy may be less effective in NSCLC with ERBB2 (HER2) mutations. 184, 1052 ter disease progression, fam-trastuzumab deruxtecan-nxki is recommended as a preferred subsequent therapy option, while ado-trastuzumab emtansine is categorized as an "other recommended" option. The panel notes that switching between agents with a similar mechanism of action at the time of progression is not recommended.

NSCLC with HER2 protein overexpression

This section is under development. Evidence Blocks™ for NSCLC). 962, 1123 Chemotherapy with or without bevacizumab is an option if eligibility criteria are met for patients with nonsquamous NSCLC and negative test results for actionable driver mutations, and with PD-L1 expression less than 1%. 1124 Chemotherapy with or without bevacizumab regimens may be used as first-line or subsequent therapy options in eligible patients with actionable driver mutations as shown in the algorithm, although they are generally not preferred options. Targeted therapy is a preferred first-line therapy option for patients with actionable driver mutations, except for EGFR exon 20 mutations or KRAS mutations. Previously, patients with brain metastases were excluded from receiving bevacizumab because of concerns about CNS hemorrhage; however, data suggest that bevacizumab can be used in patients with treated CNS metastases. 1125 A phase 3 randomized trial in older patients (70-89 years) with advanced NSCLC reported that combined therapy with weekly paclitaxel and monthly carboplatin improved survival when compared with single-agent therapy using either gemcitabine or vinorelbine (10.3 vs. 6.2 months). 1126 Systemic therapy for older patients with advanced NSCLC needs to be carefully selected to avoid adverse reactions. 1127 The NCCN NSCLC Panel does not recommend carboplatin plus vinorelbine, cisplatin plus vinorelbine, etoposide, irinotecan, and vinorelbine for patients with metastatic nonsquamous NSCLC or NSCLC NOS and negative test results for actionable driver mutations, because these regimens are rarely used in the United States.

For patients with metastatic squamous cell NSCLC and negative test results for actionable driver mutations, chemotherapy plus immunotherapy regimens-such as pembrolizumab plus carboplatin with either paclitaxel or albumin-bound paclitaxel-are recommended options (category 1; preferred). For patients with metastatic squamous cell NSCLC who have contraindications to ICIs, recommended options include cisplatin plus gemcitabine (category 1). Data show that platinum-based combination therapy is superior to best supportive care for patients with advanced, incurable disease who are not eligible for targeted therapy or immunotherapy. Cisplatin or carboplatin have been proven effective in combination with many of the following agents: docetaxel, etoposide, gemcitabine, paclitaxel (and albumin-bound paclitaxel), and pemetrexed (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for NSCLC). 738,743,788- 790,797,798,818 Carboplatin-based regimens are often used for patients with comorbidities or those who cannot tolerate cisplatin. 1128 [803] 1129 ECOG 4599, a phase 2/3 trial, randomly assigned 878 patients to either 1) bevacizumab in combination with paclitaxel plus carboplatin; or 2) paclitaxel plus carboplatin alone. 806, 1130 Both regimens were well tolerated with selected toxicities. Patients receiving bevacizumab plus paclitaxel plus carboplatin showed an improved median survival (12.3 vs. 10.3 months, P = .003) when compared to patients receiving paclitaxel plus carboplatin alone. 806 The overall 1-year survival was 51% versus 44%; 2-year survival was 23% versus 15%, respectively, in favor of the bevacizumab plus paclitaxel plus carboplatin arm. 806 More significant toxicities were observed with bevacizumab plus paclitaxel plus carboplatin compared to paclitaxel plus carboplatin (grade 4 neutropenia: 25.5% vs. 16.8%; grade 5 hemoptysis: 1.2% vs. 0%; and grade 3 hypertension: 6.8% vs. 0.5%). Treatment-related deaths were more common with bevacizumab plus paclitaxel plus carboplatin (15 patients) than with paclitaxel plus carboplatin (2 patients) (P = .001). An analysis of ECOG 4599 found that patients with adenocarcinoma histology receiving bevacizumab plus paclitaxel plus carboplatin had improved survival compared with chemotherapy alone (14.2 vs. 10.3 months). 1124 AVAiL, a phase 3 randomized trial, compared cisplatin plus gemcitabine with (or without) bevacizumab; survival was not increased with the addition of bevacizumab. 1131, 1132 [848] [849] A noninferiority trial in 1725 patients with advanced NSCLC (either stage IIIB or IV; most were stage IV) assessed cisplatin plus gemcitabine compared with cisplatin plus pemetrexed. 790 Patients with either adenocarcinoma or large cell carcinoma (ie, nonsquamous NSCLC) had improved survival with cisplatin plus pemetrexed (adenocarcinoma: 12.6 vs. 10.9 months). Patients with squamous cell carcinoma had improved survival with the cisplatin plus gemcitabine regimen (10.8 vs. 9.4 months).

When compared with the cisplatin plus gemcitabine regimen, the cisplatin plus pemetrexed regimen had significantly lower rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001). Treatment-related deaths were similar for both regimens (cisplatin plus pemetrexed, 9 patients [1.0%]; cisplatin plus gemcitabine, 6 patients [0.7%] ). An analysis of three phase 3 trials confirmed that pemetrexed improves survival for patients with nonsquamous NSCLC in first-line, subsequent, and maintenance therapy. 1133

Number of Cycles of First-Line Systemic Therapy

Data from the PARAMOUNT trial suggest that 4 cycles of platinum-based therapy is not optimal; 881 tumors can shrink between 4 to 6 cycles of chemotherapy. However, patients may not be able to tolerate more than 4 cycles of chemotherapy, and most of the maintenance trials used only 4 cycles of chemotherapy. 810 A meta-analysis suggests that continuing the initial regimen beyond 4 to 6 cycles is associated with increased PFS;

NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-94 however, patients have more adverse events. 1134 A phase 3 randomized trial suggested that continuing chemotherapy beyond 4 to 6 cycles is not beneficial; however, many patients assigned to a longer duration of therapy did not receive the planned number of cycles. 807, 808 In this phase 3 trial, taxane-based regimens were used and patients had increasing neurotoxicity as more cycles were used. 807 ny patients with adenocarcinoma receive pemetrexed-based regimens and not taxane-based regimens. Pemetrexed-based regimens are less toxic than taxane-based regimens. Thus, data suggesting that more than 6 cycles of first-line chemotherapy are not appropriate may only apply to taxane-based regimens. 810 Studies report that 60% of patients were able to receive 6 cycles of pemetrexed-based chemotherapy (and had a low incidence of toxicity), whereas only 42% were able to receive more than 5 cycles of taxane-based chemotherapy and often stopped therapy because of neurotoxicity. 807, 883 e NCCN Guidelines recommend that patients receiving first-line systemic therapy for advanced disease should be evaluated for tumor response with a CT scan. 6] [1137] Patients with responsive or stable disease can continue to receive a total of 4 to 6 cycles of systemic therapy. 714, 807, 1138 he NCCN Guidelines do not recommend continuing chemotherapy beyond 4 to 6 cycles. Generally, patients with metastatic NSCLC receive 4 cycles of initial systemic chemotherapy (eg, carboplatin plus pemetrexed plus pembrolizumab for nonsquamous NSCLC) before starting maintenance therapy. However, if patients are tolerating the therapy, then 6 cycles of systemic therapy can be considered. Approximately 25% of patients show disease progression after the initial cycle of chemotherapy; subsequent therapy is recommended for these patients (see the NCCN Guidelines for NSCLC).

Maintenance therapy is an option for patients with metastatic nonsquamous NSCLC, with responsive or stable disease after first-line systemic chemotherapy or immunotherapy with or without chemotherapy (see the NCCN Guidelines for NSCLC).

A phase 3 randomized trial in 663 patients with advanced NSCLC assessed the effect of best supportive care with (or without) switch maintenance pemetrexed in patients who had received platinum-based chemotherapy but whose tumors had not progressed. 891 Overall survival was 13.4 months (95% CI, 11.9-15.9) with pemetrexed compared with 10.6 months (95% CI, 8.7-12.0) with placebo (HR, 0.50; 95% CI, 0.42-0.61; P < .0001).

IUNO, a phase 3 randomized trial, assessed erlotinib as switch maintenance therapy (and as subsequent therapy) for patients with nonsquamous NSCLC and PS 0 to 2 but without EGFR mutations. 893 verall survival and PFS were not improved in patients receiving erlotinib when compared with placebo. The NCCN NSCLC Panel does not recommend erlotinib as switch maintenance therapy (and as subsequent therapy) for patients with nonsquamous NSCLC and PS 0 to 2 but without EGFR mutations based on clinical trial data and a revised indication by the FDA. 893 r patients with squamous cell NSCLC, pembrolizumab was used as continuation maintenance therapy if patients received either pembrolizumab plus carboplatin plus either paclitaxel or albumin-bound paclitaxel or they received pembrolizumab alone (see Immune Checkpoint Inhibitors in this Discussion). IFCT-GFPC 0502, a phase 3 randomized trial, compared maintenance therapy with either gemcitabine NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer

MS-95

or erlotinib after initial cytotoxic therapy with cisplatin plus gemcitabine in patients with advanced NSCLC. 742, 887 Continuation maintenance therapy with single-agent gemcitabine increased PFS to a greater extent (3.8 months) than switch maintenance therapy with erlotinib (2.9 months) compared with observation (1.9 months). 742, 887 A phase 3 trial assessed switch maintenance therapy with docetaxel given either immediately after chemotherapy or delayed until progression in patients with advanced NSCLC. 895 Many patients in the delayed chemotherapy arm did not receive docetaxel. 896 pending on first-line therapy, the NCCN NSCLC Panel recommends continuation maintenance therapy options for patients with nonsquamous NSCLC with atezolizumab, atezolizumab plus bevacizumab (category 1), bevacizumab (category 1), bevacizumab plus pemetrexed, cemiplimab-rwlc with or without pemetrexed (category 1), durvalumab with or without pemetrexed (category 1), gemcitabine (category 2B), nivolumab plus ipilimumab, pembrolizumab (category 1), pembrolizumab plus pemetrexed (category 1), or pemetrexed (category 1) (see the NCCN Guidelines for NSCLC). 742, 806, 812, 881, 885, 887, 1139 Switch maintenance therapy with pemetrexed is a recommended option for patients with nonsquamous NSCLC. 742, 887, 890, 891 The benefits of continuation maintenance therapy with gemcitabine were very slight; therefore, the recommendation is only category 2B. 742 For patients with squamous cell NSCLC and depending on first-line therapy, the panel recommends continuation maintenance therapy with atezolizumab, cemiplimab-rwlc (category 1), durvalumab, gemcitabine (category 2B), nivolumab plus ipilimumab, or pembrolizumab. Previously, the NCCN Panel deleted the recommendation for docetaxel (category 2B) as switch maintenance therapy for patients with squamous cell NSCLC because there are better options. 896

Second-Line and Beyond (Subsequent) Systemic Therapy

The phrase subsequent therapy is substituted for the terms second-line, third-line, and beyond systemic therapy in the NCCN Guidelines, because the line of therapy may vary depending on previous treatment with targeted agents. 1] [1142] [1143] [1144] [1145] [1146] [1147] [1148] [1149] The NCCN NSCLC Panel recommends response assessment of known or high-risk sites of disease with CT with or without contrast every 6 to 12 weeks in patients receiving subsequent therapy or maintenance therapy. 1] [1152] If patients have received and completed first-line systemic therapy (such as carboplatin plus paclitaxel), including maintenance therapy, before receiving targeted therapy for an actionable mutation, but have disease progression on targeted therapy, then certain subsequent therapy options are recommended, such as docetaxel.

If patients have not previously received an ICI, the NCCN NSCLC Panel recommends (category 1) atezolizumab, nivolumab, or pembrolizumab as preferred subsequent therapy options in eligible patients with metastatic NSCLC based on clinical trial data and FDA approvals (see Immune Checkpoint Inhibitors in this Discussion). 358, 362, 834, 835, 851, 858 Human ICI antibodies inhibit the PD-1 receptor or PD-L1, which improves antitumor immunity; PD-1 receptors are expressed on activated cytotoxic T cells. Platinum-based doublet therapy is recommended (eg, carboplatin plus paclitaxel) as subsequent systemic therapy options for patients with metastatic NSCLC (but without these genetic variants), positive PD-L1 levels (≥50%), and disease progression after first-line therapy with single-agent ICIs. For patients with metastatic NSCLC and disease progression after first-line therapy with ICIs plus chemotherapy, subsequent systemic therapy options include docetaxel (± ramucirumab), gemcitabine, albumin-bound paclitaxel, or pemetrexed (for nonsquamous only), depending on which agent was not previously given. For patients with all histologic subtypes and PS of 0 to 2, but without these genetic variants, who have disease progression during or after first-line platinum-based combination therapy, recommended subsequent systemic therapy options include single-agent ICIs or chemotherapy. If ICIs have not previously been given, the panel recommends (category 1) atezolizumab, nivolumab, or pembrolizumab as preferred subsequent therapy options for all histologic subtypes based on improved survival rates, longer duration of response, and fewer adverse events when compared with cytotoxic chemotherapy (see Immune Checkpoint Inhibitors in this Discussion). 358, 362, 834, 835, 851, 858 ta show that overall survival is improved with subsequent therapy with atezolizumab, nivolumab, or pembrolizumab compared with docetaxel. 834, 835, 858 However, some patients cannot tolerate immunotherapy or have had disease progression on immunotherapy. A phase 3 randomized trial assessed ramucirumab plus docetaxel versus docetaxel as subsequent therapy options for all histologic subtypes. 1153 Docetaxel has been proven superior to best supportive care, vinorelbine, or ifosfamide with improved survival and quality of life. 1146,1147 When compared with docetaxel, pemetrexed has similar median survival but less toxicity. 1148, 1154 Pemetrexed is a recommended subsequent therapy option for eligible patients with metastatic nonsquamous NSCLC. 891 Docetaxel is recommended for patients with wild-type EGFR tumors based on two randomized trials comparing erlotinib versus docetaxel. 1155, 1156 Patients often have a limited response to subsequent therapy other than ICIs, although chemotherapy may serve a useful palliative role. 1157 OUND, a phase 2 trial, assessed albumin-bound paclitaxel with or without oral 5-azacitidine as subsequent therapy in 161 patients with advanced nonsquamous NSCLC. 1158 Median overall survival was 8.1 months with combination therapy and 17 months with single-agent albumin-bound paclitaxel (HR, 1.7; 95% CI, 1.08-2.57). Grade 3 or greater adverse events were reported in 41% of patients receiving combination therapy and 32% of single-agent albumin-bound paclitaxel.

The NSCLC Panel recommends the following subsequent therapy options for patients with metastatic NSCLC, depending on which agents have not previously been given: 1) atezolizumab, nivolumab, or pembrolizumab if none has been previously given (all are category 1, preferred); 2) docetaxel (± ramucirumab); 3) gemcitabine; 4) albumin-bound paclitaxel; or 5) pemetrexed (nonsquamous only). In patients with PS of 3 to 4, best supportive care is recommended (see the NCCN Guidelines for NSCLC). 664, 721, 722 After second disease progression, subsequent therapy is recommended for certain patients if the following agents have not already been given: 1) atezolizumab, nivolumab, or pembrolizumab if none has been previously given; 2) docetaxel (± ramucirumab; category 2B for both); 3) gemcitabine (category 2B); 4) albumin-bound paclitaxel (category 2B); or 5) pemetrexed (nonsquamous only) (category 2B). 1141, 1156, 1159, 1160 hese patients include those with advanced NSCLC and a PS of 0 to 2.

UNO, a randomized trial, showed that overall survival and PFS were not improved in patients receiving erlotinib as a subsequent therapy option when compared with placebo. 893 The NCCN NSCLC Panel does not recommend erlotinib as a subsequent therapy option (or as switch maintenance therapy) for patients with nonsquamous NSCLC and PS of 0 to 2 but without EGFR mutations based on clinical trial data and a revised NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS-98 levels of 1% or more; the panel does not recommend using atezolizumab or pembrolizumab, or combined therapy with osimertinib and either atezolizumab or pembrolizumab in this setting.

For the 2023 update (Version 1), the NCCN NSCLC Panel expanded the criteria for using adjuvant osimertinib, atezolizumab, or pembrolizumab for eligible patients with completely resected (R0) early-stage NSCLC to include certain patients with stage IIIB (only T3,N2) disease based on differences between the AJCC staging systems for the 7 th and 8 th editions. 159 Although the 8 th edition of the AJCC staging manual is currently being used, the clinical trials used the 7 th edition.

For the 2023 update (Version 1), the NCCN NSCLC Panel recommends adagrasib as a subsequent therapy option for select patients with metastatic NSCLC and KRAS p.G12C mutations who have disease progression after treatment with platinum-based chemotherapy (± immunotherapy) based on clinical trial data and FDA approval. 315 esponsiveness to adagrasib has not been assessed for mutations other than KRAS p.G12C. The NCCN Panel clarified that adagrasib is recommended as third-line or beyond therapy if the patient has not previously received targeted therapy for KRAS p.G12C mutations. The NCCN Panel also recommends lorlatinib as a subsequent therapy option, if not previously given, for patients with ROS1-positive metastatic NSCLC and symptomatic brain metastases. 1162, 1163 r the 2023 update (Version 1), the NCCN Panel clarified that postoperative RT may be considered for select patients with high-risk N2 disease such as extracapsular extension, multistation involvement, inadequate lymph node dissection or sampling, and/or refusal or intolerance of adjuvant systemic therapy. 450, 453, 767 The Panel revised the algorithm for multiple lung cancers. For example, the NCCN Panel added an initial recommendation for multidisciplinary evaluation for patients suspected of or confirmed with having multiple lung cancers. One of the goals during multidisciplinary evaluation for multiple lung cancers is to assess whether patients have lung nodules that can be observed instead of erroneously assuming that patients have stage IV NSCLC. The panel also added the following caveats: lesions at low risk of becoming symptomatic can be observed, such as small subsolid nodules with slow growth. However, treatment should be considered if the lesion(s) show accelerating growth, increasing solid component, or increasing FDG uptake, even if the lesions are small.

|FINDINGS BIOPSY|INITIAL TREATMENT|ADJUVANT TREATMENT| |---|---|---|

|positive, M0 N2 nodes T1-3,|Definitive concurrent chemoradiation n,t (category 1)||

|CLINICAL ASSESSMENT Stage IIIB (T4, N2) Stage IIIC (T4, N3)|PRETREATMENT EVALUATION • Molecular testing for EGFR • FDG-PET/CT scan k (if not previously done) • Brain MRI with contrast r • Pathologic confirmation of N2-3 disease by either: Mediastinoscopy Supraclavicular lymph node biopsy Thoracoscopy Needle biopsy Mediastinotomy EUS biopsy EBUS biopsy • FDG-Contralateral Metastatic disease mediastinal node negative Contralateral mediastinal node positive (T4, N3)|INITIAL TREATMENT Ipsilateral mediastinal node negative (T4, N0-1) See Treatment for Metastasis Treatment for Stage IIIA (NSCL-7) limited sites (NSCL-15) or distant disease (NSCL-18) Ipsilateral mediastinal node positive (T4, N2) Definitive concurrent chemoradiation n,t (category 1) Surveillance (NSCL-17) Durvalumab t,v (if no EGFR exon 19 deletion or L858R) (category 1) or Osimertinib t,v (if EGFR exon 19 deletion or L858R) (category 1)| |---|---|---|

|Stage IVA, M1a: pleural or pericardial effusion|||

|||||NCCN Guidelines Index|NCCN Guidelines Index| |---|---|---|---|---|---|

||||||Table of Contents|

||||||Discussion|

|CLINICAL ASSESSMENT PRETREATMENT EVALUATION||INITIAL TREATMENT hh||||

|Stage IVA, M1b and Stage IVB, M1c|• Biomarker testing contrast r possible metastatic lesion, if confirmation of • Pathologic • FDG-PET/CT scan k • Brain MRI with If not previously done (NSCL-19)|PS 0-2|Multiple lesions Solitary or limited metastases confirmed gg T1-3, N0 • Pathologic Brain mediastinal nodal evaluation h and • Surgical resection m or SABR n,o Other site|(NSCL-19) Advanced/metastatic disease Stereotactic radiosurgery (SRS) alone or Surgical resection, if symptomatic or warranted for diagnosis, followed by SRS or whole brain RT (WBRT) Treatment of Thoracic Disease (NSCL-16) Definitive local therapy for metastatic site, o,ii if not already given|Treatment of Thoracic Disease (NSCL-16) Consider systemic therapy, if not already given as per advanced/ (NSCL-19) metastatic disease|

||||||NSCL-16|

|NCCN Guidelines Version 3.2025||| |---|---|---|

|Non-Small Cell Lung Cancer|Non-Small Cell Lung Cancer|Non-Small Cell Lung Cancer|

|Consider systemic therapy as per advanced/ metastatic disease (NSCL-19) and restaging z to confirm non-progression or Proceed to definitive therapy|T1-3, N1|• Pathologic mediastinal nodal evaluation h and • Chemoradiation t (preferred) or Surgical resection m or Definitive RT n|

||T1-3, N2 T4, N0-2|Definitive chemoradiation t|

|||THERAPY FOR RECURRENCE AND METASTASIS|| |---|---|---|---|

|Locoregional recurrence or symptomatic local disease|Endobronchial obstruction Resectable recurrence Mediastinal lymph node recurrence Superior vena cava (SVC) obstruction No prior RT Prior RT|Any combination of the following: • Laser/stent/other surgery m • External-beam RT or brachytherapy n • Photodynamic therapy • Reresection (preferred) m • External-beam RT or SABR n,o Concurrent chemoradiation n,t Advanced/metastatic disease (NSCL-19) • Concurrent chemoradiation n,t (No evidence of disseminated disease|Observation or Advanced/ metastatic disease (NSCL-19) (category 2B)|

||Severe hemoptysis|Evidence of disseminated disease|Advanced/ metastatic disease (NSCL-|

|Distant metastases||||

||||Table of Contents| |---|---|---|---|

||||Discussion|

|CLINICAL PRESENTATION|HISTOLOGIC SUBTYPE a|BIOMARKER TESTING nn||

|Advanced or metastatic disease|• Establish histologic subtype a with adequate tissue for molecular testing (consider rebiopsy mm or plasma testing if appropriate) • Smoking cessation counseling • Integrate palliative care c (NCCN Guidelines for Palliative Care)|• Adenocarcinoma • Large cell • NSCLC not otherwise specified (NOS) Squamous cell carcinoma|Testing Results (NSCL-20) Testing Results (NSCL-20)|

||||NSCL-19|

|Other Recommended Amivantamab-vmjw + lazertinib (category 1) tt or Osimertinib + pemetrexed + (cisplatin or carboplatin) (nonsquamous) (category 1)| |---|

|JAMA Oncol 2018;4:1112-1115; Oxnard GR, et al. Ann Oncol 2020;31:507-516;|

|NCCN Guidelines Version 3.2025|| |---|---|

|Non-Small Cell Lung Cancer||

|EGFR EXON 19 DELETION OR EXON 21 L858R MUTATIONS nn||

|Progression|Subsequent Therapy (NSCL-22)|

|Progression|Systemic Therapy, Subsequent (NSCL-K 4 of 5)|

|Progression|Subsequent Therapy (NSCL-23)|

||Progression (NSCL-22)| |---|---|

|yy,fff on erlotinib (± ramucirumab or dacomitinib gefitinib, afatinib, bevacizumab),|Progression, see therapy for multiple lesions, below Progression (NSCL|

|NCCN Guidelines Index| |---|

|Table of Contents|

|Discussion|

|EGFR S768I, L861Q, and/or G719X MUTATIONS nn|

|EGFR S768I,|

|L861Q, and/|

|or G719X mutations|

|NSCL-24|

||Amivantamab-vmjw + carboplatin/ pemetrexed rr (nonsquamous) (category 1) (preferred)| |---|---|

|EGFR exon 20 insertion mutation|or Systemic Therapy, Adenocarcinoma (NSCL-K 1 of 5) or Squamous Cell Carcinoma (NSCL-K|

|Progression|Systemic Therapy, Subsequent kkk (NSCL-K 4 of 5)|

||Systemic Therapy, Subsequent kkk (NSCL-K 4 of 5)|

||Progression|

|Table of Contents| |---|

|• Consider definitive local therapy (eg,|

|Asymptomatic|

|Progression yy,fff on alectinib or brigatinib or ceritinib or ensartinib or lorlatinib|

|Symptomatic|

|NSCL-28|

|Principles of Molecular and Biomarker Analysis (NSCL-H). rr Molecular or Biomarker-Directed Therapy for Advanced or Metastatic Disease|fff Plasma or tissue-based testing via broad molecular profiling should be considered at progression for genomic resistance mechanisms. If plasma-| |---|---|

|(NSCL-J). ss For PS 0-4.|based testing is negative, tissue-based testing with rebiopsy material is strongly recommended. Practitioners may want to consider scheduling the biopsy|

||concurrently with plasma testing referral.|

||Table of Contents| |---|---|

||Discussion|

|ROS1 REARRANGEMENT nn||

|FIRST-LINE THERAPY rr|SUBSEQUENT THERAPY rr|

|ROS1 REARRANGEMENT nn|SUBSEQUENT THERAPY rr|

||Progression, Systemic Therapy Adenocarcinoma (NSCL-K 1 of 5) or Squamous Cell Carcinoma (NSCL-K|

|Vxx = % of the whole OAR receiving ≥xx Gy.| |---|

|* NCCN Guidelines for Central Nervous System Cancers.|

|** This regimen includes one dose per week, as the phase 3 study included day 1 & 8 treatments.|

|These constraints represent doses that generally should not be exceeded, based on a| |---|

|consensus survey of NCCN Member Institutions. Because the risk of toxicity increases|

|progressively with dose to normal tissues, a key principle of radiation treatment planning is|

|to keep normal tissue doses "as low as reasonably achievable" while adequately covering|

|the target. The doses to any given OAR should typically be lower than these constraints,|

|approaching them only when there is close proximity to the target volume. ‡ Speirs CK, et al. J Thorac Oncol 2017;12:293-301; Wang K, et al. J Clin Oncol|

|2017;35:1387-1394; Amini A,|

||5 de Baere T, Tselikas L, Woodrum D, et al. Evaluating cryoablation of metastatic lung tumors| |---|---|

|1 Lam A, Yoshida EJ, Bui K, et al. Patient and facility demographics related outcomes in early-stage non-small cell lung cancer treated with radiofrequency ablation: a National Cancer Database analysis. J Vasc Interv Radiol 2018;29:1535-1541. 2 Dupuy DE, DiPetrillo T, Gandhi S, et al. Radiofrequency ablation followed by conventional radiotherapy for medically inoperable stage I non-small cell lung cancer. Chest 2006;129:738-745. 3 Lencioni R, Crocetti L, Cioni R, et al. Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncol 2008;9:621-628. 4 Dupuy DE, Fernando HC, Hillman S, et al. Radiofrequency ablation of stage IA non-small cell lung cancer in medically inoperable patients: Results from the American College of Surgeons|in patients--safety and efficacy: The ECLIPSE Trial--interim analysis at 1 year. J Thorac Oncol 2015;10:1468-1474. 6 Tada A, Hiraki T, Iguchi T, et al. Influence of radiofrequency ablation of lung cancer on pulmonary function. Cardiovasc Intervent Radiol 2012;35:860-867. 7 Abtin F, De Baere T, Dupuy DE, et al. Updates on current role and practice of lung ablation. J Thorac Imaging 2019;34:266-277. 8 Lee JM, Jin GY, Goldberg SN, et al. Percutaneous radiofrequency ablation for inoperable non-small cell lung cancer and metastases: preliminary report. Radiology 2004;230:125-134. 9 Akeboshi M, Yamakado K, Nakatsuka A, et al. Percutaneous radiofrequency ablation of lung neoplasms: initial therapeutic response. J Vasc Interv Radiol 2004;15:463-470. 10 Genshaft SJ, Suh RD, Abtin F, et al. Society of Interventional Radiology Quality Improvement Standards on Percutaneous Ablation of Non-Small Cell Lung Cancer and Metastatic Disease|

|Oncology Group Z4033 (Alliance) trial. Cancer 2015;121:3491-3498.|to the Lungs. J Vasc Interv Radiol 2021;32:1242.e1-1242.e10.|

|PERIOPERATIVE SYSTEMIC THERAPY|

|a Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of|

|immunosuppressive agents; some oncogenic drivers (ie, EGFR exon 19 deletion or exon 21 L858R; ALK, RET, or ROS1 rearrangements) have been|

|shown to be associated with less benefit from PD-1/PD-L1 inhibitors.|

|NSCL-E 1 OF 6|

|a Contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of| |---|

to be associated with less benefit from PD-1/PD-L1 inhibitors.|

|b Examples of high-risk features may include poorly differentiated tumors (including lung neuroendocrine tumors [excluding well-differentiated| |---|

|neuroendocrine tumors]), vascular invasion, wedge resection, visceral pleural involvement, and unknown lymph node status (Nx). These factors|

|independently may not be an indication and may be considered when determining treatment with adjuvant chemotherapy.|

|Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med 2022;386:1973-1985.|

|Cascone T, Awad M, Spicer J, et al. Perioperative nivolumab in resectable lung cancer. N Engl J Med 2024;390:1756-1769.|

|Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med 2023;389:491-503.|

|Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative durvalumab for resectable non-small-cell lung cancer. N Engl J Med 2023;389:1672-1684.|

|Kreuter M, Vansteenkiste J, Fishcer JR, et al. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed|

|versus cisplatin and vinorelbine: the TREAT study. Ann Oncol 2013;24:986-992.|

|Pérol M, Chouaid C, Pérol D, et al. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line|

|treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2012;30:3516-3524.|

|Afatinib 1 Erlotinib 2 Dacomitinib 3 Gefitinib 4,5 Osimertinib 6| |---|

|Osimertinib + pemetrexed + (cisplatin or carboplatin) (nonsquamous) 7 Erlotinib + ramucirumab 8 Erlotinib + bevacizumab c (nonsquamous) 9 Amivantamab-vmjw + lazertinib 10 • Subsequent therapy Osimertinib 11|

|Amivantamab-vmjw +|

|Amivantamab-vmjw + carboplatin + pemetrexed (nonsquamous) 15 • Subsequent therapy Amivantamab-vmjw| |---|

d (nonsquamous) 15 • Subsequent therapy Amivantamab-vmjw| |---|

|Dabrafenib/trametinib 36 Encorafenib/binimetinib 37 Dabrafenib 38| |---|

|Vemurafenib|

|• Subsequent therapy Dabrafenib/trametinib 38,39|

|Encorafenib/binimetinib|

|RET Rearrangement • First-line therapy Selpercatinib 46 Pralsetinib 47| |---|

|• Subsequent therapy Cabozantinib 48,49|

|ERBB2 (HER2) Mutation d • Subsequent therapy Fam-trastuzumab deruxtecan-nxki 50 Ado-trastuzumab emtansine 51|

|NRG1 Gene Fusion • Subsequent therapy Zenocutuzumab-zbco 52|

|HER2-positive IHC3+ • Subsequent therapy Fam-trastuzumab|

|deruxtecan-|

|MOLECULAR AND BIOMARKER-DIRECTED THERAPY FOR ADVANCED OR METASTATIC DISEASE b||

||PD-L1 ≥50% CONTINUATION MAINTENANCE|

|Adenocarcinoma, Large Cell, NSCLC NOS|Squamous Cell Carcinoma|

|• Pembrolizumab (category 1) i • Pembrolizumab + pemetrexed (category 1) j||

|•||

||References|

||NSCL-J 4 OF 6|

|Table of Contents Table of Contents|

|Discussion Discussion|

|a Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in|

|patients who have experienced hypersensitivity reactions after receiving paclitaxel or|

|docetaxel despite premedication, or for patients where the standard premedications|

|(ie, dexamethasone, H2 blockers, H1 blockers) are contraindicated. b Carboplatin-based regimens are often used for patients with comorbidities or those|

|who cannot tolerate cisplatin. C If first-line systemic therapy is completed before treatment for an actionable mutation,|

|and disease has progressed, see Subsequent Therapy (NSCL-K 4 of 5).|

|NSCL-J 6 OF 6 NSCL-K 1 OF 5|

|Preferred • Pembrolizumab/carboplatin/pemetrexed e (category 1) 1,2 • Pembrolizumab/cisplatin/pemetrexed e (category 1) 2 • Cemiplimab-rwlc/pemetrexed/(carboplatin or cisplatin) e (category 1) 3| |---|

|Other Recommended • Atezolizumab f /carboplatin/paclitaxel/bevacizumab e,g,h,i,j (category 1) 4 • Atezolizumab f /carboplatin/albumin-bound paclitaxel e,5 • Nivolumab/ipilimumab e,6 • Nivolumab/ipilimumab/pemetrexed/(carboplatin or cisplatin) e (category 1) 7 • Cemiplimab-rwlc/paclitaxel/(carboplatin or cisplatin) e (category 1) 3 • Tremelimumab-actl/durvalumab/carboplatin/albumin-bound paclitaxel e (category 1) 8 • Tremelimumab-actl/durvalumab/(carboplatin or cisplatin)/pemetrexed e (category 1) 8|

|SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE a,b,c|

|SQUAMOUS CELL CARCINOMA (PS 0-2)|

|Preferred • Pembrolizumab/carboplatin/paclitaxel e (category 1) 35 • Pembrolizumab/carboplatin/albumin-bound paclitaxel e (category 1) 35 • Cemiplimab-rwlc/paclitaxel/(carboplatin or cisplatin) e (category 1) 3|

|Other Recommended • Nivolumab/ipilimumab e,7 • Nivolumab/ipilimumab/paclitaxel/carboplatin (category 1) e,7|

|• Tremelimumab-actl/durvalumab/carboplatin/albumin-bound paclitaxel e,8 (category 1)|

|• Tremelimumab-actl/durvalumab/(carboplatin or cisplatin)/ gemcitabine e,8 (category 1)|

|NSCL-K 2 OF 5|

|l Monitoring During Subsequent Therapy or Maintenance Therapy: Response| |---|

|assessment with CT of known or high-risk sites of disease (eg, chest, abdomen,|

|pelvis) with or without contrast every 6-12 weeks. Timing of CT scans within|

|Guidelines parameters is a clinical decision.|

|SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE -SUBSEQUENT d,l||

|ADENOCARCINOMA, LARGE CELL, NSCLC NOS (PS 0-2)|SQUAMOUS CELL CARCINOMA (PS 0-2)|

|Preferred (no previous IO): Systemic immune checkpoint inhibitors e • Nivolumab w (category 1) • Pembrolizumab x (category 1) • Atezolizumab f (category 1) Other Recommended (no previous IO or previous IO): y|Preferred (no previous IO): Systemic immune checkpoint inhibitors e • Nivolumab w (category 1) • Pembrolizumab x (category 1) • Atezolizumab f (category 1) Other Recommended (no previous IO or previous IO): y|

|• Docetaxel|• Docetaxel|

|• Pemetrexed|• Gemcitabine|

|• Gemcitabine|• Ramucirumab/docetaxel|

|• Ramucirumab/docetaxel|• Albumin-bound paclitaxel|

|• Albumin-bound paclitaxel|• Fam-trastuzumab deruxtecan-nxki (HER2 IHC3+)|

|• Fam-trastuzumab deruxtecan-nxki (HER2 IHC3+)||

|ADENOCARCINOMA, LARGE CELL, NSCLC NOS, SQUAMOUS CELL CARCINOMA (PS 3-4)||

|Best supportive care (NCCN Guidelines for Palliative Care)||

|SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE -PROGRESSION d,l||

|ADENOCARCINOMA, LARGE CELL, NSCLC NOS e,y|SQUAMOUS CELL CARCINOMA e,y|

|• Options for PS 0-2: nivolumab, w pembrolizumab, or atezolizumab f ; fam-|• Options for PS 0-2: nivolumab, w pembrolizumab, or atezolizumab f ; fam-|

|trastuzumab deruxtecan-nxki (HER2 IHC3+); docetaxel (category 2B);|trastuzumab deruxtecan-nxki (HER2 IHC3+); docetaxel (category 2B);|

|pemetrexed (category 2B); gemcitabine (category 2B); ramucirumab/|gemcitabine (category 2B); ramucirumab/docetaxel (category 2B); or|

|docetaxel (category 2B); or albumin-bound paclitaxel (category 2B)|albumin-bound paclitaxel (category 2B)|

|• PS 3-4: Best supportive care|• PS 3-4: Best supportive care|

|• Options for further progression are best supportive care or clinical trial.|• Options for further progression are best supportive care or clinical trial.|

|d Contraindications for treatment with PD-1/PD-L1 inhibitors may include||

|active or previously documented autoimmune disease and/or current use||

|of immunosuppressive agents; some oncogenic drivers (ie, EGFR exon 19|pelvis) with or without contrast every 6-12 weeks. Timing of CT scans within|

|deletion or L858R; ALK, RET, or ROS1 rearrangements) have been shown to be associated with less benefit from PD-1/PD-L1 inhibitors. e If progression on PD-1/PD-L1 inhibitor, using a PD-1/PD-L1 inhibitor is not|Guidelines parameters is a clinical decision. w Nivolumab and hyaluronidase-nvhy subcutaneous injection may be substituted for IV nivolumab. Nivolumab and hyaluronidase-nvhy has different dosing and|

|recommended.|administration instructions compared to IV nivolumab.|

||NSCL-K 4 OF 5|

|NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer|NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion| |---|---|

|SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE -REFERENCES||

|1 Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab||

|for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label||

|KEYNOTE-021 study. Lancet Oncol 2016;17:1497-1508.||

|docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol|docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J Clin Oncol|

|2004;22:1589-1597. 35 Paz-Ares L. Luft A, Vincente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell||

|lung cancer. N Engl J Med 2018;379:2040-2051.||

||NSCL-K 5 OF 5|

|T|Primary Tumor| |---|---|

|TX|Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy|

|T0|No evidence of primary tumor|

|Tis|Carcinoma in situ Squamous cell carcinoma in situ (SCIS) Adenocarcinoma in situ (AIS): adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension|

|T1||

|NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer|NCCN Guidelines Index Table of Contents Discussion| |---|---|

||ST-1|

|Prognostic Groups|Prognostic Groups|Prognostic Groups| |---|---|---|

|T|N|M|

|Occult Carcinoma|||

||for T, N, M (continued)| |---|---|

|N|Regional Lymph Nodes|

|NX|Regional lymph nodes cannot be assessed|

|N0|No regional lymph node metastasis|

|N1|Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension|

|N2|Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)|

|N3|Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)|

|M|Distant Metastasis|

|M0|No distant metastasis|

|M1|Distant metastasis|

||M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion a|

||M1b Single extrathoracic metastasis in a single organ (including involvement of a single nonregional node)|

||M1c Multiple extrathoracic metastases in a single organ or in multiple organs|

||ST-2|

|||||NSCL-32|

||Preferred Capmatinib ss or Tepotinib ss Useful in Certain Circumstances Crizotinib ss|Progression yy|Systemic Therapy, Adenocarcinoma (NSCL-K 1 of 5) or Squamous Cell Carcinoma (NSCL-K 2 of 5)| |---|---|---|---|

|METex14 skipping mutation|or Systemic Therapy, Adenocarcinoma (NSCL-K 1 of 5) or Squamous Cell Carcinoma (NSCL-K 2 of 5)|Progression|Preferred Capmatinib or Tepotinib Useful in Certain Circumstances Crizotinib|

|Non-Small Cell Lung Cancer|||

|Preferred Pralsetinib ss or Selpercatinib ss (category 1)|Systemic Therapy, Adenocarcinoma (NSCL-K 1 of 5) or Squamous Cell Carcinoma (NSCL-K 2 of 5) or Cabozantinib Progression|Systemic Therapy, Adenocarcinoma (NSCL-K 1 of 5) or Squamous Cell Carcinoma (NSCL-K 2 of 5)|

||Systemic Therapy Adenocarcinoma (NSCL-K 1 of 5) or Squamous Cell Carcinoma (NSCL-K 2 of 5) or Cabozantinib Progression|Systemic Therapy, Adenocarcinoma (NSCL-K 1 of 5) or Squamous Cell Carcinoma (NSCL-K 2 of 5)|

|Biomarker-directed therapy (NSCL-J 2 of 6)|Systemic Therapy vvv|

||(NSCL-K 1 of 5) or|

|Progression|Systemic Therapy, Subsequent vvv|

||(NSCL-K 4 of 5)|

|Adenocarcinoma:| |---|

|◊ For small ( < 3 cm),|

|NSCL-C 6 OF 10|

|*Based on constraints used in recent RTOG SABR trials (RTOG 0618, 0813, & 0915). ^For central tumor location. NS = not specified.| |---|

0915). ^For central tumor location. NS = not specified.| |---|

NCCN Guidelines for Central Nervous System Cancers. Methods for evaluation include mediastinoscopy, mediastinotomy, EBUS, EUS, and CT-guided biopsy. An EBUS-TBNA negative for malignancy in a clinically (FDG-PET/CT and/or CT) positive mediastinum should undergo subsequent mediastinoscopy prior to surgical resection.

Temel JS, et al. N Engl J Med 2010;363:733-742. mm Complete genotyping for EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET, RET, ERBB2 (HER2), and NRG1 via biopsy and/or plasma testing. Combinations of tissue and plasma testing, either concurrently or in sequence are acceptable. Concurrent testing can improve time to test results and should be considered in the appropriate clinical situation. Negative results (meaning absence of definitive driver mutation) by one method suggests the use of a complementary method.

AJ, et al. Ann Oncol 2019;30:839-844; Oshima Y, et al.

3.2025, 01/14/25 © 2025 National Comprehensive Cancer Network ® (NCCN ® ), All rights reserved. NCCN Guidelines ® and this illustration may not be reproduced in any form without the express written permission of NCCN.

Definitive local therapy of CNS disease can include asymptomatic lesions at risk for symptomatic progression based on factors including site, location, and edema.eeeThe data in the second-line setting suggest that PD-1/PD-L1 inhibitor monotherapy is less effective, irrespective of PD-L1 expression, in EGFR exon 19 deletion or exon 21 L858R, ALK+ NSCLC.

Strauss GM, Herndon III JE, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008;26:5043-

An FDA-approved biosimilar is an appropriate substitute for bevacizumab. e Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-tqjs has different dosing and administration instructions compared to IV atezolizumab. Atezolizumab e and bevacizumab c,f (category 1) k

Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-tqjs has different dosing and administration instructions compared to IV atezolizumab.

Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al.Pembrolizumab plus chemotherapy in metastatic nonsmall-cell lung cancer.N Engl J Med 2018;378:2078-2092.3GogishviliM,Melkadze T, Makharadze T, et al.Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial.Nat Med 2022;28:2374-2380.4Socinski M, Jotte R, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018;378:2288-2301. 5 West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2019;20:924-937. 6 Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 2019;381:2020-2031. Fossella F, Periera JR, von Pawel J, et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21:3016-3024. 14 Klastersky J, Sculier JP, Lacroix H, et al. A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861. J Clin Oncol 1990;8:1556-1562. 15 Frasci G, Comella P, Panza N, et al. Carboplatin-oral etoposide personalized dosing in elderly non-small cell lung cancer patients. Gruppo Oncologico Cooperativo Sud-Italia. Eur J Cancer 1998;34:1710-1714. 16 Danson S, Middleton MR, O'Byrne KJ, et al. Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer 2003;98:542-553. 17 Ohe Y, Ohashi Y, Kubota K, et al. Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-Cardenal F, Lopez-Cabrerizo MP, Anton A, et al. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 1999;17:12-18. 20 Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage NSCLC. J Clin Oncol 2008;26:3543-3551. 21 Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002;346:92-98. 22 Pujol JL, Breton JL, Gervais R, et al. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin. Ann Oncol 2005;16:602-610. 23 Tan EH, Szczesna A, Krzakowski M, et al. Randomized study of vinorelbine--gemcitabine versus vinorelbine--carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer 2005;49:233-240. 24 Green M, Manikhas G, Orlov S, et al. Abraxane®, a novel Cremophor® -free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol 2006;17:1263-1268. 25 Rizvi N, Riely G, Azzoli C, et al. Phase I/II trial of weekly intravenous 130-nm albumin-bound paclitaxel as initial chemotherapy in patients with stage IV non-small-cell lung cancer. J Clin Oncol 2008;26:639-643. Lilenbaum RC, Herndon JE, List MA, et al. Single-agent versus combination chemotherapy in advanced non-small cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol 2005;23:190-196. 32 Ceresoli GL, Gregorc V, Cordio S, et al. Phase II study of weekly paclitaxel as second-line therapy in patients wit h advanced non-small cell lung cancer. Lung Cancer 2004;44:231-239. 33 Yasuda K, Igishi T, Kawasaki Y, et al. Phase II study of weekly paclitaxel in patients with non-small cell lung cancer who have failed previous treatments. Oncology 2004;66:347-352. 34 Hanna NH, Sheperd FA, Fossella FV, et al. Randomized phase III study of pemetrexed versus

Definitions for T, N, M

T4Tumor > 7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s) in an ipsilateral lobe different from that of the primary

AJCC

Definitions

72,74NELSON, a phase 3 randomized trial, assessed low-dose CT screening in 15,789 individuals at high risk for lung cancer based on age and smoking history; 85% were men.75Individuals were aged 50 to 74 years and currently smoked or had quit smoking within the last 10 years.NCCN, ACS, U.S. Preventive Services Task Force (USPSTF), American College of Chest Physicians, European Society for Medical Oncology (ESMO), and other organizations recommend lung cancer screening using low-dose CT for select high-risk individuals who either currently or previously smoked cigarettes based on clinical trial data (see the NCCN Guidelines for Lung Cancer Screening, available at www.NCCN.org).[75][76] [77][78] [79][80] Low-dose CT screening and follow-up are not a substitute for smoking cessation; patients should be offered smoking cessation counseling (see NCCN Guidelines for Smoking Cessation, available at www.NCCN.org).

81,82,84The guidelines contain an extensive pathology section (see Principles of Pathologic Review in the NCCN Guidelines for NSCLC and Pathologic Evaluation of Lung Cancer in this Discussion). Certain prognostic factors are predictive

[18][19] [20][21] [22][23] [24][25] Biomarker testing is recommended in eligible patients with stage IV disease, including M1a, M1b, and M1c. Testing for certain biomarkers is now also recommended in eligible patients with resectable early-stage NSCLC (see Combined Modality Therapy in this Discussion).

177Molecular testing is also recommended in eligible patients with metastatic NSCLC for less common EGFR mutations-such as EGFR S768I, L861Q, and G719X alterations-based on data showing the efficacy of certain EGFR TKIs (see NSCLC with EGFR Alterations in this Discussion). The panel also recommends testing for EGFR exon 20 insertion mutations in eligible patients with metastatic NSCLC based on data showing the efficacy of novel agents as subsequent therapy options (see NSCLC with EGFR Alterations in this Discussion). metastatic nonsquamous NSCLC or NSCLC NOS so that patients with these driver mutations can receive effective treatment with targeted agents (see Systemic Therapy for Advanced or Metastatic NSCLC in this Discussion and the NCCN Guidelines for NSCLC).

NCCN Panel has preference stratified the first-line therapy options for patients with ALK rearrangement-positive metastatic NSCLC. Alectinib, brigatinib, or lorlatinib are recommended as preferred first-line monotherapy options for patients with ALK rearrangement-positive metastatic NSCLC (see NSCLC with ALK Rearrangements in this Discussion). Ceritinib is an "other recommended" option, whereas crizotinib is "useful in certain circumstances." Data suggest that patients with ALK rearrangement-positive metastatic NSCLC do not respond to single-agent immune checkpoint inhibitors (ICIs). Patients with ALK rearrangements often have brain metastases after progression on the initial targeted therapies. Treatment of limited brain lesionsclinical trials have included up to 3-5 progressing sites-in patients with NSCLC differs from that recommended in the NCCN Guidelines for Central Nervous System Cancers, because patients with NSCLC and brain lesions often have long-term survival; therefore, the potential neurocognitive issues that may occur with whole brain RT are a concern.

257exception is the p.A763_Y764insFQEA mutation; afatinib, erlotinib, or gefitinib are effective for patients with this EGFR exon 20 insertion.257When used at high doses (160 mg/day), osimertinib is associated with response rates of about 25% in patients with EGFR exon 20 insertion mutations, which is much lower than with EGFR exon 19 deletions or EGFR exon 21 L858R mutations.

312,313rrangements do not typically overlap with EGFR, ROS1, BRAF, METex14 skipping, and ALK genetic variants.333However,afew studies suggest that RET rearrangements may infrequently overlap with EGFR or KRAS mutations.312,313NGS, FISH, and RT-PCR can be used to detect RET rearrangements (see Principles of Molecular and Biomarker Analysis in the NCCN Guidelines for NSCLC).

759,760erapy alone.Surgery was done for 83% of patients receiving nivolumab plus chemotherapy versus 75% of those receiving chemotherapy alone.Grade 3 to 4 treatment-related adverse events occurred in 33.5% of patients receiving nivolumab plus chemotherapy versus 36.9% of those receiving chemotherapy alone.NADIM, a single-arm phase 2 study, assessed neoadjuvant therapy with nivolumab plus paclitaxel plus carboplatin in 46 patients with surgically resectable stage IIIA NSCLC; 41 patients had resection.759,760At36months, updated results show that overall survival was 81.9% (95% CI, 66.8%-90.6%).759TMB and PD-L1 levels were not predictive of survival. Grade 3 or higher adverse events were reported in 30% (14/46) of patients including increased lipase (3/46, 7%) and febrile neutropenia (3/46, 7%).

Patients with stage IB NSCLC are less likely to have brain metastases; therefore, brain MRI is optional in this setting and can be considered for select patients at high risk (eg, tumors > 5 cm, central location). If brain MRI cannot be done, then CT of the head with contrast is an option. Note that PET scans are not recommended for assessing whether brain metastases are present (see the NCCN Guidelines for Central Nervous System Cancers, available at www.NCCN.org). Second-line targeted therapy options are recommended for eligible patients with metastatic NSCLC and positive test results for EGFR exon 20 insertions or KRAS p.G12C mutations. First-line immunotherapy options are recommended for eligible patients with metastatic NSCLC and negative test results for actionable driver mutations. Immunotherapy options may be used as first-line or subsequent therapy options in eligible patients with actionable driver mutations as shown in the algorithm, although they are generally not preferred options.

Depending on the extent and type of comorbidity present, patients with stage I or a subset of stage II (T1-2,N1) tumors are generally candidates for surgical resection and mediastinal lymph node dissection. Definitive RT, preferably SABR, is recommended for patients with early-stage NSCLC who are medically inoperable or refuse surgery; RT can be considered as an alternative to surgery in patients at high risk of complications (see Stereotactic Ablative Radiotherapy in this Discussion and see Initial Treatment for Stage I and II in the NCCN Guidelines for NSCLC).

[983][984] [985][986] [987][988] sease after definitive therapy.Data from randomized phase 3 trials are not available to clarify surveillance recommendations; therefore, the most appropriate schedules are controversial.[983][984] [985][986] [987][988] Thesurveillancerecommendationswerecompiledby polling the NCCN NSCLC Panel regarding their practice patterns.Details regarding the specific surveillance schedules are outlined in the algorithm based on stage and the definitive treatment (see Surveillance After Completion of Definitive Therapy in the algorithm).Surveillance schedules for most patients with metastatic disease are individualized for each patient, although the NCCN Guidelines provide a surveillance schedule for certain patients with stage IV oligometastatic disease.NLST, a large randomized trial, assessed lung screening with low-dose CT screening versus chest radiography in individuals at high risk for lung cancer.73Low-doseCTscreening decreased mortality from lung cancer (mainly adenocarcinoma) compared with chest radiography (247 vs. 309 deaths, respectively; 20% relative reduction in mortality; 95% CI, 6.8-26.7;P= .004).73Low-dose CT is recommended for screening individuals at high risk for lung cancer (see the NCCN Guidelines for Lung Cancer Screening, available at www.NCCN.org). The NCCN NSCLC Panel feels that low-dose CT is beneficial for identifying recurrences in patients previously treated for NSCLC. It is i portant to note that the surveillance recommendations for patients who have been treated for NSCLC are different from the screening recommendations for individuals at high risk for lung cancer (see the NCCN Guidelines for Lung Cancer Screening).

178, 179, 257, 295on mutations are the third most common group of EGFR mutations; they occur in approximately 2% of patients with NSCLC and 4% to 12% of patients with EGFR mutations.179,259,294,295EGFRexon 20 insertion mutations are a heterogeneous group; while NSCLC with these variants generally have low response rates to earlygeneration EGFR TKIs, variable levels of response with newer therapies have been reported, depending on the variant.178,179,257,1027

Osimertinib is a third-generation oral EGFR TKI that is approved by the U.S. Food and Drug Administration (FDA) for the treatment of NSCLC with EGFR alterations. 1028,1029 Osimertinib monotherapy and osimertinib in combination with platinum and pemetrexed chemotherapy are both indicated for the first-line treatment of adults with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R mutation.

358,827,834,83534]erations.181,250,256,[1034] [1035][1036] Erlotinib, gefitinib, and dacomitinib have all been approved by the FDA for the treatment of metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.1037-1039Erlotinib in combination with either ramucirumab 1040 or bevacizumab 1036,1041 can also be considered as options.Several studies have reported that programmed cell death protein 1 (PD-1)/PD-L1 inhibitor monotherapy in the second-line setting is less effective in EGFR exon 19 deletion or exon 21 L858R-positive NSCLC, regardless of PD-L1 expression.358,827,834,835Recentdata also suggest that PD-1 inhibitor (pembrolizumab) in combination with chemotherapy as subsequent therapy may not have an OS or PFS benefit compared with chemotherapy alone in patients with metastatic NSCLC and EGFR exon 19 deletion or exon 21 L858R.1042

1045A post-hoc analysis of several LUX-Lung trials (LUX-Lung 2, 3, and 6) assessed afatinib in patients with advanced NSCLC and the most frequent uncommon EGFR mutations (L861Q, G719X, and S768I).1026Median OS was 19.4 months. A response to afatinib was reported in 8 patients (100%) with EGFR S768I mutations. Among those with EGFR G719X mutations, an objective response to afatinib was reported in 14 patients (77.8%), while a response to afatinib was reported in 9 patients (56.3%) of those with EGFR L861Q.

2182,1063ALEX, a phase 3 randomized trial, assessed first-line therapy with alectinib versus crizotinib in 303 patients with ALK-positive advanced NSCLC including those with asymptomatic CNS disease.218Disease progressi n or death occurred in a lower proportion of patients receiving alectinib when compared with crizotinib (41% vs. 68%). Investigator-assessed PFS rate was higher with alectinib versus crizotinib (68.4% versus 48.

1072,1073A phase 2 trial assessed lorlatinib in patients with ALK-positive or ROS1-positive advanced NSCLC and disease progression after ALK inhibitor therapy; many patients had asymptomatic CNS metastases.1072In the cohort of

190,344,349,1083,1084A phase 2 single-arm trial assessed crizotinib in 127 East Asian patients with ROS1-positive advanced NSCLC who had received 3 or fewer lines of systemic therapy. The objective response rate was 71.7% with 17 complete responses; the median duration of response was 19.7 months. The median PFS was 15.9 months. 1084 PROFILE 1001, a phase 1 study, assessed crizotinib in 50 patients with advanced NSCLC and ROS1 rearrangements.

UPDATES

PRINCIPLES OF RADIATION THERAPY -REFERENCES NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer

MS-97

indication by the FDA. 893 A phase 3 randomized trial compared afatinib with erlotinib as subsequent therapy options for patients with squamous cell NSCLC . 1161 Overall survival was 7.9 months (95% CI, 7.2-8.7) for afatinib versus 6.8 months (95% CI, 5.9-7.8) for erlotinib (HR, 0.81; 95% CI, 0.69-0.95; P = .0077). Almost 60% of patients in each arm had grade 3 or higher adverse events. In contrast, the median overall survival was 9.2 months with nivolumab compared with 6.0 months for docetaxel for patients with squamous cell NSCLC. 362 In addition, only 7% of patients receiving nivolumab had grade 3 or higher adverse events. The NCCN NSCLC Panel does not recommend erlotinib as a subsequent therapy option for patients with squamous cell NSCLC based on this study comparing afatinib with erlotinib; this study was statistically significant but not clinically significant. 1161 Erlotinib or afatinib are not recommended as subsequent therapy options for patients with squamous cell NSCLC; they are less efficacious and safe compared to other available options. 1161

|Descriptor|7th Edition T/N/M|8th Edition T/N/M| |---|---|---|

|T component|||

|0 cm (pure lepidic adenocarcinoma ≤3 cm in total size)|T1a if ≤2 cm; T1b if > 2-3 cm|Tis (AIS)|

|≤0.5 cm invasive size (lepidic predominant adenocarcinoma ≤3 cm total size)|T1a if ≤2 cm; T1b if > 2-3 cm|T1mi|

|≤1 cm|T1a|T1a|

|> 1-2 cm|T1a|T1b|

|> 2-3 cm|T1b|T1c|

|> 3-4 cm|T2a|T2a|

|> 4-5 cm|T2a|T2b|

|> 5-7 cm|T2b|T3|

|> 7 cm|T3|T4|

|Bronchus < 2 cm from carina|T3|T2|

|Total atelectasis/pneumonitis|T3|T2|

|Invasion of diaphragm|T3|T4|

|Invasion of mediastinal pleura|T3|-|

|N component|||

|No assessment, no involvement, or involvement of regional lymph nodes|NX, N0, N1, N2, N3|No change|

|M component|||

|Metastasis within the thoracic cavity|M1a|M1a|

|Single extrathoracic metastasis|M1b|M1b|

|Multiple extrathoracic metastasis|M1b|M1c|

|||ST-3|

||NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer|NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer|NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer| |---|---|---|---|

|||TBNA|transbronchial needle aspiration|

|||TKI|tyrosine kinase inhibitor|

|||TNM|tumor node metastasis|

|||TTF-1|thyroid transcription factor-1|

|||TTNA|transthoracic needle aspiration|

|||UIP|usual interstitial pneumonia|

|||VATS|video-assisted thoracic surgery|

|||VEGF|vascular endothelial growth factor|

|||VMAT|volumetric modulated arc therapy|

|||VUS|variant of uncertain significance|

|SBRT|stereotactic body radiation therapy|||

|SCLC|small cell lung cancer|||

|SDOH|social determinants of health|||

|SRS|stereotactic radiosurgery|||

|SRT|stereotactic radiation therapy|||

|SUV|standardized uptake value|||

|SVC|superior vena cava|||

|The| |---|

|3,| |---|

|Ber-EP4, MOC31, and CD15; however, these markers generally do not|

|exon 21| |---|

|L858R) metastatic NSCLC. Osimertinib is a preferred first-line EGFR TKI|

|option for patients with EGFR-positive metastatic NSCLC (see NSCLC|

|with EGFR Alterations in this Discussion). Erlotinib (± bevacizumab or|

|ramucirumab), afatinib, dacomitinib, or gefitinib are "other recommended"|

|EGFR TKI options for first-line therapy. Osimertinib is recommended|

|(category 1) as second-line and beyond (subsequent) therapy for patients|

|with EGFR T790M-positive metastatic NSCLC and disease progression|

|on erlotinib (± bevacizumab or ramucirumab), afatinib, dacomitinib, or|

|gefitinib. 264,290|

|406,548-550 Image-guided thermal| |---|

|ablation (eg, cryotherapy, microwave, radiofrequency ablation [RFA]) is an|

|option for selected patients who are medically inoperable and will not|

|The median event-free survival was 31.6 months (95% CI, 30.2-not| |---|

|reached) for nivolumab plus chemotherapy versus 20.8 months (95% CI,|

|14.0-26.7) for chemotherapy alone (HR, 0.63; 97% CI, 0.43-0.91;|

|P=.005). The pathologic complete response was 24% (95% CI, 18%-|

|31%) with nivolumab plus chemotherapy versus 2.2% (95% CI, 0.6%-|

|5.6%) with chemotherapy alone (odds ratio 13.9; 99% CI, 3.49-55.7;|

|PORT-C, a phase 3 randomized trial, assessed postoperative RT versus| |---|

|no postoperative RT in 394 patients with completely resected stage IIIA|

|(N2) NSCLC who had received adjuvant chemotherapy. 453 The 3-year|

|disease-free survival rates were 40.5% with postoperative RT versus|

|32.7% with no RT (median, 22.1 vs. 18.6 months) (HR, 0.84; 95% CI,|

|Initial Therapy As previously mentioned, accurate pathologic assessment and staging are essential before treatment for NSCLC, because management varies depending on the stage, histology, presence of genetic variants, and PS. Before treatment, it is strongly recommended that determination of tumor resectability be made by thoracic surgeons who perform lung cancer surgery as a prominent part of their practice (see Principles of Surgical Therapy in the NCCN Guidelines for NSCLC). RT doses are provided in the algorithm (see Principles of Radiation Therapy in the NCCN Guidelines for NSCLC). In addition, the NCCN Guidelines also recommend regimens for targeted therapy, immunotherapy, chemotherapy, and chemoradiation (see Perioperative Systemic Therapy, Concurrent Chemoradiation Regimens, Molecular and Biomarker-Directed Therapy for Advanced or Metastatic Disease, and Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for NSCLC). First-line targeted therapy options are recommended for eligible patients with metastatic NSCLC and positive test results for actionable driver mutations such as ALK, BRAF p.V600E, EGFR, METex14 skipping, NTRK1/2/3, RET, and ROS1. Stage I,| |---|

|FLAURA, a phase 3 randomized trial, assessed first-line therapy with| |---|

|osimertinib compared with either erlotinib or gefitinib in patients with|

|metastatic NSCLC and EGFR mutations (exon 19 deletion or|

|L858R).|

|3 months vs. 4.2 months; HR, 0.48; P < .001). The objective| |---|

|response rate was 64% with amivantamab-vmjw plus chemotherapy|

|versus 36% with chemotherapy alone. No statistically significant|

|difference in OS was reported in the interim analysis. The most common|

|grade 3 or higher AEs were neutropenia, thrombocytopenia, anemia, and|

|leukopenia.|

|In the first-line setting, the NCCN NSCLC Panel recommends single-| |---|

|agent osimertinib as a preferred treatment option for patients with|

|advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21|

|L858R mutations. Single-agent erlotinib, afatinib, gefitinib, or dacomitinib|

|are other recommended first-line treatment options. All of these are|

|category 1 recommendations and are appropriate for patients with|

|performance status 0-4.|

|Osimertinib has also been studied in patients with less common EGFR| |---|

|mutations, including S768I, L861Q, and G719X. KCSG-LU15-09, a|

|phase 2 trial based in Korea, assessed first-line therapy with osimertinib|

|in patients with metastatic or recurrent NSCLC and these mutations. 291|

|The median PFS was 8.2 months and the objective response rate was|

|50%. An objective response with osimertinib was observed in 78% (7/9)|

|of those with EGFR L861Q, 53% (10/19) of those with EGFR G719X,|

|and 38% (3/8) of those with EGFR S768I). The median PFS was 15.2|

|months, 8.2 months, and 12.3 months in the L861Q, G719X and S768I|

|groups, respectively. Manageable AEs included rash, pruritus,|

|decreased appetite, diarrhea, and dyspnea. 291|

|ALK-positive patients who had received at least one previous ALK| |---|

|inhibitor, objective responses were achieved in 47% of patients; there|

|were 4 complete responses and 89 partial responses. In those with|

|measurable baseline CNS lesions, an objective intracranial response|

|was observed in 63% of patients. Lorlatinib was effective in patients who|

|had received up to three previous ALK inhibitors. Grade 3 to 4 AEs|

|included hypercholesterolemia and hypertriglyceridemia. Serious|

|treatment-related AEs occurred in 7% of patients including cognitive|

|effects in 1%; the cognitive effects resulted in permanent discontinuation|

|of lorlatinib.|

Summary

Management of NSCLC is described in the NCCN Guidelines for NSCLC, which include the algorithm and this supporting Discussion text. Revisions for the 2023 update of the NCCN Guidelines for NSCLC are described in this Discussion and outlined in the algorithm (see Summary of the Guidelines Updates in the algorithm). Most lung cancer (approximately 85%) is due to NSCLC; SCLC accounts for about 15% of lung cancer. Recommendations for SCLC are provided in a different guideline (see the NCCN Guidelines for Small Cell Lung Cancer, available at www.NCCN.org). The NCCN Guidelines for NSCLC are updated at least once a year by the NCCN NSCLC Panel; there were 6 updates to the 2022 guidelines.

For the 2023 update (Version 1), the NCCN NSCLC Panel revised the Principles of Molecular and Biomarker Analysis. For example, the NCCN Panel added testing recommendations for ERBB2 (HER2) mutations.

NGS-based approaches are best able to detect the broad spectrum of genomic ERBB2 (HER2) alterations that may occur, although Sanger sequencing and targeted PCR approaches may also be used. The NCCN Panel also revised the Principles of Diagnostic Evaluation in the NCCN Guidelines for NSCLC. For example, the NCCN Panel clarified that a preoperative biopsy may be useful for patients with early-stage NSCLC (ie, clinical stage IB or more) who may be candidates for systemic therapy before surgery (also known as neoadjuvant, induction, or preoperative therapy). 107 The NCCN Panel added a recommendation that patients should be evaluated for perioperative (neoadjuvant or adjuvant) therapy before surgery. Neoadjuvant therapy should not be used to attempt to induce resectability in patients who do not already meet criteria for resectability on initial evaluation.

For the 2023 update (Version 2), the NCCN Panel added a recommendation for adjuvant pembrolizumab for eligible patients with completely resected (R0) stage IIB to IIIA, stage IIIB (only T3,N2), or high-risk stage IIA NSCLC who are negative for EGFR exon 19 deletions, EGFR exon 21 L858R mutations, or ALK fusions and who have previously received adjuvant chemotherapy. 751 The panel added a caveat that the benefit of adjuvant pembrolizumab is unclear for patients with PD-L1 levels less than 1%. The NCCN Panel also expanded the molecular testing criteria to include ALK rearrangements because patients with completely resected (R0) NSCLC who have ALK rearrangements, EGFR exon 19 deletions, or EGFR exon 21 L858R mutations have less benefit from ICIs. 184 Single-agent therapy with osimertinib is recommended for eligible patients with completely resected (R0) stage IB-IIIA or stage IIIB (T3, N2) NSCLC if patients have EGFR exon 19 deletions or EGFR exon 21 L858R mutations, regardless of PD-L1 levels. The NCCN Panel clarified that adjuvant chemotherapy followed by single-agent therapy with osimertinib is recommended for eligible patients with completely resected (R0) early-stage NSCLC if patients have both EGFR mutations and PD-L1 NCCN Guidelines Version 3.2025 Non-Small Cell Lung Cancer MS- 99

References

引用 / 出处

NCCN临床实践指南：非小细胞肺癌（2025.V3）. 2025.