2025 ATORG专家共识声明：非小细胞肺癌的围手术期管理

A B S T R A C T

Keywords: Asian Consensus statement Peri-operative NSCLC

The peri -operative management of non-small cell lung cancer (NSCLC) in earlier stage disease has seen significant advances in recent years with the incorporation of immune checkpoint inhibitors and targeted therapy. However, many unanswered questions and challenges remain, including the application of clinical trial data to routine clinical practice. Recognising the unique demographic profile of Asian patients with NSCLC and heterogeneous healthcare systems, the Asian Thoracic Oncology Research Group (ATORG) convened a consensus meeting in Singapore on 26 April 2024 to discuss relevant issues spanning diagnostic testing to post-neoadjuvant treatment considerations and future directions. An interdisciplinary group of 19 experts comprising medical oncologists, thoracic surgeons, radiation oncologists, pulmonologists and pathologists from Singapore, Hong Kong, Mainland China, Korea, Japan, Taiwan, India, Malaysia, Thailand, Vietnam and Australia met to discuss emerging data, identify existing gaps in clinical care and develop a multidisciplinary, multinational expert consensus statement on the peri -operative management of NSCLC tailored to the Asia-Pacific region.

S.P.L. Saw et al.

1. Introduction

For almost two decades, cisplatin-based chemotherapy was the only adjuvant therapy to demonstrate a statistically significant, albeit modest, improvement in overall survival (OS) among patients with stage II-III and select stage IB non-small cell lung carcinoma (NSCLC). [1] Leveraging the biomarker-directed approach to guide systemic treat ment in advanced stage NSCLC, the introduction of immune checkpoint inhibitors (ICI) and targeted therapies for sensitizing epidermal growth factor receptor ( EGFR ) and anaplastic lymphoma kinase ( ALK ) alter ations have since improved treatment outcomes for patients with non-metastatic disease, leading to a paradigm shift in adjuvant treatment recommendations. [2 – 6] Most recently, peri -operative immunotherapy plus chemotherapy approaches have gained traction following the readouts of multiple phase III randomised controlled trials (RCTs) demonstrating that the addition of PD-(L)1 inhibitors to neoadjuvant chemotherapy improves complete pathological response (pCR) rates, event-free survival (EFS) and even OS. [7 – 13] Despite these advances, controversies still exist particularly where current evidence remains limited.

In Asia, where oncogenic driver mutations such as EGFR are more prevalent relative to Caucasian populations [14] , patient selection for peri -operative approaches requires special attention. Accessibility and healthcare resources also heavily influence clinical practice and contribute to the disparity between clinical trial data and real-world management. With these considerations in mind, the Asian Thoracic Oncology Research Group (ATORG) convened an interdisciplinary consensus meeting comprising 19 experts from Singapore, Hong Kong, Mainland China, Korea, Japan, Taiwan, India, Malaysia, Thailand, Vietnam and Australia. This manuscript presents the consensus recom mendations with supporting evidence and outlines important research priorities for the region.

2. Methods

A multidisciplinary panel of 19 experts from various countries comprising medical oncology, thoracic surgery, radiation oncology, respiratory medicine, lung and molecular pathology was convened by ATORG to discuss emerging data, identify existing gaps in clinical care and develop a consensus statement on the peri -operative management of NSCLC tailored to the Asia-Pacific region. Topics discussed included (i): Molecular testing and diagnostics; (ii) Local therapies; (iii) Peri-operative immunotherapy plus chemotherapy; (iv) Adjuvant targeted therapy and (v) Future directions. For consistency, the 8th edition of TNM staging was referenced throughout unless otherwise specified [15] . Each statement was discussed in detail during the meeting and consensus was reached only if all 19 experts agreed. Each recommen dation was accompanied by a level of evidence and strength of recom mendation adapted from the ‘Infectious Diseases Society of America-United States Public Health Service Grading System ’ ( Supplementary Table S1 ), indicated in parentheses [16 – 17] . The final manuscript was reviewed and approved by all authors.

3. Results

3.1. Molecular testing and diagnostics

3.1.1. Should all patients with pathologically confirmed stage IB-III NSCLC patients be tested for PD-L1, EGFR mutation and ALK rearrangement?

Statement: All patients with stage IB-III NSCLC should be offered PD-L1 testing. For non-squamous histology, EGFR mutation and ALK -rear rangement should also be tested. [I,A].

Discussion: The predictive value of high PD-L1 tumour proportion score (TPS) in selecting patients for ICI monotherapy is well established in the metastatic setting [18 – 19] . While a similar observation was seen in IMpower010 where only the $\tt T P S\ \geq\ 50\ \%$ subgroup derived a

statistically significant disease-free survival (DFS) and OS benefit from adjuvant atezolizumab, PD-L1 TPS score was not predictive of benefit from adjuvant pembrolizumab in PEARLS/KEYNOTE-091 [5 – 6] . Pos tulations for the discordant results include overperformance of the control arm in PEARLS/KEYNOTE-091 and possible imbalances be tween the control and study arm given molecular testing was not mandated, although these hypotheses remain exploratory. These results notwithstanding, PD-L1 testing was mandated in all the peri -operative immunotherapy plus chemotherapy trials on pre-treatment biopsy samples and TPS was used as a stratification factor [7 – 12] . Therefore, PD-L1 testing should be routinely offered to all patients with stage IB-III NSCLC to facilitate discussions on the extent to which they may benefit from treatment.

As patients with EGFR mutations and ALK -rearrangements were generally excluded from most of the peri -operative immunotherapy plus chemotherapy trials, non-squamous NSCLC tumours should be tested for these 2 oncogene alterations [7,10 – 12] . Furthermore, patients with common sensitizing EGFR mutations (ex19del/L858R) or ALK -rear rangements may be candidates for adjuvant osimertinib or alectinib respectively [2 – 3,20] . Given the prevalence of these oncogene drivers in Asia, particularly EGFR, testing should be routinely performed for stage IB-III non-squamous NSCLC [14] .

3.1.2. Should PD-L1, EGFR and ALK testing be done on pre-operative diagnostic biopsies for patients with clinical stage IB-IIIA NSCLC?

Statement: For patients with clinical Stage II-IIIA NSCLC: PD-L1, EGFR and ALK should be routinely performed pre-operatively. [I,C] Consensus was not reached for stage IB.

Discussion: PD-L1, EGFR and ALK testing should be performed on the diagnostic biopsies for all patients being considered for peri -operative immunotherapy plus chemotherapy as outlined above, especially in Asia [7 – 12,14] . While all panelists agreed that this should be routinely done for clinical stage II-IIIA tumours, some experts highlighted that pre-operative biopsies are not always performed for clinical stage IB tu mours before surgery. Reasons cited include technical considerations such as small tumour size which may make pre-operative biopsy chal lenging to perform and low index of suspicion for cancer pre-surgery. Staging may also be uncertain pre-surgery. Furthermore, stage IB (as per TNM 8th edition [15] was not included in the peri -operative immu notherapy plus chemotherapy trials, hence testing for EGFR, ALK and PD-L1 can reasonably be deferred to the post-operative surgical spec imen when considering adjuvant therapy. Nonetheless, the panel agreed these considerations should be discussed with all patients including clinical stage IB prior to surgery, considering the risk – benefit ratio.

3.1.3. Should multi-disciplinary team (MDT) discussion be mandated for all stage IB-III resectable NSCLC pre-operatively?

Statement: MDT discussion does not need to be mandated pre-operatively for all patients with stage IB NSCLC but should be made available for all patients with clinical stage II-III NSCLC. [V,C]

Discussion: Although improvements in survival are inconsistent, multidisciplinary care has been shown in multiple studies to improve treatment outcomes in patients with NSCLC [21 – 25] . Some centers also offer multidisciplinary clinics where patients are seen by various spe cialists in the same clinic, which has been reported to improve patient satisfaction and shorten time to treatment initiation [26 – 28] . The main purpose of MDT discussion is to arrive at an interdisciplinary consensus on optimal patient management, particularly for challenging cases. However, MDT discussions require a significant time commitment from physicians across multiple disciplines such as medical oncology, thoracic surgery, radiation oncology, respiratory medicine, pathology and interventional radiology. Given the significant time and resources needed for MDT discussions, the panel agreed that more complex cases such as stage II-III NSCLC should be prioritized and MDT discussion be made optional for stage IB except for less straightforward cases. None theless, the panel acknowledges that this is an evolving space depending

S.P.L. Saw et al.

on emerging trial data and updated staging systems [29] , and MDT discussions should be made available for optimal patient care wherever possible.

3.1.4. Should PET CT scan be performed pre-operatively for all patients with clinical IB-III NSCLC planned for surgery?

Statement: PET CT scan should be performed pre-operatively for all patients with pathologically confirmed, clinical stage IB-III NSCLC planned for surgery. [III,B].

Discussion: Fludexoyglucose-18 positron-emission tomography and computed tomography (FDG PET/CT) is recommended for NSCLC staging as it has been shown to be more accurate in detecting inoperable disease as compared with contrast-enhanced computed tomography (CT) scan of the chest and upper abdomen [30] . The current National Comprehensive Cancer Network (NCCN) guidelines recommend per forming staging scans within 60 days before proceeding with surgical evaluation. While FDG PET/CT is the preferred imaging modality for staging, the panel recognizes that reimbursement policies are a limiting factor in the real-world and would like to advocate for access to prevent unnecessary thoracic surgeries [31] . In cases where the diagnosis of NSCLC is only made post-operatively, especially for patients who did not undergo a diagnostic biopsy prior to surgery, a PET CT scan should be performed post-operatively to complete staging.

3.1.5. Should brain imaging be performed pre-operatively for all patients with clinical IB-III NSCLC planned for surgery?

Statement: Contrast-enhanced CT or MRI Brain should be performed pre-operatively for all patients with pathologically-confirmed, clinical stage II-III NSCLC but is optional for stage IB in otherwise asymptomatic patients. [III,B].

Discussion: Magnetic resonance imaging (MRI) is known to increase the detection of brain metastases over CT and is the preferred staging modality for NSCLC [32] . Higher stage disease is known to predict for brain metastases, estimated at $0–1\;\%$ in stage IA and up to $21\,\%$ in stage IIIA in otherwise asymptomatic patients [33 – 36] . The presence of brain metastases affects staging, prognosis and management decisions, underscoring the importance of early detection even in asymptomatic patients. The panel recognizes that MRI is not as widely available as CT and costs may also be prohibitive in some settings. In such situations, contrast-enhanced CT brain is a reasonable alternative to MRI for completion of staging to avoid delaying treatment. In cases where the diagnosis of NSCLC is only made post-operatively, especially for patients who did not undergo a diagnostic biopsy prior to surgery, brain imaging should be performed post-operatively to complete staging.

3.1.6. Should imaging be repeated after neoadjuvant immunotherapy plus chemotherapy for all patients before surgery?

Statement: Contrast-enhanced cross-sectional imaging should be performed for all patients after neoadjuvant immunotherapy plus chemotherapy to assess suitability for surgical resection. [I,A].

Discussion: Contrast-enhanced cross-sectional imaging is required to assess response to neoadjuvant immunotherapy plus chemotherapy and was mandated prior to surgery in all the peri -operative RCTs, with CT scans as the most commonly used imaging modality [7 – 12] . Although the proportion of patients who had progressive disease while on neo adjuvant immunotherapy plus chemotherapy in these trials were generally low, ranging from $3~-~7~\mathrm{~\textperthousand~}$ [7 – 12] , objective radiologic assessment should be performed to assess suitability for surgery to avoid unnecessary morbidity.

3.1.7. Should brain imaging be repeated after neoadjuvant immunotherapy plus chemotherapy for all patients before surgery?

Statement: Contrast-enhanced CT or MRI Brain does not need to be repeated after neoadjuvant immunotherapy plus chemotherapy in otherwise asymptomatic patients before surgery. [I,C].

Discussion: Repeat brain imaging after neoadjuvant immunotherapy

plus chemotherapy was not stipulated prior to surgery in any of the peri - operative trials [7 – 12] . Although prospective data is lacking, the panel feels that the risk of developing intracranial metastases in this popula tion after neoadjuvant immunotherapy plus chemotherapy is generally low especially if baseline brain scans were negative. Therefore, repeat brain imaging prior to surgery is not necessary in otherwise asymp tomatic patients to avoid unnecessary costs and conserve healthcare resources.

3.1.8. Should pCR and MPR be standardized and integrated into routine pathology report post-neoadjuvant therapy?

Statement: pCR and MPR definitions should be standardized and integrated into routine pathology reports post-neoadjuvant therapy. [I, B].

Discussion: The International Association for the Study of Lung Cancer (IASLC) has proposed standardized definitions for pCR (patho logic complete response) and MPR (major pathologic response) in 2020, namely no viable tumour and less than or equal to $10\,\%$ of viable tumour respectively [37] . Given the growing interest in using pathological response as a primary endpoint in RCTs, it is imperative that these definitions are internationally standardized [7,9 – 10,12,27] . The panel highlighted concerns in the real-world setting where not all pathologists may be familiar with handling and reading specimens post-neoadjuvant therapy and hence pathologic response including pCR or MPR may be inappropriately accessed. However, given that peri -operative immuno therapy plus chemotherapy approaches are the new standard of care and will become more widely used, it is crucial that pathologists reporting lung cancer develop the necessary expertise. Accurate pathological assessment will also be essential when considering adapting adjuvant treatment based on pCR/MPR status, which will likely be incorporated in future trial designs.

3.1.9. Should ctDNA levels be used as a clinical decision-making tool in the peri-operative setting?

Statement: At present, ctDNA levels should not be used as a clinical decision-making tool in the peri -operative setting. [III,C].

Discussion: The concept of minimal residual disease (MRD) to select patients for adjuvant therapies is attractive. A true positive MRD test should identify patients at high risk for relapse so adjuvant therapies can be administered to eliminate micrometastatic disease, whilst a true negative MRD test should indicate a patient is cured after surgery and does not need further treatment. Therefore, the success of MRD-based approaches is highly contingent on assay performance. While a posi tive circulating tumour DNA (ctDNA) result is well established as a poor prognostic biomarker, current commercially available MRD assays do not achieve a sufficient negative predictive value [38 – 43] . This was alluded to in the exploratory analysis of IMpower010 where patients who had a negative post-operative ctDNA result still derived a DFS benefit from adjuvant atezolizumab, suggesting that the assay used was of insufficient sensitivity [44] . Therefore, using a negative ctDNA result to recommend treatment de-escalation is not appropriate at present given the current technological limitations. While treatment intensifi cation based on a positive MRD result is a strategy that is of interest, this should be studied prospectively in a randomised trial. Therefore, based on the current data available, ctDNA levels should not be used as a clinical decision-making tool in the peri -operative setting.

3.2. Local therapy

3.2.1. What constitutes upfront surgically unresectable disease in an otherwise medically fit patient?

Statement: The goal of surgery is to achieve complete (R0) resection. The pathologically confirmed N3 disease is considered surgically unre sectable. [III,A]. Consensus was not reached on the resectability of multi-station N2, T4 tumours and single station bulky N2 disease.

Discussion: One of the primary goals of surgery is to achieve R0

3

S.P.L. Saw et al.

resection. Clinical practice follows the definition of complete resection proposed by the International Association for the Study of Lung Cancer (IASLC) in 2005, which includes negative margins, systematic medias tinal lymph node dissection or lobe-specific lymph node dissection, negative highest mediastinal lymph nodes, and no extracapsular extension of tumor in nodes [45] . The concept of resectability not only implies that the patient ’ s condition can tolerate surgery and that com plete resection is technically feasible but also suggests the potential for achieving a favorable prognosis through surgical intervention, indi cating oncological resectability. The assessment of resectability is influenced by both the technical capabilities of the surgeon and their understanding of tumor biology; therefore, it should be evaluated by experienced surgeons within a multidisciplinary team environment.

Given that induction therapy, particularly immunotherapy plus chemotherapy, can reduce tumor burden, improve surgical resectability, and eliminate micrometastases [46] . a critical question arises: does the resectability definition proposed in the era of chemotherapy still apply in the era of neoadjuvant immunotherapy plus chemotherapy? Stage III lung cancer is categorized as unresectable when there is contralateral mediastinal or hilar lymph node involvement (N3). The ACCP Evidence-Based Clinical Practice Guidelines stratify highly heterogeneous stage IIIA N2 disease based on different clinical time points, size of nodes, and numbers of positive N2 lymph nodes into four subsets for clinical treatment decisions [47] . The resectability of multi-station N2, T4 tu mors, and single station bulky N2 disease is contentious and should be considered potentially resectable. The EORTC-Lung Cancer Group pre sented an international multidisciplinary survey on resectability of stage III NSCLC at WCLC 2023, revealing substantial consensus and diver gence among scholars of different specialties regarding resectability understanding [48] . In the future, the definition of resectability may evolve with the introduction of new technologies. Robot-assisted thor acoscopic surgery offers certain advantages in complex thoracic pro cedures, for example more thorough lymph node dissection [49] , which may enhance the upper limits of surgical technique. MRD techniques based on ctDNA can identify high-risk recurrence populations post operatively [50] , with the potential to redefine complete resection from a biological perspective.

3.2.2. In which patients should definitive chemoradiation be favoured over a peri-operative approach in an otherwise medically fit patient?

Statement: Definitive chemoradiation should be the preferred approach for N3 disease and patients with upfront unresectable clinical stage III NSCLC. [I,A].

Discussion: For unresectable stage III NSCLC or N3 disease, definitive chemoradiation is the standard of care (SOC) [51 – 53] . The addition of immune checkpoint inhibitors (ICI) has demonstrated synergistic ef fects. The PACIFIC trial compared the efficacy of durvalumab versus placebo for one year following concurrent chemoradiation in unresect able stage III NSCLC, showing significant improvements in progression-free survival (PFS) and OS [4] . Additionally, a phase III study, GEMSTONE-301, reported similar results in patients with locally advanced, unresectable stage III NSCLC treated with concurrent or sequential chemoradiation followed by sugemalimab versus placebo [54] . However, it should be noted that after receiving definitive che moradiation, approximately $13.6\,\%$ to $34.8\,\%$ of patients did not receive consolidation durvalumab due to reasons such as toxicities or disease progression [55 – 57] . For patients with sensitizing EGFR mutations, consolidation osimertinib post-definitive chemoradiation is recom mended following the LAURA trial as elaborated in statement 21 below [58] .

Although N3 disease is currently considered an oncologically unre sectable subset, certain unresectable NSCLC cases such as T4 tumours may potentially convert to resectable status after induction therapy. The concept of conversion strategies is discussed further in the “ Future Di rections ” section in statement 23 below. While definitive chemo radiation and consolidation durvalumab are the current SOC for

unresectable N3 stage III NSCLC, further exploration and discussion are needed in the future regarding the potential for conversion from unre sectable to resectable status after induction therapy.

3.2.3. If a patient is unable to undergo surgery after pre-operative immunotherapy plus chemotherapy, should definitive radiation be considered?

Statement: If a patient is unable to undergo surgery after pre-operative immunotherapy plus chemotherapy, definitive radiation should be considered if no distant metastases are present and the patient remains suitable for radiotherapy. [I,B].

Discussion: If a patient is assessed to be unsuitable for surgery after neoadjuvant immunotherapy plus chemotherapy and has no distant metastases, consideration should be given to radiotherapy. It must be emphasized that not all patients benefit from peri -operative immuno therapy plus chemotherapy. In the neoadjuvant immunotherapy plus chemotherapy trials, $16.8\;\%$ to $19.4\ \%$ of patients did not proceed with curative surgery post-neoadjuvant treatment [7 – 10] . The main reasons cited include disease progression, side effects, patient refusal, unre sectability, or poor lung function. In KEYNOTE-671, radiotherapy was administered to patients who did not undergo surgery for any reason other than local progression or metastatic disease post-neoadjuvant therapy, although the outcomes of these patients have not been re ported [8] . The panel agreed that patients with locally advanced disease who are deemed unsuitable for curative surgery after induction immu notherapy plus chemotherapy should undergo restaging and re-evaluation of their performance status. Thereafter, the suitability for curative radiotherapy should be assessed in a multidisciplinary team setting.

3.3. Peri-operative immunotherapy plus chemotherapy

3.3.1. Should all patients with upfront resectable stage IB-II (EGFR and ALK negative) NSCLC receive neoadjuvant immunotherapy plus chemotherapy if there are no medical contraindications?

Statement: Neoadjuvant immunotherapy plus chemotherapy is optional for patients with upfront resectable stage IB-II ( EGFR and ALK negative) NSCLC regardless of PD-L1 score, if there are no medical contraindications. [I,C].

Discussion: The optimal treatment approach for patients with resectable non-oncogene-driven stage IB-II NSCLC is still unclear. Even in patients with stage IB-II NSCLC without lymph node involvement, locoregional or distant recurrence after surgery remains a significant challenge. 59 [59] CheckMate 816 showed an event-free survival (EFS) hazard ratio (HR) of 0.87 ( $-95\;\%$ confidence interval (CI): 0.48 – 1.56) in stage IB-II patients comparing neoadjuvant nivolumab plus chemo therapy versus chemotherapy [7] . Similarly, KEYNOTE-671, AEGEAN, and CheckMate 77 T demonstrated only a trend towards benefit with the addition of peri -operative PD-(L)1 inhibitors in stage II patients, with EFS HRs of 0.65 ( $95\;\%$ CI: 0.42 – 1.01), 0.76 ( $-95~\%$ CI: 0.43 – 1.34), and 0.81 ( $.95~\%$ CI: 0.46 – 1.43), respectively [8 – 9,11] . However, subgroup analysis from RATIONALE-315 showed a significant EFS benefit with the addition of peri -operative tislelizumab to chemotherapy in stage II, with a HR of 0.47 (0.26 – 0.87) [12] . A meta -analysis comprising phase II and III studies of resectable stage IB-II disease treated with neoadjuvant immunotherapy combined with chemotherapy compared to neo adjuvant chemotherapy alone showed a significant 2-year EFS benefit, with a HR of 0.75 ( $95\,\%$ CI, 0.57 – 0.97) [60] . Conversely in the adjuvant ICI trials, IMpower010 demonstrated a DFS HR of 0 ⋅ 68 (95 % CI: 0.46 – 1.00) in favor of adjuvant atezolizumab for all PD-L1-expressing stage IIA [5] , while PEARLS/KEYNOTE-091 demonstrated a signifi cant DFS benefit with a HR of 0.70 ( $95~\%$ CI: 0.55 – 0.91) in favor of adjuvant pembrolizumab among PD-L1 unselected stage II [6] . Currently, the field of lung cancer research still lacks phase III studies like NADINA that directly compare neoadjuvant immunotherapy fol lowed by pathological response-guided adjuvant treatment against

S.P.L. Saw et al.

upfront surgery followed by adjuvant immunotherapy in resectable stage III melanoma [61] . Immunotherapy likely plays a role in the treatment for non-oncogene-driven stage IB-II NSCLC, but it is unclear whether a neoadjuvant alone, adjuvant alone or perioperative approach is superior, as the neoadjuvant and perioperative approaches do result in a subset of patients being unable to proceed to curative surgery. How ever, based on the current evidence, the panel agreed that neoadjuvant immunotherapy plus chemotherapy should be considered as one of the treatment options for patients with upfront resectable stage IB-II ( EGFR and ALK negative) NSCLC.

3.3.2. Should all patients with upfront resectable stage IIIA (EGFR and ALK negative) NSCLC receive neoadjuvant immunotherapy plus chemotherapy if there are no medical contraindications?

Statement: Patients with upfront resectable stage IIIA ( EGFR and ALK negative) NSCLC should be considered for neoadjuvant immunotherapy plus chemotherapy regardless of PD-L1 score, if there are no medical contraindications. [I,A].

Discussion: Several phase II and III studies have demonstrated sig nificant benefits in EFS and pathological response with neoadjuvant immunotherapy combined with chemotherapy in patients with resect able stage III ( EGFR and ALK negative) NSCLC. Meta-analyses show that these benefits remain significant even in PD-L1 negative populations [60,62] . Compared with stage I-II, the benefit of neoadjuvant immu notherapy plus chemotherapy is more pronounced in stage III NSCLC. In CheckMate 816, patients with stage IIIA NSCLC achieved an EFS benefit of HR 0.54 ( $-95\ \%$ CI: 0.37 – 0.80) with the addition of nivolumab to neoadjuvant chemotherapy [7] . Similarly, KEYNOTE-671 showed an EFS benefit of the addition of peri -operative pembrolizumab to chemo therapy with a HR of 0.54 ( $95~\%$ CI: 0.42 – 0.70) in patients with stage IIIA disease [8] . AEGEAN and NEOTORCH also demonstrated statisti cally significant improvements in EFS with the addition of peri -operative durvalumab and toripalimab to chemotherapy in stage IIIA populations, with HRs of 0.57 ( $.95~\%$ CI: 0.39 – 0.83) and 0.44 ( $95~\%$ CI: 0.29 – 0.66) respectively [9 – 10] . Therefore, there is robust evidence supporting the use of neoadjuvant immunotherapy plus chemotherapy in patients with upfront resectable stage IIIA (EGFR/ALK-negative) NSCLC and the panel agreed this would be the preferred approach.

3.3.3. Assuming equal accessibility, is there a preferred PD-(L)1 inhibitor in the peri-operative setting?

Statement: Assuming equal accessibility, any PD-(L)1 inhibitor that has proven efficacy in the peri -operative setting can be considered. [I,A].

Discussion: Several phase III studies involving the use of ICI in the peri -operative setting for resectable NSCLC have demonstrated relatively consistent benefits with different PD-(L)1 inhibitors [8 – 12] . Currently, there is no head-to-head evidence to confirm which ICI is superior. Therefore, considering the differences in drug availability, reimburse ment policies, patient preferences, and approved indications in different regions, a careful evaluation and selection based on specific circum stances are warranted. All PD-(L)1 inhibitors that have been proven to be safe and efficacious in phase III peri -operative NSCLC trials are po tential treatment options. It is recommended to make decisions in a multidisciplinary setting considering various factors to minimize indi vidual selection bias.

3.3.4. What is the acceptable time interval between completion of neoadjuvant immunotherapy plus chemotherapy and surgical resection?

Statement: The preferred time interval between completion of neo adjuvant immunotherapy plus chemotherapy and surgical resection is 4 – 6 weeks. [I,A].

Discussion: Most of the phase III neoadjuvant and peri -operative immunotherapy plus chemotherapy trials stipulate that surgery should be performed within 4 – 6 weeks after the last neoadjuvant treatment, defining surgery beyond 6 weeks as surgical delays [7,9 – 12] . An anal ysis based on the NCDB (National Cancer Database) suggests that

delaying surgery beyond 6 weeks after neoadjuvant treatment signifi cantly reduces OS for patients [63] . Distinctively, the KEYNOTE-671 trial allowed an interval of 4 – 8 weeks from the last treatment to sur gery if patients received fewer than 4 cycles of neoadjuvant therapy. The overall study design allowed for an interval from the first cycle of treatment to surgery of no more than 20 weeks [8] . In light of these data, the panel agreed that the preferred time interval between completion of neoadjuvant immunotherapy plus chemotherapy and surgical resection is 4 – 6 weeks.

3.3.5. Should all patients who receive neoadjuvant immunotherapy plus chemotherapy continue adjuvant ICI after surgery?

Statement: Selected patients should continue adjuvant ICI after sur gery post-neoadjuvant immunotherapy plus chemotherapy. [I,A]. Consensus was not reached on which patients should receive adjuvant ICI after surgery post-neoadjuvant immunotherapy plus chemotherapy.

Discussion: Continuation of adjuvant ICI for approximately 9 – 12 months post-neoadjuvant immunotherapy plus chemotherapy and sur gery was mandated in all the peri -operative trials [8 – 12] . However, a significant proportion of patients ranging from $12.6\ \%$ to $59.4~\%$ dis continued their adjuvant treatment [8 – 12] . Given that adjuvant ICI was not given in the control arm, the incremental benefit of continuing ICI post-operatively remains poorly defined. Considering the added toxic ities and financial burden, all panelists agreed that only selected patients should continue ICI in the adjuvant setting post-neoadjuvant immuno therapy plus chemotherapy. However, consensus could not be reached on how these patients should be selected. In CheckMate 816 where only neoadjuvant immunotherapy plus chemotherapy was given (without adjuvant ICI), patients who achieved pCR had excellent survival out comes with a 24-month EFS rate of $93~\%$ [64] . Some experts felt adju vant ICI could be omitted in patients who achieved pCR given their good prognosis, whereas others countered it was reasonable to continue adjuvant ICI for these patients given the efficacy observed. More pro spective data is needed to identify biomarkers that predict for benefit of continuing adjuvant ICI post-neoadjuvant immunotherapy plus chemotherapy.

3.4. Adjuvant targeted therapy

3.4.1. What is the preferred treatment approach for patients with upfront resectable stage IB NSCLC with common sensitizing EGFR mutations (ex19del/L858R)?

Statement: For patients with stage IB NSCLC with common sensi tizing EGFR mutations (ex19del/L858R), upfront surgery followed by adjuvant osimertinib for 3 years is the preferred approach. [I,A].

Discussion: The ADAURA trial established 3 years of adjuvant osi mertinib as the standard of care for completely resected stage IB – IIIA (by the 7th edition of TNM staging) [65] NSCLC with an EGFR ex19del/ L858R mutation, following a significant improvement in both DFS and OS as compared with placebo [2,20] . Adjuvant chemotherapy was optional in both the study and control arm. However, only $26\ \%$ of patients with stage IB received adjuvant chemotherapy in ADAURA and DFS benefit of osimertinib across the stages was achieved regardless of chemotherapy use [66] . Prior to ADAURA, the benefit of adjuvant chemotherapy in stage IB (by the 7th edition of TNM staging) was controversial [1,67] . With these considerations in mind, the panel agreed that upfront surgery followed by adjuvant osimertinib is the preferred treatment approach for patients with completely resected stage IB (by the 7th edition of TNM staging) NSCLC with an EGFR ex19del/L858R mutation.

3.4.2. What is the preferred treatment approach for patients with upfront resectable stage II-IIIA NSCLC with common sensitizing EGFR mutations (ex19del/L858R)?

Statement: For patients with upfront resectable stage II-IIIA NSCLC with common sensitizing EGFR mutations (ex19del/L858R), upfront

5

S.P.L. Saw et al.

surgery followed by adjuvant osimertinib for 3 years with/without chemotherapy is the preferred approach. [I,A].

Discussion: Four cycles of adjuvant cisplatin-based doublet chemo therapy is generally recommended for completely resected stage II-IIIA NSCLC, with an absolute improvement in 5-year survival of approxi mately $5\,\%$ . While adjuvant chemotherapy was encouraged for stage II-IIIA (by the 7th edition of TNM staging) [65] in the ADAURA trial, it was not mandated in either the study or control arm. Accordingly, $76~\%$ of patients with stage II-IIIA NSCLC received adjuvant chemotherapy in ADAURA [66] . However, as mentioned in the previous section, the DFS benefit of adjuvant osimertinib was observed regardless of stage and chemotherapy use. While patients with EGFR mutations were included in 2 of the peri -operative immunotherapy plus chemotherapy trials [8 – 9] , molecular testing was not mandated and the numbers of these patients in the trials are too small to draw definitive conclusions. Therefore, upfront surgery followed by adjuvant osimertinib with/ without chemotherapy is the preferred approach for patients with stage II-IIIA NSCLC with an EGFR ex19del/L858R mutation.

3.4.3. What is the preferred treatment approach for patients with upfront resectable stage IB-IIIA NSCLC with ALK-rearrangements?

Statement: For stage IB-III NSCLC with ALK -rearrangements, upfront surgery followed by adjuvant alectinib for 2 years is the preferred approach. [I,A].

Discussion: The ALINA trial established 2 years of adjuvant alectinib as the new standard of care for patients with completely resected ALK - rearranged stage IB – IIIA (by the 7th edition of TNM staging) [65] NSCLC by demonstrating a significant improvement in DFS over plat inum double chemotherapy [3] . Intracranial DFS was also significantly improved in the alectinib arm, which is of particular relevance to pa tients with ALK -rearrangements given the predilection for brain me tastases – estimated at up to $70\,\%$ lifetime risk [68] . While patients with ALK -rearrangements were included in KEYNOTE-671 [8] , subgroup analyses should be interpreted with caution given the small numbers. Although adjuvant chemotherapy has established OS benefit for stage II-IIIA NSCLC [1] , the incremental benefit of adjuvant chemotherapy in addition to alectinib is uncertain and needs to be examined in a pro spective randomised trial. As such, upfront surgery followed by adjuvant alectinib is the preferred approach for patients with completely resected ALK -rearranged stage IB – IIIA.

3.4.4. What is the preferred treatment approach for patients with upfront unresectable stage III NSCLC with either sensitizing EGFR mutations (ex19del/L858R) or ALK-rearrangements?

Statement: For unresectable stage III NSCLC with common sensi tizing EGFR mutations (ex19del/L858R) or ALK -rearrangements, definitive chemoradiation is the preferred approach. Consolidation durvalumab should not be given for patients with sensitizing EGFR mutations [I,A] or ALK -rearrangements [IV,B].

Discussion: The PACIFIC trial established the role of consolidation durvalumab after definitive concurrent chemoradiation for patients with unresectable stage III NSCLC [4] . However, subgroup analysis from PACIFIC and real-world data suggested limited benefit from consolida tion durvalumab among patients with EGFR or ALK aberrations [69 – 70] . This is in keeping with observations in the metastatic setting where patients with EGFR or ALK aberrations generally derive limited benefit from ICI monotherapy [71 – 72] . The recently published LAURA trial demonstrated a significant improvement in PFS of consolidation osi mertinib till disease progression over placebo [58] . In light of this data, consolidation durvalumab should not be given post-chemoradiation in unresectable stage III NSCLC with sensitizing EGFR mutations. While randomised data for patients with ALK -rearrangements is awaited, the panel recommends not giving consolidation durvalumab to these pa tients in view of the limited efficacy and concerns of overlapping toxicity when ICI are given prior to ALK TKI [73] . Fig. 1 summarizes stage-based treatment recommendations.

3.5. Future directions

3.5.1. Should PD-L1 testing be repeated on the surgical specimen if already performed pre-operatively on the diagnostic biopsy?

Statement: Consensus was not reached on whether PD-L1 testing should be repeated on the surgical specimen if already performed pre-operatively on the diagnostic biopsy.

Discussion: Studies investigating concordance of PD-L1 expression between diagnostic biopsy and surgical specimens have shown con flicting results, with some studies showing high concordance rates above $90\;\%$ [74 – 75] , while others showing discordance rates over $50\;\%$ [76] . One potential reason is intratumoural heterogeneity of PD-L1 expression [77] . This may be clinically relevant as the approvals and reimburse ment policies for adjuvant ICI are determined based on the PD-L1 expression in many countries.

There are limited studies reporting on the impact of neoadjuvant immunochemotherapy on PD-L1 expression. Analysis of 30 paired tumour samples from the SAKK 16/14 trial showed no significant change in PD-L1 expression after neoadjuvant durvalumab and chemotherapy. Upregulation or downregulation of PD-L1 expression after neoadjuvant treatment also did not impact recurrence risk or OS [78] . Further research is warranted to study the changes and predictive value of PD-L1 expression after neoadjuvant immunotherapy plus chemotherapy.

3.5.2. Should neoadjuvant therapy be used to downstage unresectable NSCLC to facilitate curative surgery?

Statement: Neoadjuvant therapy should not be routinely used to downstage unresectable NSCLC to facilitate curative surgery. [V,C].

Discussion: At present, all randomized neoadjuvant or peri -operative NSCLC trials only enrolled patients with upfront resectable disease and have not addressed whether unresectable tumours can be converted to resectable via neoadjuvant treatment [7 – 12,79] . Therefore, the role of neoadjuvant therapy in downstaging unresectable NSCLC to resectable disease remains exploratory and should not be routinely recommended in clinical practice.

Given the high radiological response rates observed with immuno therapy plus chemotherapy and targeted therapy, the conversion strat egy is currently being investigated in multiple prospective trials. A phase II study [NCT04580498] included patients with unresectable stage III NSCLC who received 3 cycles of induction SHR-1701 (a novel anti-PD-L1/TGF β RII fusion protein) combined with chemotherapy or SHR-1701 alone, followed by multidisciplinary team discussion and reassessment of resectability. If deemed resectable, patients underwent surgical treatment; otherwise, they received definitive chemoradiation. Among 107 patients enrolled, 27 $(25\,\%)$ underwent surgery and all achieved R0 resection, with better prognosis than patients who did not undergo surgery [80] . Another multi-national phase II trial MDT-Bridge [NCT05925530] is ongoing to evaluate the role of neoadjuvant immu notherapy plus chemotherapy in patients with borderline resectable NSCLC. Subjects will be reassessed by a multidisciplinary team for resectability after two cycles of neoadjuvant durvalumab plus chemo therapy. The primary endpoint is resection rate [81] . The role of in duction TKI for unresectable stage III EGFR -mutated NSCLC is currently being evaluated in the APPROACH/CTONG2101 study [NCT04841811]. After 8 weeks of neoadjuvant almonertinib, patients will then be reassessed in MDT for resectability. This study is also evaluating the role of MRD in guiding the duration of adjuvant almo nertinib. These studies will generate important insights on the feasibility and efficacy of “ conversion strategies ” .

Fig. 2 Illustrates potential trial designs to evaluate the following concepts: (A) Platform trial investigating the activity of novel immu notherapy combinations in the neoadjuvant setting, (B) Converting unresectable stage III NSCLC to resectable disease with neoadjuvant therapy and (C) Adapting adjuvant therapy based on pathological response, including MRD. Acknowledging that NSCLC is a

S.P.L. Saw et al.

 Stage-based treatment recommendations. \*If CheckMate 816 or NEOTORCH regimens were used pre-operatively.

S.P.L. Saw et al.

  ClinicalQuestion Feasibility of converting unresectable tumours to resectablewith induction therapy

C)Adaptingadjuvanttherapybasedonpathologicalresponsetoneoadjuvanttherapy

 Fig. 2. Potential trial designs to address research priorities.

S.P.L. Saw et al.

heterogeneous disease, the ability to adapt treatment recommendations based on an individual tumor ’ s response to systemic therapy is an attractive approach ( Fig. 2 C). However, conducting a phase III RCT to evaluate the efficacy of every novel combination in the neoadjuvant or adjuvant setting is not practical given the anticipated sample size and follow up time required. In light of these considerations, neoadjuvant platform trials provide the unique opportunity to evaluate various novel combinations in tandem ( Fig. 2 A). Besides the efficiency of evaluating multiple treatments simultaneously, such trial designs also accord the flexibility of adding study arms such as new combinations with proven efficacy in the metastatic setting. Ultimately, the success of this approach will depend on the robustness of pathological response as a surrogate for survival [82] .

4. Conclusion

The treatment landscape of non-metastatic NSCLC is increasingly complex and most patients require multidisciplinary management. In this consensus statement, we have provided a framework and recom mendations for the management of these patients contextualized to the Asia-Pacific region ( Fig. 1 , Table 1 ). Ongoing challenges include providing access to biomarker testing and appropriate therapies while managing financial toxicities. An emerging challenge is the contribution of components especially with peri -operative approaches, where tradi tional endpoints of OS can be obfuscated by intervening therapies. Enhanced risk stratification of patients and adopting robust validated surrogate endpoints is an important priority. Risk-stratified approaches to de-escalate or escalate treatment accordingly should be explored to improve treatment outcomes while providing cost-effective care, which necessitates collaborative research.

CRediT authorship contribution statement

Stephanie P.L. Saw: Writing – review & editing, Writing – original draft, Visualization, Project administration, Methodology, Investigation, Data curation, Conceptualization. Wen-Zhao Zhong: Writing – review & editing, Writing – original draft, Methodology, Investigation, Data curation. Rui Fu: Writing – review & editing, Writing – original draft, Methodology, Investigation, Data curation. Molly S.C. Li: Writing – review & editing, Writing – original draft, Visualization, Methodology, Investigation, Data curation. Yasushi Goto: Writing – review & editing, Methodology, Investigation, Data curation. Stephen B. Fox: Writing – review & editing, Methodology, Investigation, Data curation. Yasushi Yatabe: Writing – review & editing, Methodology, Investigation, Data curation. Boon-Hean Ong: Writing – review & editing, Methodology, Investigation, Data curation. Calvin S.H. Ng: Writing – review & edit ing, Methodology, Investigation, Data curation. David D.W. Lee: Writing – review & editing, Methodology, Investigation, Data curation. Pham Cam Phuong: Writing – review & editing, Methodology, Inves tigation, Data curation. In Kyu Park: Writing – review & editing, Methodology, Investigation, Data curation. James C.H. Yang: Writing – review & editing, Methodology, Investigation, Data curation. Masahiro Tsuboi: Writing – review & editing, Methodology, Investigation, Data curation. Lye Mun Tho: Writing – review & editing, Methodology, Investigation, Data curation. Thomas John: Writing – review & editing, Methodology, Investigation, Data curation. Hsao-Hsun Hsu: Writing – review & editing, Methodology, Investigation, Data curation. Daniel S. W. Tan: Writing – review & editing, Supervision, Resources, Investi gation, Funding acquisition, Data curation, Conceptualization. Tony S. K. Mok: Writing – review & editing, Supervision, Resources, Investi gation, Funding acquisition, Data curation, Conceptualization. Tha nyanan Reungwetwattana: Writing – review & editing, Supervision, Methodology, Investigation, Data curation. Navneet Singh: Writing – review & editing, Supervision, Methodology, Investigation, Data curation.

Table 1

No. Statement Level of evidence, strength of recommendation Molecular testing and diagnostics 1 All patients with stage IB-III NSCLC should be I,A offered PD-L1 testing. For non-squamous histology, EGFR mutation and ALK-rearrangement should also be tested. 2 For patients with clinical Stage II-IIIA NSCLC: I,C PD-L1, EGFR and ALK should be routinely performed pre-operatively. \*Consensus was not reached for stage IB. 3 MDT discussion does not need to be V,C mandated pre-operatively for all patients with stage IB NSCLC but should be made available for all patients with clinical stage II-III NSCLC. 4 PET CT scan should be performed pre- III,B operatively for all patients with pathologically-confirmed, clinical stage IB-III NSCLC planned for surgery. 5 Contrast-enhanced CT or MRI Brain should be III,B performed pre-operatively for all patients with pathologically-confirmed, clinical stage II-III NSCLC but is optional for stage IB in otherwise asymptomatic patients. 6 Contrast-enhanced cross-sectional imaging I,A should be performed for all patients after neoadjuvant immunotherapy plus chemotherapy to assess suitability for surgical resection. 7 Contrast-enhanced CT or MRI Brain does not I,C need to be repeated after neoadjuvant immunotherapy plus chemotherapy in other asymptomatic patients before surgery. 8 pCR & MPR definitions should be I,B standardized and integrated into routine pathology reports post-neoadjuvant therapy. 9 At present, ctDNA levels should not be used III,C as a clinical decision making tool in the peri - operative setting. Local therapy 10 The goal of surgery is to achieve R0 resection, III,A pathologically confirmed N3 disease is considered surgically unresectable. \*Consensus was not reached on the resectability of multi-station N2, T4 tumours and single station bulky N2 disease. 11 Definitive chemoradiation should be the I,A preferred approach for N3 disease and patients with upfront unresectable clinical stage III NSCLC. 12 If a patient is unable to undergo surgery after I,B pre-operative immunotherapy plus chemotherapy, definitive radiation should be considered if no distant metastases are present and the patient remains suitable for radiotherapy. Peri-operative immunotherapy plus chemotherapy 13 Neoadjuvant immunotherapy plus I,C chemotherapy is optional for patients with upfront resectable stage IB-II (EGFR and ALK negative) NSCLC regardless of PD-L1 score, if no medical contraindications. 14 Patients with upfront resectable stage IIIA I,A (EGFR and ALK negative) NSCLC should be considered for neoadjuvant immunotherapy plus chemotherapy regardless of PD-L1 score, if no medical contraindications. 15 Assuming equal accessibility, any PD-(L)1 I,A inhibitor that has proven efficacy in the peri - operative setting can be considered.

S.P.L. Saw et al.

Table 1 ( continued )

|NO_|Statement| Level of evidence, strength of recommendation | |---|---|---| |16||| || The preferred time interval between completion of neoadjuvant immunotherapy plus chemotherapy and surgical resection is |IA| |H√| Selected patients should continue adjuvant ICI after surgery post-neoadjuvant immunotherapy plus chemotherapy. |IA| |H√| *Consensus was not reached on which patients should receive adjuvant ICI afer || ||surgery post-neoadjuvant immunotherapy|| |Adjuvant targeted therapy||| |18| For patients with stage IB NSCLC with sensitizing EGFR mutations (ex19del/ |I,A| || sensitizing EGFR mutations (ex19del/ L858R), upfront surgery followed by adjuvant osimertinib for 3 years is the || |19| adjuvant osimertinib for 3 years is the preferred approach. || |19| For patients with upfront resectable stage II- IIIA NSCLC with sensitizing EGFR mutations (ex19del/L858R), upfront surgery followed by adjuvant osimertinib for 3 years with/ |I,A| |19| by adjuvant osimertinib for 3 years with/ without chemotherapy is the preferred approach. || |19||| |19| rearrangements, upfront surgery followed by adjuvant alectinib for 2 years is the preferred approach. |IA| |21| For unresectable stage II NSCLC with sensitizing EGFR mutations (ex19del/L858R) |I,A [EGFR]| || sensitizing EGFR mutations (ex19del/L858R) or ALK-rearrangements, definitive chemoradiation is the preferred approach. |IV,B [ALK]| ||Consolidation Durvalumab should not be|| || given for patients with sensitizing EGFR mutations or ALK-rearrangements. || |Future Directions||| |22|*Consensus was not reached on whether PD-|| || L1 testing should be repeated on the surgical specimen if already performed pre- operatively on the diagnostic biopsy. || |23| operatively on the diagnostic biopsy. Neoadjuvant therapy should not be routinely used to downstage unresectable NSCLC to facilitate curative surgery. |V，C|

\*No level of evidence or strength of recommendation was assigned when consensus was not reached.

Funding

Meeting support for the in-person meeting in Singapore on 26 April 2024 was provided by AstraZeneca. No medical writing assistance or scientific input for this manuscript was provided by AstraZeneca.

Declaration of competing interest

The authors declare the following financial interests/personal re lationships which may be considered as potential competing interests: Dr Saw reports grants from AstraZeneca, consulting fees from Pfizer, Bayer, AstraZeneca and Daiichi Sankyo, honoraria from Astra Zeneca, MSD, Bristol-Myers Squibb, Daiichi Sankyo, Roche and Takeda, meeting support from MSD and Astra Zeneca from Pfizer, advisory board participation from Astra Zeneca, Daiichi Sankyo and Pfizer, outside the submitted work.

Dr Zhong reports honoraria from AstraZeneca, Eli Lilly, Pfizer, Roche Holdings AG, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, and Bristol-Myers Squib, outside the submitted work.

Dr Fu declares that he has no conflict of interest.

Dr Li reports grants from Gilead, MSD, AstraZeneca and Takeda, honoraria from AstraZeneca, Novartis, Amgen, Pfizer, Takeda, ACE Oncology, Gilead, Guardant Health, Janssen, Merck and MSD, meeting

support from AstraZeneca, Daiichi Sankyo, Roche, MSD and Amgen, advisory board participation from AstraZeneca, Pfizer, Amgen, Anheart Therapeutics, Takeda, Yuhan and Blossomhill Therapeutics, outside the submitted work.

Dr. Goto reports honoraria from AstraZeneca, Eli Lilly, Chugai, Taiho, Boehringer Ingelheim, Ono, Bristol Myers Squibb, Pfizer, MSD, Novartis, Merck, Thermo Fischer, Guardant Health Inc., Takeda, Towa, Amgen, Daiichi Sankyo, grants/research support from AstraZeneca, Abbvie, Eli Lilly, Pfizer, Bristol Myers Squibb, Ono, Novartis, Kyorin, Daiichi Sankyo, MSD, Ono, Guardant Health Inc., Prefered Network, consultation from AstraZeneca, Chugai, Boehringer Ingelheim, Eli Lilly, Glaxo Smith Kline, Taiho, Pfizer, Novartis, Kyorin, Guardant Health Inc., Illumina, Daiichi-Sankyo, Merck, MSD, Ono, Janssen, and institutional support from IQVIA Services Japan, MSD, Astellas Pharma, AstraZeneca, AbbVie, Amgen, Syneos Health Clinical, Sysmex Corporation, CMIC, Novartis Pharma, Bayer Pharmaceuticals, Bristol-Myers Squibb, Med Pace Japan, Janssen Pharma, Clinical Research Support Center Kyushu, SATOMI, Ono Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceutical, Chugai Pharmaceutical, NPO Thoracic Oncology Research Group, Eli Lilly Japan, Preferred Network, outside the submitted work.

Dr Fox reports grants and/or honoraria from Astra Zeneca, BMS, MSD, Bayer, GSK, Illumina, Janssen, Thermo Fisher, Roche, Gilead, Amgen, SOPHiA, outside the submitted work.

Dr Yatabe reports grants from Merk Biopharma, Chugai-pharma and Konica-Minolta REALM; Consultant fee from AstraZeneca; and hono raria from MSD, Chugai-pharma, AstraZeneca, Merk Biopharma, Novartis, Amgen, Daiichi-Sankyo, Thermo Fisher Science outside the submitted work.

Dr Ong reports honoraria from AstraZeneca, Bristol-Myers Squibb, Medtronic, MSD and Roche and meeting support from MSD, outside the submitted work.

Dr Ng reports honoraria from Astra Zeneca, MSD, Bristol-Myers Squibb, Roche, Johnson & Johnson, Medtronic, meeting support from MSD, Astra Zeneca, Roche, Bristol-Myers Squibb, Johnson & Johnson, Medtronic, advisory board participation from Astra Zeneca, Johnson & Johnson, Medtronic, outside the submitted work.

Dr Lee reports honoraria from Ipsen, MSD, Pfizer, Juniper Biologics, Zuellig Pharma, Roche, Takeda, Astra Zeneca and AbbVie, meeting support from Astra Zeneca, Takeda, MSD, Juniper Biologics, Ipsen, Merck and Servier, consulting fees from Ipsen, Eisai, Zuellig Pharma, Pfizer, outside the submitted work.

Dr Pham reports grants from Astra Zeneca, consulting fees and honoraria from Roche, MSD, Astra Zeneca, Taiho, Pierre Fabre, meeting support from MSD, Astra Zeneca, advisory board participation from Astra Zeneca, MSD, Roche, Boehringer Ingelheim, Pierre Fabre, outside the submitted work.

Dr Park declares that he has no conflict of interest.

Dr. Yang reports personal fees and other from Amgen, grants, per sonal fees and other from AstraZeneca, personal fees and other from Bayer, personal fees and other from Boehringer Ingelheim, personal fees and other from Bristol Myers Squibb, other from Daiichi Sankyo, other from Eli Lilly, other from Merck KGaA, Darmstadt, Germany, other from Merck Sharp & Dohme, other from Novartis, from Ono Pharmaceuticals, from Pfizer, grants and other from Roche/Genentech, other from Takeda Oncology, other from Yuhan Pharmaceuticals, other from Janssen Pharmaceuticals, other from Gilead Sciences Inc, other from GSK, other from BeiGene, other from Regeneron Pharmaceutical, other from Taiho Pharmaceutical, other from ArriVent, other from AnHeart Therapeutics, outside the submitted work.

Dr Tsuboi reports grants from MSD, AstraZeneca KK, Bristol-Myers Squibb KK, Ono Pharmaceutical Co., Ltd, Eli Lilly Japan, Novartis, MiRXES; honoraria from Johnson & Johnson Japan, Medtronic Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical CO., Ltd, Taiho Pharma, Bristol-Myers Squibb KK, Ono Pharmaceutical Co., Ltd, Novartis, MSD, Daiichi-Sankyo, Amgen KK; advisory board participation for Chugai Pharmaceutical CO., Ltd, AstraZeneca KK, MSD, Novartis,

S.P.L. Saw et al.

MiRXES and sits on the board of directors for the Japan Lung Cancer Society, outside the submitted work.

Dr Tho reports honoraria from AstraZeneca, Novartis, Amgen, MSD, Merck, Taiho Pharma, Bristol-Myers Squibb, Pfizer and is the president of the Lung Cancer Network of Malaysia, outside the submitted work.

Dr John reports honoraria/advisory board from BMS, AstraZeneca, Amgen, Roche, Pfizer, Takeda, Boehringer Ingelheim, MSD, Merck, Puma, Specialised Therapeutics, Gilead, Seagen, Johnson and Johnson; travel/speaker fees from AstraZeneca and research grant from Astra Zeneca, outside the submitted work.

Dr Hsu declares that he has no conflict of interest.

Dr. Tan reports grants from ACM Biolabs, Amgen, Astra Zeneca, Bayer and Pfizer, consulting fees from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, DKSH, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche and Takeda, honoraria from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda, Beigene, Regeneron, Zymeworks, meeting support from Bayer, Merck, Pfizer, Regeneron and Zymeworks, outside the submitted work.

Dr Mok reports grants from AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, XCovery, consulting fees from Abbvie Inc, ACEA Pharma, Adagene, Alentis Therapeutics AG, Alpha Biopharma Co., Ltd, Amgen, Amoy Diagnostics Co, AnHeart Therapeutics Inc, AVEO Phar maceuticals, Inc, Bayer Healthcare Pharmaceuticals Ltd, BeiGene, Ber GenBio ASA, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol Myers Squibb, Bowtie Life Insurance Company Limited, Bridge Biotherapeutics Inc, Covidien LP, C4 Thera peutics Inc, Cirina Ltd, CStone Pharmaceuticals, Curio Science, D3 Bio Ltd, Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd./ Genentech, Fishawack Facilitate Ltd, G1 Therapeutics Inc, geneDecode Co., Ltd, Gilead Sciences, Inc, GLG ’ s Healthcare, Gritstone Oncology, Inc, Guardant Health, Hengrui Thera peutics Inc, HiberCell, Inc., HutchMed, Ignyta Inc., Illumina Inc., Incy teCorporation, Inivata, IQVIA, Janssen, Lakeshore Biotech Ltd, Lilly, Lunit USA, Inc, Loxo-Oncology, Lucence Health Inc, Medscape LLC/ WebMD, Medtronic, Merck Serono, MSD, Mirati Therapeutics Inc, MiRXES, MoreHealth, Novartis, Novocure GmbH, Omega Therapeutics Inc, OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, PrIME Oncology, Prenetics Global Limited, Puma Biotechnology Inc, Qiming Development (HK) Ltd, Regen Medtech Holdings Limited, Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals/ Diagnostics/ Foundation One, Sanofi-Aventis, SFJ Pharmaceutical Ltd, Simcere of America Inc, Synergy Research, Summit Therapeutics Sub, Inc, Takeda Pharmaceu ticals HK Ltd, Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc, Yuhan Corporation, honoraria from ACEA Pharma, Alpha Biopharma Co. Ltd, Amgen, Amoy Diagnostics Co. Ltd, AstraZeneca (before 1/1/19), BeiGene, BI, BMS, Daiichi Sankyo, Daz Group, Fishawack Facilitate Ltd., InMed Medical Communication, Janssen Pharmaceutica NV, Jiahui Holdings Co. Limited, LiangYiHui Healthcare, Lilly, Lucence Health Inc., MD Health Brazil, Medscape LLC, Merck Pharmaceuticals HK Ltd., Merck Sharp & Dohme, MiRXES, Novartis, OrigiMed Co. Ltd., P. Permanyer SL, PeerVoice, Physicians ’ Education Resource, Pfizer, PrIME Oncology, Research to Practice, Roche Pharmaceuticals/ Diagnostics/ Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co. Ltd, Taiho Pharmaceu tical Co. Ltd, Takeda Oncology, Touch Independent Medical Education Ltd, meeting support from Novartis, Roche, Pfizer, AstraZeneca, Daiichi Sankyo, BI, MiRXES, BMS, MSD, Abbvie, Zai Lab, Liangyihui, advisory board for AbbVie Inc., ACEA Pharma, Amgen, AstraZeneca, Alentis Therapeutics AG, BerGenBio ASA, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim, Bowtie Life Insurance Co Ltd, Bris tol Myers Squibb, C4 Therapeutics Inc, Covidien LP, CStone Pharma ceuticals, Curio Science, D3 Bio Ltd., Daiichi Sankyo Inc., Eisai, Fishawack Facilitate Ltd., G1 Therapeutics Inc., Gilead Sciences Inc., Gritstone Oncology Inc, Guardant Health, geneDecode Co. Ltd. (un compensated), Hengrui Therapeutics Inc., HutchMed, Ignyta Inc.,

Incyte Corporation, Imagene AI Ltd., Inivata, IQVIA, Janssen, Lakeshore Biotech, Lily, Loxo-Oncology Inc., Lunit Inc, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MiRXES Group, Novartis, OrigiMed, Pfizer, Prenetics Global Limited, Puma Biotechnology Inc., Roche/Genentech, Regeneron Pharmaceuticals Inc, Sanofi-Aventis R & D, SFJ Pharmaceutical, Simcere of America Inc., Simcere Zaiming, Inc., Takeda, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc, Yuhan Corporation, being member in the Board of Directors for AstraZeneca PLC, HutchMed, Aurora, Insighta, holding stock / stock option of AstraZeneca, Aurora Tele-Oncology Ltd., Biolidics Ltd., HutchMed, Prenetics Global Limited, D3 Bio, Lunit, Bowtie Life Insur ance, Lakeshore Biotech Ltd, Loxo-oncology, Virtus Medical Group, Yinson Capital Pte. Ltd., Phanes Therapeutics, Inc., Insighta, Alentis Therapeutics AG, outside the submitted work. Dr Li reports grants from Gilead, MSD and Astra Zeneca, honoraria from Astra Zeneca, Novartis, Amgen, Pfizer. Takeda, ACE Oncology, Merck, Guardant Health, Gilead, Janssen and MSD, meeting support from Astra Zeneca, Pfizer, Daiichi Sankyo, MSD, Amgen, advisory board for Astra Zeneca, Pfizer, AnHeart Therapeutics, Amgen, Takeda, Yuhan and Blossomhill therapeutics, outside the submitted work.

Dr Reungwetwattana reports research grants from AstraZeneca, MSD, Roche, Yuhan; honoraria from AstraZeneca, Amgen, Pfizer, Takeda, Janssen, BMS, and MSD; advisory board participation from AstraZeneca, Pfizer, Amgen, Takeda, Yuhan, Roche, Janssen, BMS, and MSD, outside the submitted work.

Dr Singh declares that he has no conflict of interest..

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.lungcan.2024.108076 .

References

[1] J.P. Pignon, H. Tribodet, G.V. Scagliotti, J.Y. Douillard, F.A. Shepherd, R. J. Stephens, A. Dunant, V. Torri, R. Rosell, L. Seymour, S.G. Spiro, E. Rolland, R. Fossati, D. Aubert, K. Ding, D. Waller, T. Le Chevalier, Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group, J. Clin. Oncol. 26 (21) (2008) 3552 – 3559 . [2] Y.L. Wu, M. Tsuboi, J. He, T. John, C. Grohe, M. Majem, J.W. Goldman, K. Laktionov, S.W. Kim, T. Kato, H.V. Vu, S. Lu, K.Y. Lee, C. Akewanlop, C.J. Yu, F. de Marinis, L. Bonanno, M. Domine, F.A. Shepherd, L. Zeng, R. Hodge, A. Atasoy, Y. Rukazenkov, R.S. Herbst, Osimertinib in resected EGFR-mutated non-small-cell lung cancer, N. Engl. J. Med. 383 (18) (2020) 1711 – 1723 . [3] Y.L. Wu, R. Dziadziuszko, J.S. Ahn, F. Barlesi, M. Nishio, D.H. Lee, J.S. Lee, W. Zhong, H. Horinouchi, W. Mao, M. Hochmair, F. de Marinis, M.R. Migliorino, I. Bondarenko, S. Lu, Q. Wang, T. Ochi Lohmann, T. Xu, A. Cardona, T. Ruf, J. Noe, B.J. Solomon, Alectinib in resected ALK-positive non-small-cell lung cancer, N. Engl. J. Med. 390 (14) (2024) 1265 – 1276 . [4] S.J. Antonia, A. Villegas, D. Daniel, D. Vicente, S. Murakami, R. Hui, T. Kurata, A. Chiappori, K.H. Lee, M. de Wit, B.C. Cho, M. Bourhaba, X. Quantin, T. Tokito, T. Mekhail, D. Planchard, Y.C. Kim, C.S. Karapetis, S. Hiret, G. Ostoros, K. Kubota, J.E. Gray, L. Paz-Ares, J. de Castro Carpe no, C. Faivre-Finn, M. Reck, J. Vansteenkiste, D.R. Spigel, C. Wadsworth, G. Melillo, M. Taboada, P.A. Dennis, M. Ozgüro glu, Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC, N. Engl. J. Med. 379 (24) (2018) 2342 – 2350 . [5] E. Felip, N. Altorki, C. Zhou, T. Cs oszi, I. Vynnychenko, O. Goloborodko, A. Luft, A. Akopov, A. Martinez-Marti, H. Kenmotsu, Y.M. Chen, A. Chella, S. Sugawara, D. Voong, F. Wu, J. Yi, Y. Deng, M. McCleland, E. Bennett, B. Gitlitz, H. Wakelee, Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial, Lancet 398 (10308) (2021) 1344 – 1357 . [6] M. O ’ Brien, L. Paz-Ares, S. Marreaud, U. Dafni, K. Oselin, L. Havel, E. Esteban, D. Isla, A. Martinez-Marti, M. Faehling, M. Tsuboi, J.S. Lee, K. Nakagawa, J. Yang, A. Samkari, S.M. Keller, M. Mauer, N. Jha, R. Stahel, B. Besse, S. Peters, Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial, Lancet Oncol. 23 (10) (2022) 1274 – 1286 . [7] P.M. Forde, J. Spicer, S. Lu, M. Provencio, T. Mitsudomi, M.M. Awad, E. Felip, S. R. Broderick, J.R. Brahmer, S.J. Swanson, K. Kerr, C. Wang, T.E. Ciuleanu, G. B. Saylors, F. Tanaka, H. Ito, K.N. Chen, M. Liberman, E.E. Vokes, J.M. Taube, C. Dorange, J. Cai, J. Fiore, A. Jarkowski, D. Balli, M. Sausen, D. Pandya, C. Y. Calvet, N. Girard, Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer, N. Engl. J. Med. 386 (21) (2022) 1973 – 1985 . [8] H. Wakelee, M. Liberman, T. Kato, M. Tsuboi, S.H. Lee, S. Gao, K.N. Chen, C. Dooms, M. Majem, E. Eigendorff, G.L. Martinengo, O. Bylicki, D. Rodríguez-

S.P.L. Saw et al.

Abreu, J.E. Chaft, S. Novello, J. Yang, S.M. Keller, A. Samkari, J.D. Spicer, Perioperative pembrolizumab for early-stage non-small-cell lung cancer, N. Engl. J. Med. 389 (6) (2023) 491 – 503 . [9] J.V. Heymach, D. Harpole, T. Mitsudomi, J.M. Taube, G. Galffy, M. Hochmair, T. Winder, R. Zukov, G. Garbaos, S. Gao, H. Kuroda, G. Ostoros, T.V. Tran, J. You, K.Y. Lee, L. Antonuzzo, Z. Papai-Szekely, H. Akamatsu, B. Biswas, A. Spira, J. Crawford, H.T. Le, M. Aperghis, G.J. Doherty, H. Mann, T.M. Fouad, M. Reck, Perioperative durvalumab for resectable non-small-cell lung cancer, N. Engl. J. Med. 389 (18) (2023) 1672 – 1684 . [10] S. Lu, W. Zhang, L. Wu, W. Wang, P. Zhang, W. Fang, W. Xing, Q. Chen, L. Yang, J. Mei, L. Tan, X. Sun, S. Xu, X. Hu, G. Yu, D. Yu, N. Yang, Y. Chen, J. Shan, L. Xing, H. Tian, X. Zhang, M. Zhou, H. Fang, G. Wu, Y. Liu, M. Ye, L. Cao, J. Jiang, X. Li, L. Zhu, D. Li, M. Kang, A. Zhong, K. Chen, N. Wu, Q. Sun, H. Ma, K. Cai, C. Wang, G. Lin, K. Zhu, Y. Zhang, X. Zhang, H. Hu, W. Zhang, J. Chen, Z. Yang, X. Hang, J. Hu, Y. Huang, Z. Zhang, L. Zhang, L. Zhang, L. Liu, D. Lin, J. Zhang, G. Chen, Y. Li, L. Zhu, W. Wang, W. Yu, D. Cao, P. Keegan, S. Yao, Perioperative toripalimab plus chemotherapy for patients with resectable non-small cell lung cancer: the neotorch randomized clinical trial, J. Am. Med. Assoc. 331 (3) (2024) 201 – 211 . [11] T. Cascone, M.M. Awad, J.D. Spicer, J. He, S. Lu, B. Sepesi, F. Tanaka, J.M. Taube, R. Cornelissen, L. Havel, N. Karaseva, J. Kuzdzal, L.B. Petruzelka, L. Wu, J.L. Pujol, H. Ito, T.E. Ciuleanu, L. de Oliveira Muniz, A. Koch, A. Janssens, S. Alexandru, F. V. Bohnet, Y. Moiseyenko, Y. Gao, C.C. Watanabe, P. Erdmann, S. Sathyanarayana, S.I. Meadows-Shropshire, M.P. Blum, Pulla, Perioperative nivolumab in resectable lung cancer, N. Engl. J. Med. 390 (19) (2024) 1756 – 1769 . [12] D. Yue, W. Wang, H. Liu, Q. Chen, C. Chen, L. Liu, P. Zhang, G. Zhao, F. Yang, G. Han, Y. Cheng, B. Yu, Y. Yang, H. Chen, J. Jiang, B. Yao, S. Wang, R. Wang, W. Zheng, C. Wang, VP1-2024: RATIONALE-315: Event-free survival (EFS) and overall survival (OS) of neoadjuvant tislelizumab (TIS) plus chemotherapy (CT) with adjuvant TIS in resectable non-small cell lung cancer (NSCLC), Ann. Oncol. 35 (3) (2024) 332 – 333 . [13] J. Spicer, N. Girard, M. Provencio, C. Wang, T. Mitsudomi, M.M. Awad, E.E. Vokes, J.M. Taube, L. Lupinacci, G.B. Saylors, F. Tanaka, M. Liberman, S.Y. Lee, A. Alexandru, M. D ’ Arcangelo, P. Tran, J. Mahmood, V.S. Gharpure, A. Bhingare, P.M. Forde, Neoadjuvant nivolumab (NIVO) chemotherapy (chemo) vs chemo in + patients (pts) with resectable NSCLC: 4-year update from CheckMate 816, J. Clin. Oncol. 42 (17_suppl) (2024). LBA8010-LBA8010 . [14] A.C. Tan, D.S.W. Tan, Targeted therapies for lung cancer patients with oncogenic driver molecular alterations, J. Clin. Oncol. 40 (6) (2022) 611 – 625 . [15] W.D. Travis, H. Asamura, A.A. Bankier, M.B. Beasley, F. Detterbeck, D.B. Flieder, J. M. Goo, H. MacMahon, D. Naidich, A.G. Nicholson, C.A. Powell, M. Prokop, R. Rami-Porta, V. Rusch, P. van Schil, Y. Yatabe, The IASLC lung cancer staging project: proposals for coding T categories for subsolid nodules and assessment of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM classification of lung cancer, J. Thorac. Oncol. 11 (8) (2016) 1204 – 1223 . [16] A.R. Khan, S. Khan, V. Zimmerman, L.M. Baddour, I.M. Tleyjeh, Quality and strength of evidence of the infectious diseases society of america clinical practice guidelines, Clin. Infect. Dis. 51 (10) (2010) 1147 – 1156 . [17] A. Passaro, N. Leighl, F. Blackhall, S. Popat, K. Kerr, M.J. Ahn, M.E. Arcila, O. Arrieta, D. Planchard, F. de Marinis, A.M. Dingemans, R. Dziadziuszko, C. Faivre-Finn, J. Feldman, E. Felip, G. Curigliano, R. Herbst, P.A. J anne, T. John, T. Mitsudomi, T. Mok, N. Normanno, L. Paz-Ares, S. Ramalingam, L. Sequist, J. Vansteenkiste, J. Wistuba II, Y.L. Wolf, S.R. Wu, J.C.H. Yang, Y. Yang, G. Yatabe, S.P. Pentheroudakis, ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer, Ann. Oncol. 33 (5) (2022) 466 – 487 . [18] M. Reck, D. Rodríguez-Abreu, A.G. Robinson, R. Hui, T. Cs oszi, A. Fül op, M. Gottfried, N. Peled, A. Tafreshi, S. Cuffe, M. O ’ Brien, S. Rao, K. Hotta, M. A. Leiby, G.M. Lubiniecki, Y. Shentu, R. Rangwala, J.R. Brahmer, Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer, N. Engl. J. Med. 375 (19) (2016) 1823 – 1833 . [19] R.S. Herbst, G. Giaccone, F. de Marinis, N. Reinmuth, A. Vergnenegre, C.H. Barrios, M. Morise, E. Felip, Z. Andric, S. Geater, M. Ozgüro glu, W. Zou, A. Sandler, I. Enquist, K. Komatsubara, Y. Deng, H. Kuriki, X. Wen, M. McCleland, S. Mocci, J. Jassem, D.R. Spigel, Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC, N. Engl. J. Med. 383 (14) (2020) 1328 – 1339 . [20] M. Tsuboi, R.S. Herbst, T. John, T. Kato, M. Majem, C. Groh e, J. Wang, J. W. Goldman, S. Lu, W.C. Su, F. de Marinis, F.A. Shepherd, K.H. Lee, N.T. Le, A. Dechaphunkul, D. Kowalski, L. Poole, A. Bolanos, Y. Rukazenkov, Y.L. Wu, Overall survival with osimertinib in resected EGFR-mutated NSCLC, N. Engl. J. Med. 389 (2) (2023) 137 – 147 . [21] M.Y. Heinke, S.K. Vinod, A review on the impact of lung cancer multidisciplinary care on patient outcomes, Transl Lung Cancer Res 9 (4) (2020) 1639 – 1653 . [22] H.Y. Hung, Y.H. Tseng, H.S. Chao, C.H. Chiu, W.H. Hsu, H.S. Hsu, Y.C. Wu, T. Y. Chou, C.K. Chen, K.L. Lan, Y.W. Chen, Y.H. Wu, Y.M. Chen, Multidisciplinary team discussion results in survival benefit for patients with stage III non-small-cell lung cancer, PLoS One 15 (10) (2020) e0236503 . [23] A. Kowalczyk, J. Jassem, Multidisciplinary team care in advanced lung cancer, Transl Lung Cancer Res 9 (4) (2020) 1690 – 1698 . [24] F. Leo, N. Venissac, M. Poudenx, J. Otto, J. Mouroux, Multidisciplinary management of lung cancer: how to test its efficacy? J. Thorac. Oncol. 2 (1) (2007) 69 – 72 . [25] M.M. Boxer, S.K. Vinod, J. Shafiq, K.J. Duggan, Do multidisciplinary team meetings make a difference in the management of lung cancer? Cancer 117 (22) (2011) 5112 – 5120 . [26] C.J.L. Stone, H.M. Vaid, R. Selvam, A. Ashworth, A. Robinson, G.C. Digby, Multidisciplinary clinics in lung cancer care: a systematic review, Clin. Lung Cancer 19 (4) (2018) 323 – 330.e3 . [27] S.P.L. Saw, K.L.M. Chua, B.H. Ong, D.W.T. Lim, G.G.Y. Lai, D.S.W. Tan, M.K. Ang, Multidisciplinary lung cancer clinic: an emerging model of care, Ann. Acad. Med. Singap. 51 (12) (2022) 793 – 795 . [28] J. Senter, C. Hooker, M. Lang, K.R. Voong, R.K. Hales, Thoracic multidisciplinary clinic improves survival in patients with lung cancer, Int. J. Radiat. Oncol., Biol. Phys. 96 (2) (2016) S134 . [29] F.C. Detterbeck, M. Ostrowski, H. Hoffmann, R. Rami-Porta, R.U. Osarogiagbon, J. Donnington, M. Infante, M. Marino, E.M. Marom, J. Nakajima, A.G. Nicholson, P. van Schil, W.D. Travis, M.S. Tsao, J.G. Edwards, H. Asamura, The international association for the study of lung cancer lung cancer staging project: proposals for revision of the classification of residual tumor after resection for the forthcoming (ninth) edition of the TNM classification of lung cancer, J. Thorac. Oncol. 19 (7) (2024) 1052 – 1072 . [30] B. Fischer, U. Lassen, J. Mortensen, S. Larsen, A. Loft, A. Bertelsen, J. Ravn, P. Clementsen, A. H ø gholm, K. Larsen, T. Rasmussen, S. Keiding, A. Dirksen, O. Gerke, B. Skov, I. Steffensen, H. Hansen, P. Vilmann, G. Jacobsen, V. Backer, N. Maltbaek, J. Pedersen, H. Madsen, H. Nielsen, L. H ø jgaard, Preoperative staging of lung cancer with combined PET-CT, N. Engl. J. Med. 361 (1) (2009) 32 – 39 . [31] C.E. Reed, D.H. Harpole, K.E. Posther, S.L. Woolson, R.J. Downey, B.F. Meyers, R. T. Heelan, H.A. MacApinlac, S.H. Jung, G.A. Silvestri, B.A. Siegel, V.W. Rusch, Results of the American College of Surgeons Oncology Group Z0050 trial: the utility of positron emission tomography in staging potentially operable non-small cell lung cancer, J. Thorac. Cardiovasc. Surg. 126 (6) (2003) 1943 – 1951 . [32] G.A. Silvestri, A.V. Gonzalez, M.A. Jantz, M.L. Margolis, M.K. Gould, L.T. Tanoue, L.J. Harris, F.C. Detterbeck, Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines, Chest 143 (5 Suppl) (2013) e211S – e250 . [33] A.A. Balekian, J.M. Fisher, M.K. Gould, Brain imaging for staging of patients with clinical stage IA non-small cell lung cancer in the national lung screening trial: adherence with recommendations from the choosing wisely campaign, Chest 149 (4) (2016) 943 – 950 . [34] T. Yohena, I. Yoshino, M. Kitajima, T. Uehara, T. Kanematsu, T. Teruya, J. Ikeda, Y. Ichinose, Necessity of preoperative screening for brain metastasis in non-small cell lung cancer patients without lymph node metastasis, Ann. Thorac. Cardiovasc. Surg. 10 (6) (2004) 347 – 349 . [35] M.M. Hochstenbag, A. Twijnstra, P. Hofman, E.F. Wouters, G.P. ten Velde, MR-imaging of the brain of neurologic asymptomatic patients with large cell or adenocarcinoma of the lung. Does it influence prognosis and treatment? Lung Cancer 42 (2) (2003) 189 – 193 . [36] J. Schoenmaekers, A.C. Dingemans, L.E.L. Hendriks, Brain imaging in early stage non-small cell lung cancer: still a controversial topic? J. Thorac. Dis. 10 (Suppl 18) (2018) S2168 – S2171 . [37] W.D. Travis, S. Dacic, I. Wistuba, L. Sholl, P. Adusumilli, L. Bubendorf, P. Bunn, T. Cascone, J. Chaft, G. Chen, T.Y. Chou, W. Cooper, J.J. Erasmus, C.G. Ferreira, J. M. Goo, J. Heymach, F.R. Hirsch, H. Horinouchi, K. Kerr, M. Kris, D. Jain, Y.T. Kim, F. Lopez-Rios, S. Lu, T. Mitsudomi, A. Moreira, N. Motoi, A.G. Nicholson, R. Oliveira, M. Papotti, U. Pastorino, L. Paz-Ares, G. Pelosi, C. Poleri, M. Provencio, A.C. Roden, G. Scagliotti, S.G. Swisher, E. Thunnissen, M.S. Tsao, J. Vansteenkiste, W. Weder, Y. Yatabe, IASLC multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy, J. Thorac. Oncol. 15 (5) (2020) 709 – 740 . [38] B. Pellini, A.A. Chaudhuri, Circulating tumor DNA minimal residual disease detection of non-small-cell lung cancer treated with curative intent, J. Clin. Oncol. 40 (6) (2022) 567 – 575 . [39] C. Abbosh, N.J. Birkbak, G.A. Wilson, M. Jamal-Hanjani, T. Constantin, R. Salari, J. Le Quesne, D.A. Moore, S. Veeriah, R. Rosenthal, T. Marafioti, E. Kirkizlar, T.B. K. Watkins, N. McGranahan, S. Ward, L. Martinson, J. Riley, F. Fraioli, M. Al Bakir, E. Gr onroos, F. Zambrana, R. Endozo, W.L. Bi, F.M. Fennessy, N. Sponer, D. Johnson, J. Laycock, S. Shafi, J. Czyzewska-Khan, A. Rowan, T. Chambers, N. Matthews, S. Turajlic, C. Hiley, S.M. Lee, M.D. Forster, T. Ahmad, M. Falzon, E. Borg, D. Lawrence, M. Hayward, S. Kolvekar, N. Panagiotopoulos, S.M. Janes, R. Thakrar, A. Ahmed, F. Blackhall, Y. Summers, D. Hafez, A. Naik, A. Ganguly, S. Kareht, R. Shah, L. Joseph, A. Marie Quinn, P.A. Crosbie, B. Naidu, G. Middleton, G. Langman, S. Trotter, M. Nicolson, H. Remmen, K. Kerr, M. Chetty, L. Gomersall, D.A. Fennell, A. Nakas, S. Rathinam, G. Anand, S. Khan, P. Russell, V. Ezhil, B. Ismail, M. Irvin-Sellers, V. Prakash, J.F. Lester, M. Kornaszewska, R. Attanoos, H. Adams, H. Davies, D. Oukrif, A.U. Akarca, J.A. Hartley, H.L. Lowe, S. Lock, N. Iles, H. Bell, Y. Ngai, G. Elgar, Z. Szallasi, R.F. Schwarz, J. Herrero, A. Stewart, S. A. Quezada, K.S. Peggs, P. Van Loo, C. Dive, C.J. Lin, M. Rabinowitz, H. Aerts, A. Hackshaw, J.A. Shaw, B.G. Zimmermann, C. Swanton, Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution, Nature 545 (7655) (2017) 446 – 451 . [40] D. Biswas, N.J. Birkbak, R. Rosenthal, C.T. Hiley, E.L. Lim, K. Papp, S. Boeing, M. Krzystanek, D. Djureinovic, L. La Fleur, M. Greco, B. D ome, J. Fillinger, H. Brunnstr om, Y. Wu, D.A. Moore, M. Skrzypski, C. Abbosh, K. Litchfield, M. Al Bakir, T.B.K. Watkins, S. Veeriah, G.A. Wilson, M. Jamal-Hanjani, J. Moldvay, J. Botling, A.M. Chinnaiyan, P. Micke, A. Hackshaw, J. Bartek, I. Csabai, Z. Szallasi, J. Herrero, N. McGranahan, C. Swanton, A clonal expression biomarker associates with lung cancer mortality, Nat. Med. 25 (10) (2019) 1540 – 1548 . [41] A.C. Tan, G.G.Y. Lai, S.P.L. Saw, K.L.M. Chua, A. Takano, B.H. Ong, T.P.T. Koh, A. Jain, W.L. Tan, Q.S. Ng, R. Kanesvaran, T. Rajasekaran, E. Kalashnikova, D. Renner, S. Sudhaman, M. Malhotra, H. Sethi, M.C. Liu, A. Aleshin, W.T. Lim, E. H. Tan, A.J. Skanderup, M.K. Ang, D.S.W. Tan, Detection of circulating tumor DNA with ultradeep sequencing of plasma cell-free DNA for monitoring minimal

S.P.L. Saw et al.

residual disease and early detection of recurrence in early-stage lung cancer, Cancer 130 (10) (2024) 1758 – 1765 . [42] A.A. Chaudhuri, J.J. Chabon, A.F. Lovejoy, A.M. Newman, H. Stehr, T.D. Azad, M. S. Khodadoust, M.S. Esfahani, C.L. Liu, L. Zhou, F. Scherer, D.M. Kurtz, C. Say, J. N. Carter, D.J. Merriott, J.C. Dudley, M.S. Binkley, L. Modlin, S.K. Padda, M. F. Gensheimer, R.B. West, J.B. Shrager, J.W. Neal, H.A. Wakelee, B.W. Loo Jr., A. A. Alizadeh, M. Diehn, Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling, Cancer Discov. 7 (12) (2017) 1394 – 1403 . [43] H.A. Jung, B.M. Ku, Y.J. Kim, S. Park, J.M. Sun, S.H. Lee, J.S. Ahn, J.H. Cho, H. K. Kim, Y.S. Choi, Y.L. Choi, S.H. Shin, B.H. Jeong, S.W. Um, H. Kim, K. Kim, M. J. Ahn, J. Kim, Longitudinal monitoring of circulating tumor DNA from plasma in patients with curative resected stages I to IIIA EGFR-mutant non-small cell lung cancer, J. Thorac. Oncol. 18 (9) (2023) 1199 – 1208 . [44] C. Zhou, M. Das Thakur, M.K. Srivastava, W. Zou, H. Xu, M. Ballinger, E. Felip, H. Wakelee, N.K. Altorki, M. Reck, R. Liersch, A. Kryzhanivska, M. Harada, H. Tanaka, J. Hamm, S. McCune, V. McNally, E. Bennett, B. Gitlitz, S. Novello, 2O IMpower010: Biomarkers of disease-free survival (DFS) in a phase III study of atezolizumab (atezo) vs best supportive care (BSC) after adjuvant chemotherapy in stage IB-IIIA NSCLC, Ann. Oncol. 32 (2021) S1374 . [45] R. Rami-Porta, C. Wittekind, P. Goldstraw, Complete resection in lung cancer surgery: proposed definition, Lung Cancer 49 (1) (2005) 25 – 33 . [46] A. Araújo, A. Barroso, B. Parente, C. Travancinha, E. Teixeira, F. Martelo, G. Fernandes, G. Paup erio, H. Queiroga, I. Duarte, J.D. da Costa, M. Soares, P. Borralho, P. Costa, P. Chinita, T. Almod ovar, F. Barata, Unresectable stage III non-small cell lung cancer: insights from a Portuguese expert panel, Pulmonology 30 (2) (2024) 159 – 169 . [47] L.A. Robinson, J.C. Ruckdeschel, H. Wagner Jr., C.W. Stevens, Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines (2nd edition), Chest 132 (3 Suppl) (2007), 243s-265s . [48] I. Houda, I. Bahce, C. Dickhoff, T.E. Kroese, S.G.C. Kroeze, A.V. Mariolo, M. Tagliamento, L. Moliner, M. Brandao, J. Edwards, I. Opitz, C. Faivre-Finn, D. de Ruysscher, J. Remon, T. Berghmans, A.M.C. Dingemans, B. Besse, L.E.L. Hendriks, OA06.03 An international EORTC survey on resectability of stage III non-small cell lung cancer, J. Thorac. Oncol. 18 (11, Supplement) (2023) S55 – S56 . [49] J. Zeng, B. Yi, R. Chang, Y. Chen, Z. Yu, Y. Gao, Safety and feasibility of robotic-assisted thoracic surgery after neoadjuvant chemoimmunotherapy in non-small cell lung cancer, Front. Oncol. 13 (2023) 1134713 . [50] R. Fu, J. Huang, X. Tian, C. Liang, Y. Xiong, J.T. Zhang, B. Jiang, S. Dong, Y. Gong, W. Gao, F. Li, Y. Shi, Z. Liu, X. Gao, R. Chen, W. Zhong, Y. Zhang, Postoperative circulating tumor DNA can refine risk stratification in resectable lung cancer: results from a multicenter study, Mol. Oncol. 17 (5) (2023) 825 – 838 . [51] C. Schaake-Koning, W. van den Bogaert, O. Dalesio, J. Festen, J. Hoogenhout, P. van Houtte, A. Kirkpatrick, M. Koolen, B. Maat, A. Nijs, et al., Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer, N. Engl. J. Med. 326 (8) (1992) 524 – 530 . [52] W.E. Eberhardt, D. De Ruysscher, W. Weder, C. Le P echoux, P. De Leyn, H. Hoffmann, V. Westeel, R. Stahel, E. Felip, S. Peters, 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer, Ann. Oncol. 26 (8) (2015) 1573 – 1588 . [53] K.S. Albain, J.J. Crowley, A.T. Turrisi 3rd, D.R. Gandara, W.B. Farrar, J.I. Clark, K. R. Beasley, R.B. Livingston, Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019, J. Clin. Oncol. 20 (16) (2002) 3454 – 3460 . [54] Q. Zhou, M. Chen, O. Jiang, Y. Pan, D. Hu, Q. Lin, G. Wu, J. Cui, J. Chang, Y. Cheng, C. Huang, A. Liu, N. Yang, Y. Gong, C. Zhu, Z. Ma, J. Fang, G. Chen, J. Zhao, A. Shi, Y. Lin, G. Li, Y. Liu, D. Wang, R. Wu, X. Xu, J. Shi, Z. Liu, N. Cui, J. Wang, Q. Wang, R. Zhang, J. Yang, Y.L. Wu, Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial, Lancet Oncol. 23 (2) (2022) 209 – 219 . [55] S. Tanzawa, T. Makiguchi, S. Tasaka, M. Inaba, R. Ochiai, J. Nakamura, K. Inoue, T. Kishikawa, M. Nakashima, K. Fujiwara, T. Kohyama, H. Ishida, S. Kuyama, N. Miyazawa, T. Nakamura, H. Miyawaki, N. Oda, N. Ishikawa, R. Morinaga, K. Kusaka, Y. Miyamoto, T. Yokoyama, C. Matsumoto, T. Tsuda, S. Ushijima, K. Shibata, T. Shibayama, A. Bessho, K. Kaira, T. Misumi, K. Shiraishi, N. Matsutani, N. Seki, Prospective analysis of factors precluding the initiation of durvalumab from an interim analysis of a phase II trial of S-1 and cisplatin with concurrent thoracic radiotherapy followed by durvalumab for unresectable, locally advanced non-small cell lung cancer in Japan (SAMURAI study), Ther Adv Med Oncol 14 (2022), 17588359221116603 . [56] T. Eichkorn, F. Bozorgmehr, S. Regnery, L.A. Dinges, A. Kudak, N. Bougatf, D. Weber, P. Christopoulos, T. Muley, S. Kobinger, L. K onig, J. H orner-Rieber, S. Adeberg, C.P. Heussel, M. Thomas, J. Debus, R.A. El Shafie, Consolidation immunotherapy after platinum-based chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer-cross-sectional study of eligibility and administration rates, Front. Oncol. 10 (2020) 586449 . [57] A. Bruni, V. Scotti, P. Borghetti, S. Vagge, S. Cozzi, E. D ’ Angelo, N. Giaj Levra, A. Fozza, M. Taraborrelli, G. Piperno, V. Vanoni, M. Sepulcri, M. Trov o, V. Nardone, E. Lattanzi, S. Bou Selman, F. Bertolini, D. Franceschini, F. Agustoni, B. A. Jereczek-Fossa, S.M. Magrini, L. Livi, F. Lohr, A.R. Filippi, A. Real-World, Multicenter, observational retrospective study of durvalumab after concomitant or sequential chemoradiation for unresectable stage III non-small cell lung cancer, Front Oncol 11 (2021) 744956 . [58] S. Lu, T. Kato, X. Dong, M.J. Ahn, L.V. Quang, N. Soparattanapaisarn, T. Inoue, C. L. Wang, M. Huang, J.C. Yang, M. Cobo, M. Ozgüro glu, I. Casarini, D.V. Khiem, V. Sriuranpong, E. Cronemberger, T. Takahashi, Y. Runglodvatana, M. Chen, X. Huang, E. Grainger, D. Ghiorghiu, T. van der Gronde, S.S. Ramalingam, Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC, N. Engl. J. Med. 391 (7) (2024) 585 – 597 . [59] H. Uramoto, F. Tanaka, Recurrence after surgery in patients with NSCLC, Transl Lung Cancer Res 3 (4) (2014) 242 – 249 . [60] G.L. Banna, M.A. Hassan, A. Signori, E.F. Giunta, A. Maniam, S. Anpalakhan, S. Acharige, A. Ghose, A. Addeo, Neoadjuvant chemo-immunotherapy for early-stage non-small cell lung cancer: A systematic review and meta-analysis, JAMA Netw. Open 7 (4) (2024) e246837 . [61] C.U. Blank, M.W. Lucas, R.A. Scolyer, B.A.v.d. Wiel, A.M. Menzies, M.I. Lopez-Yurda, A.C.J.V. Akkooi, W.J.V. Houdt, R.P.M. Saw, A.T. Acosta, S.N. Lo, G. Hospers, M.S. Carlino, J.W.D. Groot, E. Kapiteijn, K. Suijkerbuijk, P. Rutkowski, S. Sandhu, A.A.M.V.D. Veldt, G.V. Long, Neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in macroscopic, resectable stage III melanoma: The phase 3 NADINA trial, J. Clin. Oncol. 42 (17_suppl) (2024). LBA2-LBA2 . [62] S.L. Zhang, Y. Tian, J. Yu, J.H. Zhang, L. Sun, L.T. Huang, J.T. Ma, C.B. Han, Is neoadjuvant immunotherapy necessary in patients with programmed death ligand 1 expression-negative resectable non-small cell lung cancer? A systematic review and meta-analysis, Lung Cancer 191 (2024) 107799 . [63] S.J. Gao, C.D. Corso, E.H. Wang, J.D. Blasberg, F.C. Detterbeck, D.J. Boffa, R. H. Decker, A.W. Kim, Timing of surgery after neoadjuvant chemoradiation in locally advanced non-small cell lung cancer, J. Thorac. Oncol. 12 (2) (2017) 314 – 322 . [64] J.S. Deutsch, A. Cimino-Mathews, E. Thompson, M. Provencio, P.M. Forde, J. Spicer, N. Girard, D. Wang, R.A. Anders, E. Gabrielson, P. Illei, J. Jedrych, L. Danilova, J. Sunshine, K.M. Kerr, M. Tran, J. Bushong, J. Cai, V. Devas, J. Neely, D. Balli, T.R. Cottrell, A.S. Baras, J.M. Taube, Association between pathologic response and survival after neoadjuvant therapy in lung cancer, Nat. Med. 30 (1) (2024) 218 – 228 . [65] S.B. Edge, C.C. Compton, The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM, Ann. Surg. Oncol. 17 (6) (2010) 1471 – 1474 . [66] Y.L. Wu, T. John, C. Grohe, M. Majem, J.W. Goldman, S.W. Kim, T. Kato, K. Laktionov, H.V. Vu, Z. Wang, S. Lu, K.Y. Lee, C. Akewanlop, C.J. Yu, F. de Marinis, L. Bonanno, M. Domine, F.A. Shepherd, L. Zeng, A. Atasoy, R.S. Herbst, M. Tsuboi, Postoperative chemotherapy use and outcomes from ADAURA: Osimertinib as adjuvant therapy for resected EGFR-mutated NSCLC, J. Thorac. Oncol. 17 (3) (2022) 423 – 433 . [67] G.M. Strauss, J.E. Herndon 2nd, M.A. Maddaus, D.W. Johnstone, E.A. Johnson, D. H. Harpole, H.H. Gillenwater, D.M. Watson, D.J. Sugarbaker, R.L. Schilsky, E. E. Vokes, M.R. Green, 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. 26 (31) (2008) 5043 – 5051 . [68] V. Ernani, T.E. Stinchcombe, Management of brain metastases in non-small-cell lung cancer, J. Oncol. Pract. 15 (11) (2019) 563 – 570 . [69] D.R. Spigel, C. Faivre-Finn, J.E. Gray, D. Vicente, D. Planchard, L. Paz-Ares, J. F. Vansteenkiste, M.C. Garassino, R. Hui, X. Quantin, A. Rimner, Y.L. Wu, M. Ozgüro glu, K.H. Lee, T. Kato, M. de Wit, T. Kurata, M. Reck, B.C. Cho, S. Senan, J. Naidoo, H. Mann, M. Newton, P. Thiyagarajah, S.J. Antonia, Five-year survival outcomes from the PACIFIC Trial: Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer, J. Clin. Oncol. 40 (12) (2022) 1301 – 1311 . [70] M. Riudavets, E. Auclin, M. Mosteiro, N. Dempsey, M. Majem, R. Lobefaro, R. L opez-Castro, J. Bosch-Barrera, S. Pilotto, E. Escalera, M. Tagliamento, J. Mosquera, G. Zalcman, F. Aboubakar-Nana, S. Ponce, A. Dal Maso, M. Spotti, X. Mielgo-Rubio, E. Mussat, R. Reyes, J.C. Benítez, L. Lupinacci, B. Duchemann, A. De Giglio, J. Blaquier, C. Audigier-Valette, M. Scheffler, E. Nadal, G. Lopes, D. Signorelli, R. Garcia-Campelo, J. Menis, V. Bluthgen, M. Campayo, G. Recondo, B. Besse, D. Planchard, L. Mezquita, Durvalumab consolidation in patients with unresectable stage III non-small cell lung cancer with driver genomic alterations, Eur. J. Cancer 167 (2022) 142 – 148 . [71] C.K. Lee, J. Man, S. Lord, M. Links, V. Gebski, T. Mok, J.C. Yang, Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-a meta-analysis, J. Thorac. Oncol. 12 (2) (2017) 403 – 407 . [72] J. Mazieres, A. Drilon, A. Lusque, L. Mhanna, A.B. Cortot, L. Mezquita, A.A. Thai, C. Mascaux, S. Couraud, R. Veillon, M. Van den Heuvel, J. Neal, N. Peled, M. Früh, T.L. Ng, V. Gounant, S. Popat, J. Diebold, J. Sabari, V.W. Zhu, S.I. Rothschild, P. Bironzo, A. Martinez-Marti, A. Curioni-Fontecedro, R. Rosell, M. Lattuca-Truc, M. Wiesweg, B. Besse, B. Solomon, F. Barlesi, R.D. Schouten, H. Wakelee, D. R. Camidge, G. Zalcman, S. Novello, S.I. Ou, J. Milia, O. Gautschi, Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry, Ann. Oncol. 30 (8) (2019) 1321 – 1328 . [73] J.J. Lin, E. Chin, B.Y. Yeap, L.A. Ferris, V. Kamesan, I.T. Lennes, L.V. Sequist, R. S. Heist, M. Mino-Kenudson, J.F. Gainor, A.T. Shaw, Increased hepatotoxicity associated with sequential immune checkpoint inhibitor and crizotinib therapy in patients with non-small cell lung cancer, J. Thorac. Oncol. 14 (1) (2019) 135 – 140 . [74] J.J. Heymann, W.A. Bulman, D. Swinarski, C.A. Pagan, J.P. Crapanzano, M. Haghighi, L. Fazlollahi, M.B. Stoopler, J.R. Sonett, A.G. Sacher, C.A. Shu, N. A. Rizvi, A. Saqi, PD-L1 expression in non-small cell lung carcinoma: Comparison among cytology, small biopsy, and surgical resection specimens, Cancer Cytopathol. 125 (12) (2017) 896 – 907 .

S.P.L. Saw et al.

[75] S. Kitazono, Y. Fujiwara, K. Tsuta, H. Utsumi, S. Kanda, H. Horinouchi, H. Nokihara, N. Yamamoto, S. Sasada, S. Watanabe, H. Asamura, T. Tamura, Y. Ohe, Reliability of small biopsy samples compared with resected specimens for the determination of programmed death-ligand 1 expression in non – small-cell lung cancer, Clin. Lung Cancer 16 (5) (2015) 385 – 390 . [76] M. Ilie, E. Long-Mira, C. Bence, C. Butori, S. Lassalle, L. Bouhlel, L. Fazzalari, K. Zahaf, S. Lalv ee, K. Washetine, J. Mouroux, N. V enissac, M. Poudenx, J. Otto, J. C. Sabourin, C.H. Marquette, V. Hofman, P. Hofman, Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies, Ann. Oncol. 27 (1) (2016) 147 – 153 . [77] Y. Saito, S. Horiuchi, H. Morooka, T. Ibi, N. Takahashi, T. Ikeya, Y. Shimizu, E. Hoshi, Inter-tumor heterogeneity of PD-L1 expression in non-small cell lung cancer, J. Thorac. Dis. 11 (12) (2019) 4982 – 4991 . [78] D. K onig, S. Savic Prince, S. Hayoz, P. Zens, S. Berezowska, W. Jochum, E. Stauffer, V. Braunersreuther, B. Trachsel, S. Thierstein, M. Mark, S. Schmid, A. Curioni-Fontecedro, A. Addeo, I. Opitz, M. Guckenberger, M. Früh, D.C. Betticher, H.B. Ris, R. Stupp, S.I. Rothschild, L. Bubendorf, M. Pless, Neoadjuvant treatment does not influence PD-L1 expression in stage III non-small-cell lung cancer: a retrospective analysis of tumor samples from the trials SAKK 16/96, 16/00, 16/01, and 16/14, ESMO Open 8 (4) (2023), 101595 . [79] W.Z. Zhong, K.N. Chen, C. Chen, C.D. Gu, J. Wang, X.N. Yang, W.M. Mao, Q. Wang, G.B. Qiao, Y. Cheng, L. Xu, C.L. Wang, M.W. Chen, X. Kang, W. Yan, H.H. Yan, R. Q. Liao, J.J. Yang, X.C. Zhang, Q. Zhou, Y.L. Wu, Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer (EMERGING-CTONG 1103): A randomized phase II study, J. Clin. Oncol. 37 (25) (2019) 2235 – 2245 . [80] Q. Zhou, Y. Pan, X. Yang, Y. Zhao, G. Han, Q. Pang, Z. Zhang, Q. Wang, J. Yao, H. Wang, W. Yang, B. Liu, Q. Chen, X. Du, K. Cai, B. Li, Y. Huang, X. Li, L. Song, W. Shi, Y.L. Wu, Neoadjuvant SHR-1701 with or without chemotherapy in unresectable stage III non-small-cell lung cancer: A proof-of-concept, phase 2 trial, Cancer Cell 42 (7) (2024) 1258 – 1267.e2 . [81] M. Reck, E. Nadal, N. Girard, A.R.R. Filippi, L.W. Martin, C.M. Gay, C. Petersen, D. Gale, H.R. Bridge, N. Donner, N.E. Georgoulia, J. Spicer, 115TiP MDT-BRIDGE: A phase II study of neoadjuvant durvalumab (D) chemotherapy (CT) followed by + either surgery and adjuvant D or chemoradiotherapy (CRT) and consolidation D in patients (pts) with resectable or borderline resectable stage IIB – IIIB NSCLC, Immuno-Oncology and Technology 20 (2023) 100587 . [82] J.B. Hines, R.B. Cameron, A. Esposito, L. Kim, L. Porcu, A. Nuccio, G. Viscardi, R. Ferrara, G. Veronesi, P.M. Forde, J. Taube, E. Vokes, C.M. Bestvina, J. M. Dolezal, M. Sacco, M. Monteforte, T. Cascone, M.C. Garassino, V. Torri, Evaluation of major pathologic response and pathologic complete response as surrogate end points for survival in randomized controlled trials of neoadjuvant immune checkpoint blockade in resectable in NSCLC, J. Thorac. Oncol. 19 (7) (2024) 1108 – 1116 .