2026 中国专家共识：不可切除的III期驱动基因阳性非小细胞肺癌的诊断和治疗（英文版）

1. Introduction

According to the latest research data from the National Cancer Center, approximately 4,824,700 new cancer cases occurred in China in 2022. Lung cancer accounted for 1,060,600 of the new cases and 733,300 deaths, ranking first among all malignancies [1]. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, constituting 80 %-85 % of all lung cancers [2], and approximately one-third of patients with NSCLC are diagnosed at stage III. Accurate

staging is the prerequisite for precision therapy. Comprehensive imaging examinations, including contrast-enhanced brain magnetic resonance imaging (MRI), are recommended for staging. Positron emission tomography-computed tomography (PET-CT) or endobronchial ultra-sound is suggested for eligible patients and hospitals to ensure accurate staging. The treatment strategy for stage III NSCLC should be formulated through multidisciplinary team (MDT) consultation, considering the patient's general condition, stage, pathological type, and molecular subtype. The MDT comprises experts from medical oncology, radiation

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oncology, thoracic surgery, respiratory medicine and pathology. This process involves in-depth case analysis from each specialty's perspective, culminating in an integrated, optimal, and personalized comprehensive treatment plan collaboratively formulated for the patient.

The resectability of stage III NSCLC remains controversial. Previous studies considered unresectable stage III NSCL to include the following situations: (1) tumor invasion into the esophagus, heart, and great vesels (IIIA: T4N0–1), (2) single-station N2 mediastinal lymph node (short axis ≥3 cm) or ipsilateral multi-station mediastinal lymph node metastasis or fused lymph nodes, (3) all N3 metastases involving contralateral hilar, mediastinal lymph nodes, or ipsilateral/contralateral scalene/supraclavular lymph nodes [3,4]. However, an EORTC study revealed a lack of consensus on the resectability of cT4 tumors, with surgeons from high-volume centers more likely to classify cT4 tumors as resectable, for patients with multi-station N2 NSCLC undergoing induction therapy followed by surgical resection, the R0 resection rate reached 80 % [5]. Therefore, resectability should be determined by the MDT on the basis of tumor invasion extent, lymph node metastasis status, and systemic functional status. Patients who received induction therapy should undergo re-evaluation by the MDT to assess resectability.

In the treatment landscape of unresectable stage III driver gene-positive NSCLC, the LAURA [6] and POLESTAR [7] studies have established a standard model of targeted consolidation therapy (osimertinib or aumolertinib) following definitive CRT for patients with EGFR-sensitive mutations. However, treatment for patients with other driver gene mutations, such as ROLI warings or ROLI rearrangement, still lacks high-level evidence-based medical evidence. To develop the first expert consensus on the diagnosis and treatment of unresectable stage III driver gene-positive NSCLC, this study identified key clinical questions, conducted extensive literature and conference report searches, analyzed existing research data, and engaged in-depth discussion on the basis of clinical experience, aiming to guide clinical practice.

2. Methods

2.1. Composition of the expert panel

This consensus was developed by a multidisciplinary panel of experts from radiation oncology, medical oncology, respiratory medicine, thoracic surgery, and pathology. These experts represent major tertiary hospitals and cancer centers across China.

2.2. Scope of the review

The working group identified key clinical issues in managing unsectable stage III driver gene-positive NSCLC. A comprehensive literature review of the PubMed, Embase and ClinicalTrials.gov databases was conducted, focusing on published guidelines, randomized controlled trials (RCTs), cohort studies, retrospective analyses, and meta-analyses. Differences in international practices and available evidence were critically analyzed.

2.3. Formation of the consensus

The drafting committee developed one or more preliminary recommendations for each key clinical issue, based on available evidence-

based data and collective clinical expertise. A modified Delphi method was employed, in which panel members participated in multiple rounds of in-person discussions and anonymous voting to reach consensus. A recommendation was considered approved when at least 75 % of the voting experts endorsed it. Recommendations failing to meet this threshold were revised based on panel feedback and re-voted upon until consensus was achieved. The consensus level was categorized into four tiers (Table 1). Recommendations were primarily based on available evidence (RCTs, cohort studies), collections of common practice data, and expert opinions. This consensus has been registered on the International Practice Guidelines Registry and Transparency Platform at https://www guidelines-registry.cn/. The registration number is PRE-PARE-2025CN407.

3. Clinical questions and consensus recommendations

Question 1: Is genetic testing recommended for all pathological types of unresectable stage III NSCLC?

Consensus Recommendation 1: Genetic testing is recommended for patients with unresectable stage III non-squamous non-small cell lung cancer. For patients with squamous cell carcinoma, particularly non-smokers, genetic testing may be considered. (Consensus level: 98.4 %; Strength: Grade II)

Rationale:

The prevalence of driver gene mutations in NSCLC shows significant geographical variation. EGFR gene mutation rates are notably higher in Chinese lung cancer patients compared with those in Western populations, particularly in adenocarcinoma [8]. With the rapid advances in genetic testing technology and the development of new drugs, targeted therapies are becoming available for a growing number of driver gene mutations. The currently recommended essential genes for testing in NSCLC include EGFR (30 %-55 %), ALK (5 %-10 %), ROS1 (2 %-3 %), MET exon 14 skipping mutations (0.9 %-4.0 %), RET (1 %-4 %), BRAF (1 %-2 %), and NTRK (<1 %). Extended gene testing includes KRAS G12C mutations (2.4 %-4 %), HER2 mutations (2 %-4 %), MET amplification (2 %-4 %), NRG1/2 fusions (<1 %), and FGFR aberrations (1.3 %-1.9 %) [9–13].

The incidence of EGFR (7 %-14 %), ALK (1.6 %-4 %), ROS1 (0.3 %), BRAF (0.8 %), and MET (2.1 %) mutations is lower in squamous cell carcinoma than in adenocarcinoma [10,12]. Conversely, FGFR abrations are more common in squamous cell carcinoma (6.8 %) than in adenocarcinoma (1.3 %) [14]. Non-smokers with squamous cell carcinoma have a higher EGFR mutation rate than smokers [15], and squamous cell carcinoma patients with driver mutations benefit from corresponding targeted therapies. The POLESTAR and LAURA studies, which established the role of targeted consolidation in EGFR-mutant NSCLC, included 10 % and 3 % non-adenocarcinoma patients, respectively, providing high-level evidence for targeted consolidation in this subgroup [6,7]. Based on current evidence, routine genetic testing is recommended for patients with unresectable stage III non-squamous NSCLC. For those with lung squamous cell carcinoma, particularly non-smokers and mixed histology, genetic testing may be considered to identify individuals who may benefit from targeted treatment.

Regarding testing, tumor tissue samples are preferred. If unavailable, circulating tumor DNA (ctDNA) from peripheral blood may be considered [16]. The selection of detection technology needs to be evaluated

Table 1

Classification of recommendation levels based on expert voting consensus.

|Recommendation Grade|Expert Consensus Rate|Consensus Strength & Clinical Implication| |---|---|---| |Level I|100 %|Full consensus; corresponds to "strong recommendation/opposition" (highest strength)| |Level II|75 %-99 %|High consensus; corresponds to "moderately strong recommendation/opposition" (second-highest strength)| |Level III|50 %-74 %|Majority consensus (minor divergence); corresponds to "weak recommendation/opposition" (moderate strength)| |Level IV|<50 %|No consensus; no clear recommendation/opposition (lowest strength)|

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Table 2

The key consensus points for the diagnosis and treatment of unresectable stage III driver gene-positive NSCLC.

|Questions|Points|Consensus level| |---|---|---| |1. Is genetic testing recommended for all pathological types of unresectable stage III NSCLC?|Consensus Recommendation 1: Genetic testing is recommended for patients with unresectable stage III non-squamous non-small cell lung cancer. For patients with squamous cell carcinoma, particularly non-smokers, genetic testing may be considered. Consensus Recommendation 2.1: Definitive concurrent chemoradiotherapy (cCRT) is recommended. If cCRT is not tolerated, sequential chemoradiotherapy (sCRT) or radiotherapy alone may be considered. The recommended radiotherapy dose is 60 Gy ± 10 % (range: 54-66 Gy), delivered at 1.8-2.0 Gy per fraction. Platinum-based doublet chemotherapy is the preferred regimen. Consensus Recommendation 2.2: Where available, multimodal imaging (PET-CT or MRI) should be used to guide target volume delineation. Advanced radiotherapy techniques such as image-guided radiotherapy (IGRT), adaptive radiotherapy (ART), simultaneous integrated boost (SIB), and proton therapy may be considered. Consensus Recommendation 3.1: Osimertinib or aumolertinib targeted consolidation therapy is recommended for patients without disease progression after definitive chemoradiotherapy (cCRT or sCRT), until disease progression, the development of intolerable toxicity, or the emergence of other criteria necessitating treatment discontinuation. Consensus Recommendation 3.2: Targeted consolidation therapy is recommended to commence within 42 days after completing CRT. For patients unable to start within 42 days, consolidation therapy should be initiated as soon as feasible thereafter.|98.4 %| |3. What is the recommended treatment for patients with unresectable stage III EGFR-mutant NSCLC?|Consensus Recommendation 4: For patients with ALK fusion without disease progression after CRT, targeted consolidation therapy with an ALK tyrosine kinase inhibitor (TKI) may be considered. However, high-level evidence-based medical study is currently lacking. Enrollment in clinical trials is strongly encouraged. Consensus Recommendation 5.1: Immunotherapy consolidation provides limited benefit in patients with EGFR mutations or ALK fusions and is not recommended after CRT. Consensus Recommendation 5.2: For patients with other driver gene mutations, there is currently a lack of evidence-based medical evidence to support targeted consolidation therapy. Immunotherapy consolidation may be considered and it is encouraged to participate in clinical trials investigating targeted consolidation following CRT.|100 %| |6. What is the recommended treatment for patients with unresectable stage III driver gene-positive NSCLC with bulky tumor?|Consensus Recommendation 6: For patients with bulky tumor initially deemed unsuitable for definitive radiotherapy, induction therapy with targeted agents ± chemotherapy for 8-12 weeks is recommended, followed by MDT re-assessment to evaluate for the feasibility of definitive CRT.|98.4 %| |7. How to identify the patient population with unresectable stage III driver gene-positive NSCLC that is suitable for treatment de-escalation?|Consensus Recommendation 7.1: For patients intolerant to chemotherapy, radiotherapy combined with targeted therapy (without chemotherapy) may be considered. However, this approach lacks high-level evidence and cannot be routinely recommended. Enrollment in phase III randomized controlled trials is strongly encouraged. Consensus Recommendation 7.2: For patients who are intolerant to definitive radiotherapy, targeted therapy based on the driver gene mutation type is recommended. For patients achieving good tumor response, individualized radiotherapy to residual lesions may be considered. Consensus Recommendation 8.1: Differentiate between infectious pneumonia and non-infectious pneumonia. Infectious pneumonia requires prompt anti-infective therapy. Non-infectious pneumonia primarily includes radiation pneumonitis (RP) and drug-related interstitial lung disease (ILD). Consensus Recommendation 8.2: For non-infectious pneumonia ≥ grade 2: Administer systemic corticosteroids ± antifrotic agents, hospitalization may be necessary. For grade 3: After symptomatic improvement to < grade 2, targeted therapy may be cautiously resumed. For grade 4: Permanently discontinue targeted therapy.|96.8 %| |8. How should pneumonia occurring during RT and targeted therapy or targeted therapy following RT for unresectable stage III driver gene-positive NSCLC be managed?||98.4 %|

by the MDT in terms of detection purpose, effectiveness, timeliness, and economy. RT-PCR or small-panel NGS is recommended for testing of essential genes. Fluorescence in situ hybridization may be used for single-gene detection of mutations in genes such as ALK, ROS1, RET, and MET. Immunohistochemistry may serve as a standalone detection method for ALK fusions. Large-panel NGS can detect thousands of genes simultaneously, identifying rare mutations, co-mutations, resistance mutations, and providing biomarkers like tumor mutational burden and microsatellite instability [17]. It can be used in well-equipped institutions or for eligible patients to guide precision therapy. PD-L1 testing should be performed as a companion diagnosis. The key consensus points for the diagnosis and treatment of unresectable stage

III driver gene-positive NSCLC as shown in Table 2.

Question 2: Which chemoradiotherapy regimen is recommended for patients with unresectable stage III driver gene-positive NSCLC?

Consensus Recommendation 2.1: Definitive concurrent chemotherapy (cCRT) is recommended. If cCRT is not tolerated, sequential chemoradiotherapy (sCRT) or radiotherapy alone may be considered. The recommended radiotherapy dose is 60 Gy ± 10 % (range: 54–66 Gy), delivered at 1.8–2.0 Gy per fraction. Platinum-based doublet chemotherapy is the preferred regimen. (Consensus level: 100 %; Strength: Grade 1)

Consensus Recommendation 2.2: Where available, multimodal imaging (PET-CT or MRI) should be used to guide target volume

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delineation. Advanced radiotherapy techniques such as image-guided radiotherapy (IGRT), adaptive radiotherapy (ART), simultaneous integrated boost (SIB), and proton therapy may be considered. (Consensus level: 100 %; Strength: Grade I)

Rationale:

Multiple studies, including RTOG7301 and RTOG9410, have demonstrated that cCRT significantly improves survival compared with sCRT or radiotherapy alone in patients with stage III NSCLC [18,19]. Therefore, definitive cCRT is recommended as the first-line treatment for patients with unresectable stage III NSCLC. For those who are intolerant of cCRT, sCRT or RT alone may be considered. A platinum-based doublet regimen is the preferred chemotherapy choice. However, gemicitabine is not recommended in concurrent settings due to its associated risk of pulmonary toxicity [20]. The RT regimen should be determined based on a comprehensive evaluation of tumor burden, performance status, and cardiopulmonary function by the MDT. The RTOG 0617 study showed that escalating the dose to 74 Gy did not improve median overall survival (mOS) (20.3 vs. 28.7 months, HR 1.38) and increased the risk of severe esophagitis (21 % vs. 7 %, p < 0.0001) [21]. Patients in the LAURA, POLESTAR, and ADVANCE studies received doses of approximately 60 Gy (range 54-66 Gy) [6,7,22]. Therefore, 60 Gy ± 10 % (54-66 Gy) at 1.8-2.0 Gy/fraction is recommended, with adjustments based on individual patient factors.

PET-CT/MRI aids in defining tumor extent, characterizing lymph nodes, and improving target delineation accuracy. Studies showed that PET-CT altered planning volumes in 36 % of cases, reduced geographic misses and avoided over-irradiation of normal tissues [23]. MRI offers distinct advantages in guiding the delineation of the boundaries between tumors and atelectatic lung tissue. Multimodal imaging may represent an effective approach for precisely defining tumor volume [24]. Therefore, it is recommended that cancer centers with available resources use multimodal imaging, such as PET-CT or MRI, to guide target delineation, thereby enhancing therapeutic efficacy and reducing adverse effects.

Advanced techniques like IGRT, volumetric modulated arc therapy, helical tomotherapy, ART, and proton therapy show potential advantages over conventional 3D-CRT/IMRT in reducing toxicity and potentially improving outcomes [25–28]. The prospective RTEP7-IFCT-1402 study of patients with unresectable stage III NSCLC demonstrated that compared with standard radiotherapy (66 Gy), PET-CT-guided adaptive RT (up to 74 Gy) achieved a significantly improved median progression-fur survival (mPFS) (22.3 vs. 12.3 months), along with reduced incidences of grade 3–4 adverse events (AEs) within 90 days post-CRT (29 % vs. 45 %) and grade ≥3 radiation esophagitis (1 % vs. 4 %) [29].

Proton radiotherapy represents a potential novel approach for treating unresectable stage III NSCL. Leveraging the unique Bragg peak effect of proton beams, proton radiotherapy precisely delivers maximal energy upon reaching the tumor target, achieving highly conformal irradiation of lesions while reducing the radiation dose to normal tissues along the beam path and distal to the tumor, thereby mitigating the risk of normal tissue damage [30]. Passive scattering proton therapy (PSPT) yielded similar local control rates and pneumonitis incidence to IMRT [31]. However, intensity-modulated proton therapy (IMPT) is currently the most commonly used method and demonstrates significant improvements over PSPT in reducing toxicities, effectively lowering the risks of grade ≥3 pulmonary toxicity (2 vs 17%, cardiac toxicity (0 vs 11 %), and esophageal toxicity (6 % vs. 28 %) [32]. For stage III NSCLC, proton therapy is associated with a lower incidence of adverse effects compared to conventional photon-based radiotherapy [33,34]. Therefore, proton radiotherapy maintains a favorable safety profile with low toxicity rates, for patients with unresectable stage III NSCLC, proton radiotherapy may serve as an effective treatment modality to reduce radiation-induced toxicities, including the lungs and heart. However, robust evidence from phase III randomized controlled trials regarding the local control rates and overall effectiveness remains lacking. Before

clinical application, the potential benefits need to be fully evaluated by the MDT.

Hypofractionation is under investigation. A phase II study showed that adaptive CRT with high-dose SABR boost improved local control but not OS [27]. A phase III clinical trial demonstrated that hypo-franctioned radiotherapy (Hypo-RT, 60 Gy in 20 fractions) led to a 20% improvement in the 3-year OS rate compared with conventional radiotherapy (58.4 % vs. 38.4 %), with a median OS prolonged by 11 months (41.30 months; HR = 0.61). And there was no significant difference in the incidence of adverse events between the two groups [35]. In general, the current clinical promotion of advanced radiotherapy techniques should strictly adhere to the ACR-ASTRO Radiation Therapy Practice Guidelines. Further standardized clinical studies are warranted to validate their efficacy and safety.

Question 3: What is the recommended treatment for patients with unresectable stage III EGFR-mutant NSCLC?

Consensus Recommendation 3.1: Osimertinib or aumolertinib targeted consolidation therapy is recommended for patients without disease progression after definitive chemoradiotherapy (cCRT or sCRT), until disease progression, the development of intolerable toxicity, or the emergence of other criteria necessitating treatment discontinuation. (Consensus level: 100 %; Strength: Grade I)

Consensus Recommendation 3.2: Targeted consolidation therapy is recommended to commence within 42 days after completing CRT. For patients unable to start within 42 days, consolidation therapy should be initiated as soon as feasible thereafter. (Consensus level: 98.4 %; Strength: Grade II)

Rationale:

GFR mutation rates in stage III NSCLC range from 32.2 % to 35.6 % [10]. Previously, durvalumab or sugemalimab consolidation was standard after CRT for all patients without progression. However, PACIFIC subgroup analysis showed no significant benefit in mPFS (11.2 vs. 10.9 months) or mOS (46.8 vs. 43.0 months) with durvalumab versus placebo in 35 patients with EGFR-mutant tumors [36]. An international retrospective study reported a 2-year PFS rate of 86 % with osimertinib consolidation versus 30 % with durvalumab consolidation post-CRT in patients with EGFR-mutant stage III NSCLC (n = 136) [37], suggesting superior efficacy of targeted consolidation over immunotherapy.

The LAURA study, a prospective randomized, double-blind, placebo-controlled phase III trial, evaluated osimertinib consolidation in patients with EGFR-mutant NSCLC without progression after CRT (n = 216, including 40 Chinese patients). Osimertinib significantly improved mPFS (39.1 vs. 5.6 months; HR 0.16, p < 0.001). Grade ≥ 3 AE rates were higher with osimertinib (35 % vs. 12 %), radiation pneumonitis occurred in 48 % of patients that received osimertinib compared with 38 % in placebo [6].

The POLESTAR study, a phase III randomized, double-blind, placebo-controlled trial in Chinese patients (n = 147), demonstrated significantly superior mPFS with aumolertinib versus placebo (30.4 vs. 38 months; HR 0.20). Benefit was consistent across subgroups. Grade ≥3 AE rates were similar between groups, the overall safety was manageable [7].

The optimal timing for consolidation initiation lacks definitive evidence. The PACIFIC study mandated durvalumab within 42 days post-CRT [38]. PACIFIC-R real-world data showed a median time to durvalumab of 56 days post-radiotherapy, with a mPFS of 21.7 months, comparable to the results of the PACIFIC trial [39]. In both the LAURA and POLESTAR studies, targeted consolidation therapy was initiated within 1-42 days after chemoradiotherapy. It is therefore recommended that patients who have not progressed and are without symptomatic pneumonitis initiate treatment with osimertinib 80 mg once daily or aumolertinib 110 mg once daily within 42 days following chemo-radiotherapy. Nevertheless, individual patient variations must be considered in clinical practice. For those unable to initiate therapy within the 42-day window, targeted consolidation treatment should commence at the earliest feasible opportunity once conditions permit. In

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both studies, treatment was continued until disease progression, unacceptable toxicity, or other discontinuation criteria. Therefore, osimertinib or aumolertinib consolidation is the standard of care post-CRT for patients with EGFR-mutant unresectable stage III NSCLC, significantly prolonging PFS and reducing the risk of distant metastasis.

Question 4: What is the recommended treatment for patients with unresectable stage III AK fusion-positive NSCLC?

Consensus Recommendation 4: For patients with ALK fusion without disease progression after CRT, targeted consolidation therapy with an ALK tyrosine kinase inhibitor (TKI) may be considered. However, high-level evidence-based medical study is currently lacking. Enrollment in clinical trials is strongly encouraged. (Consensus level: 100 %); Strength: Grade I)

Rationale:

ALK fusion mutations represent a common class of driver gene mutations in NSCLC. A global, multicenter retrospective study demonstrated that patients with unresectable stage III AK fusion-positive MSCLC reusing ALK-TKIs (alectinib, crizotinib, lorlatinib, brigatib) consolidation therapy following chemoradiotherapy had significantly longer mPFS than those receiving durvalumab consolidation or undergoing observation (ALK-TKIs vs. durvalumab: HR 0.12; ALK-TKIs vs. observation: HR 0.04) [40]. Therefore, for patients with ALK fusion mutations, consolidation therapy with ALK-TKIs following chemoradiotherapy may further prolong survival. For patients with unresectable stage III NSCLC harboring ALK fusion mutations who show no disease progression after chemoradiotherapy, consolidation treatment with ALK-TKIs may be considered.

Multiple studies have investigated the efficacy and safety of different sequencing combinations of targeted therapy and radiotherapy in patients with unresectable stage III NSCLC harboring ALK fusion mutations. A study of crizotinib combined with radiotherapy revealed a relatively high incidence of pneumonitis when crizotinib was administered concurrently with radiotherapy, with a higher rate observed in the concurrent regimen compared with the findings in the sequential regimen (100 % vs. 37.5 %) [41]. Therefore, the concurrent administration of ALK-TKIs with radiotherapy is currently not recommended. The RTOG-1306 study demonstrated that for patients with ALK fusion mutations, the group receiving crizotinib induction therapy for 12 weeks followed by concurrent chemoradiotherapy failed to exhibit a prolongation in mPFS compared to the group receiving chemoradiotherapy alone (14.7 months vs. not reached) [42]. The ongoing INNOVATION study is exploring irupinalibk (WX0593) induction + CRT + irupinalkib consolidation in stage II-III unresectable ALK/ROS1 fused NSCLC. Preliminary results show an ORF of 86 % and DCR of 100 %, with pneumonitis (grade 1: 4/7 patients, grade 2: 3/7 patients) [43]. These results are primarily exploratory, and prospective randomized trials are needed to establish high-level evidence.

The RTOG-1306 study demonstrated that for patients with ALK fusion mutations, the group receiving crizotinib induction therapy for 12 weeks followed by concurrent chemoradiotherapy failed to exhibit a prolongation in mPFS compared to the group receiving chemoradiotherapy alone (14.7 months vs. not reached) [42]. The ongoing INNOVATION study is exploring irupinalibk (WX0593) induction + CRT + irupinalkib consolidation in stage II-III unresectable ALK/ROS1 fused NSCLC. Preliminary results show an ORF of 86 % and DCR of 100 %, with pneumonitis (grade 1: 4/7 patients, grade 2: 3/7 patients) [43]. These results are primarily exploratory, and prospective randomized trials are needed to establish high-level evidence.

Question 5: Is immunotherapy consolidation recommended for patients with driver gene-positive unresectable stage III NSCLC without progression after CRT?

Consensus Recommendation 5.1: Immunotherapy consolidation provides limited benefit in patients with EGFR mutations or ALK fusions and is not recommended after CRT. (Consensus level: 100 %); Strength: Grade I)

Consensus Recommendation 5.2: For patients with other driver gene mutations, there is currently a lack of evidence-based medical evidence to support targeted consolidation therapy. Immunotherapy consolidation may be considered and it is encouraged to participate in clinical trials investigating targeted consolidation following CRT. (Consensus level: 95.2 %; Strength: Grade II)

Rationale:

From the results of the LAURA and POLESTAR studies, osimertinib or aumolertinib consolidation is the standard for patients with EGFR-mutant NSCLC post-CRT. PACIFIC subgroup analyses showed no benefit with durvalumab over placebo in patients with EGFR-mutant or ALKmutant NSCLC [36,38]. The GEMSTONE-301 study excluded

EGFR/ALK-mutant patients [44]. Real-world data in ALK-mutant patients showed poor outcomes with durvalumab consolidation (mPFS 11.3 months), while ALK-TKIs markedly reduced progression risk (HR 0.12) [40]. Therefore, immunotherapy consolidation is not recommended for EGFR-mutant or ALK fusion-positive NSCLC.

For patients with other driver gene mutations, while there is currently a lack of evidence-based medicine evidence supporting the use of targeted consolidation therapy, the applicability of immunotherapy has garnered significant attention. A meta-analysis of retrospective data (86 studies, n = 4524) showed modest ORRs to immunotherapy: BRAF (24 %), MET (23 %), HER2 (14 %), RET (7 %), and ROS1 (8 %) [45]. Austrian registry data reported a promising 2-year OS rate of 84 % with immunotherapy consolidation in patients with KRAS-mutant stage III NSCL [46]. Another study suggested that, for unresectable stage III NSCLC carrying other rare mutations, the patients who received durvalumab after cCRT exhibited a trend toward longer mPFS (12.9 vs. 7.6 months, p = 0.23) than those treated without durvalumab [47]. The prospective phase I-III HORIZON-01 trial (NCT05170204) is evaluating biomarker-based targeted consolidation therapy versus durvalumab in patients with unresectable stage III ALK/RET/ROS1 mutated NSCLC. Until results from such trials are available, immunotherapy consolidation may be an option for patients with other driver gene mutations lacking targeted consolidation evidence. Participation in targeted therapy trials is encouraged.

Question 6: What is the recommended treatment for patients with unresectable stage III driver gene-positive NSCLC with bulky tumor?

Consensus Recommendation 6: For patients with bulky tumor initially deemed unsuitable for definitive radiotherapy, induction therapy with targeted agents ± chemotherapy for 8–12 weeks is recommended, followed by MDT re-assessment to evaluate for the feasibility of definitive CRT. (Consensus level: 98.4%; Strength: Grade II)

Rationale:

Bulky tumor in stage III NSCLC is often defined as a primary tumor diameter ≥5 cm, metastatic lymph node short axis ≥2 cm, or multistation lymphadenopathy with extracapsular extension [48,49]. This type of tumor poses challenges, such as increased risk of radiation pneumonitis and tumor hypoxia leading to radioresistance and poor local control. Approximately 32 % of patients with bulky tumor may not be suitable for immediate definitive radiotherapy [50]. Larger tumor volume correlates significantly with worse mOS (10 vs. 19 months, p = 0.0003) [51].

Immunotherapy-based induction has shown promise in bulky stage III NSCLC. A retrospective study showed that two cycles of chemomunotherapy induction significantly reduced gross tumor volume (GTV), mean lung dose, and lung volumes in patients receiving ≥5 Gy, ≥20 Gy, and ≥30 Gy. The ORR was 76.1%, increasing to 86.7% post-CRT, with a mPFS of 30.6 months [52]. The prospective InTRist study confirmed significant tumor shrinkage, improved ORR and PFS, and no grade 4/5 pneumonitis with two cycles of chemoimmunotherapy induction in patients with pulky stage III NSCLC [53]. Other prospective studies are further validating this strategy. For instance, the BRIDGE study (phase II, NCT04765709) is also exploring the survival benefits of concurrent chemoradiotherapy followed by consolidation therapy after induction with immunotherapy ± chemotherapy, aiming to provide a novel therapeutic option for patients with large tumors.

For driver gene-positive bulky tumors, induction with targeted agents ± chemotherapy offers a strategy to reduce tumor burden and enable definitive CRT. Third-generation EGFR-TKIs show high ORRs (70 %–80 %) in the metastatic first-line setting [54,55]. The FLAURA2 and AENEAS2 studies reported ORRs of 83 % and 93.2 % with osi-mertinib or aumolertinib combined with chemotherapy, respectively, in EGFR-mutant patients [56,57]. The ADVANCE study showed significantly prolonged mPFS with aumolertinib induction (9 weeks) followed by radiotherapy versus CRT alone (34.0 vs. 7.8 months, HR 0.15) in patients with stage III EGFR-mutant NSCLC [22]. The RTOG 1306 study reported improved mPFS with TKI induction (12 weeks) followed by

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CRT versus CRT alone in EGFR/ALK mutated patients (mPFS 21.1 vs. 9.2 months) [42]. The BRIGHTSTAR study investigated brigatinib combined with local consolidative therapy in TKI-naïve patients with ALK-mutant advanced NSCLC, demonstrating an ORR of 79 % after 8 weeks of brigatinib induction. This approach enabled 94.1 % of patients to subsequently receive local consolidative therapy [58]. Tumor shrinkage is feasible after 2-3 months of targeted ± chemotherapy induction in driver gene-positive bulky stage III NSCLC [59].

Therefore, from existing research data and clinical practice, it is recommended that patients with driver gene-positive bulky tumors may receive 8–12 weeks of targeted drug therapy ± chemotherapy as induction treatment to shrink tumor volume as much as possible. The feasibility of radical chemoradiotherapy should be determined depending on tumor regression and cardiopulmonary function, and centers with the necessary resources may conduct a comprehensive evaluation by MDT. Furthermore, if significant tumor regression is achieved, the GTV of the primary lesion should be delineated based on the current post-induction CT imaging. The nodal GTV should encompass all lymph nodes initially involved prior to induction therapy. For patients in whom radical radiotherapy remains difficult to implement after targeted drug induction therapy, to ensure patient safety, individualized radiotherapy approaches can be considered, such as delinating only the residual lesions, and/or expanding directly from the GTV to the planning target volume (PTV), and/or reducing the radiotherapy dose.

Beyond this, multiple studies have reported that neoadjuvant/induction chemoimmunotherapy holds therapeutic potential for converting initially unresectable stage III NSCL into resectable disease [4,60]. A similar trend has been observed in EGFR-mutant unresectable stage III NSCL. A single-arm Phase II clinical trial evaluated the feasibility of neoadjuvant aumolertinib, showed that among 51 treated patients, 45.1 % were successfully downstaged to resectable disease and underwent surgery [61]. Therefore, the "convertible potential" of unresectable disease under neoadjuvant therapy warrants further exploration. For patients who achieve significant downstaging, the possibility of surgery should be assessed by MDT.

Question 7: How to identify the patient population with unresectable stage III driver gene-positive NSCLC that is suitable for treatment de-escalation?

Consensus Recommendation 7.1: For patients intolerant to chemotherapy, definitive radiotherapy combined with targeted therapy (without chemotherapy) may be considered. However, this approach lacks high-level evidence and cannot be routinely recommended. Enrollment in phase III randomized controlled trials is strongly encouraged. (Consensus level: 100 %; Strength: Grade I)

Consensus Recommendation 7.2: For patients who are intolerant to definitive radiotherapy, targeted therapy based on the driver gene mutation type is recommended. For patients achieving good tumor response, individualized radiotherapy to residual lesions may be considered. (Consensus level: 106.8 %; Strength: Grade II)

Rationale:

The efficacy and safety of the radiotherapy combined with targeted therapy approach for patients with unresectable stage III NSLC harboring EGFR mutations have been validated in multiple clinical studies. The RECEL study showed significantly longer mPFS with concurrent erlotinib and radiotherapy (24.5 months) than with CRT (9.0 months, p < 0.001) in stage III EGFR-mutant NSCLC [62]. The WJOG6911L study of patients with locally advanced NSCLC (n = 27) reported a mPFS of 18.6 months and mOS of 61.3 months with gefitinib concurrent thoracic radiotherapy [63]. The ADVANCE study of patients with unresectable EGFR-mutated stage III NSCLC demonstrated significantly prolonged mPFS (34.0 vs. 7.8 months, HR 0.15) and reduced rates of neutropenia and nausea (p < 0.05) with aumolertinib concurrent radiotherapy versus CRT [22]. In the BRIGHTSTAR study, patients with ALK-mutant NSCLC receiving brigatinib combined with local therapy (85.3 % being radiation therapy) showed 1-year, 2-year, and 3-year PFS

rates of 94 %, 80 %, and 66 %, respectively, with grade ≥3 local treatment-related AEs occurring in 12 % of patients [58].

Currently, multiple innovative treatment modalities are at the exploratory stage, such as the multicenter study of furmonertinib combined with concurrent radiotherapy versus sequential chemotherapy followed by furmonertinib consolidation therapy for patients with unresectable stage II–III NSCLC harboring EGFR-sensitive mutations (FLAME-001) and the study of aumolertinib combined with concurrent radiotherapy for patients with unresectable stage II–III NSCLC harboring EGFR-sensitive mutations (POLESTAR2) [64]. Although existing data suggest that the combined radiotherapy-targeted therapy regimen represents a potentially feasible chemotherapy-free approach, its clinical application is still constrained because of insufficient high-grade evidence-based support. This approach may be an option for specific populations intolerant to chemotherapy (e.g., elderly populations, poor performance status, severe comorbidities). It is recommended that treatment indications be strictly adhered to in clinical practice, and high-quality studies are urgently needed to further clarify the efficacy and safety.

For patients who are intolerant to definitive radiotherapy, treatment should follow strategies for metastatic driver gene-positive NSCLC. In NSCLC and AENEAS studies, the mPFS for patients with advanced EGFR-mutated NSCLC treated with osimertinib/aumolertinib was 18.9 months and 19.3 months, respectively [54,56]. In the ALESIA study, the mPFS of patients with advanced ALK fusion-positive NSCLC treated with alectinib was 41.6 months [65]. Targeted therapies for other driver genes (ROS1, RET, MET, HER2, BRAF) also show significant benefits [66–70] and may serve as an alternative for patients who cannot tolerate radical radiotherapy. A prospective study showed that consolidative radiotherapy for residual lesions after first-line third-generation EGFR-TKIs significantly prolonged mPFS vs. TKI alone (29.9 vs. 19.0 months; HR 0.46, p = 0.002) [71]. On the basis of these data, targeted therapy is recommended for patients with unresectable stage III driver gene-positive NSCLC who cannot tolerate radical radiotherapy. For those with good tumor regression, individualized palliative radiotherapy for residual lesions can be considered, and the radiotherapy regimen should be formulated with consideration of both efficacy and safety. The superimposed toxicity of targeted drugs and RT (especially pneumonia, esophagitis, and cardiac irradiation) may increase the treatment risk. Future clinical studies should formulate corresponding safety guarantee measures, including patient screening criteria, dose-volume constraints, imaging/laboratory monitoring indicators, as well as rules for treatment suspension and re-challenge.

gene-positive NSCLC who cannot tolerate radical radiotherapy. For those with good tumor regression, individualized palliative radiotherapy for residual lesions can be considered, and the radiotherapy regimen should be formulated with consideration of both efficacy and safety. The superimposed toxicity of targeted drugs and RT (especially pneumonia, esophagitis, and cardiac irradiation) may increase the treatment risk. Future clinical studies should formulate corresponding safety guarantee measures, including patient screening criteria, dose-volume constraints, imaging/laboratory monitoring indicators, as well as rules for treatment suspension and re-challenge.

Question 8: How should pneumonia occurring during RT and targeted therapy or targeted therapy following RT for unresectable stage III driver gene-positive NSCLC be managed?

Consensus Recommendation 8.1: Differentiate between infectious pneumonia and non-infectious pneumonia. Infectious pneumonia requires prompt anti-infective therapy. Non-infectious pneumonia primarily includes radiation pneumonitis (RP) and drug-related interstitial lung disease (ILD). (Consensus level: 100 %; Strength: Grade I)

Consensus Recommendation 8.2: For non-infectious pneumonia ≥ grade 2: Administer systemic corticosteroids ± antifibrotic agents, hospitalization may be necessary. For grade 3: After symptomatic improvement to < grade 2, targeted therapy may be cautiously resumed. For grade 4: Permanently discontinue targeted therapy. (Consensus level: 98.4 %; Strength: Grade II)

Rationale:

Pneumonia occurring during treatment requires prompt differentiation between infectious and non-infectious causes. Infectious pneumonia requires targeted antimicrobial therapy. Non-infectious causes are primarily RP and drug-induced ILD. RP occurs in 12%–30% of stage III NSCLC patients post-radiotherapy, with ≥grade 3 RP in 4%–7% [6,7, 19,21]. Sequential targeted therapy post-CRT may increase RP risk (POLESTAR/LAURA: RP increased by 10%–15%, ≥grade 3 RP by 0%–4% [6,7,22]). Concurrent use carries a higher risk. Osimertinib

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Table 3

Management recommendations for pneumonia occurring during RT and targeted therapy or targeted therapy following RT.

|Pneumonia grade|Management principle|Tapering and re-treatment conditions| |---|---|---| |Grade 1|Close monitoring, initiate steroid therapy early if worsening; Steroids may be withheld or used discretionarily|Monitor until imaging stabilizes, manage as higher grade if progression occurs| |Grade 2|Hold targeted therapy, initiate steroid therapy; Prednisone tablets: 1-2 mg/kg/day|May resume targeted therapy once imaging improves to ≤ Grade 1, taper steroids slowly at 5-10 mg per week| |Grade 3|Hold targeted therapy, hospital admission recommended, rule out infection, empiric antibiotics if needed; Methylprednisolone IV: 2-4 mg/kg/day, switch to oral steroids when imaging improves to ≤ Grade 2|May cautiously resume targeted therapy (full or reduced dose) after shared decision-making once imaging improves to ≤ Grade 1; taper steroids at 5-10 mg per week| |Grade 4|Permanently discontinue targeted therapy; inpatient steroid pulse therapy; rule out infection, empiric antibiotics if needed; IV steroid pulse therapy, dose adjusted per clinical condition|Do not resume targeted therapy, slow steroid taper|

Notes: PO, oral administration; IV, Intravenous injection.

concurrent with thoracic radiotherapy resulted in ≥grade 2 pneumonitis in 56.63% and grade 4-5 in 6.3% -9.1% [73,74]. Aumolertinib concurrent radiotherapy caused ≥ grade 2 pneumonitis in 42.9%, with no grade 4-5 events [75]. Crizotinib concurrent radiotherapy caused ≥ grade 2 pneumonitis in 100% [41]. Therefore, for patients who are scheduled to receive sequential/concurrent targeted therapy following radiotherapy, it is essential to control the radiation dose to normal lung tissue and minimize the irradiated volume during radiotherapy administration, so as to reduce the risk of interstitial pneumonia.

Pneumonitis during sequential/concurrent targeted therapy and radiotherapy is complex. MDT or pulmonary consultation may be needed for diagnosis. Early identification and appropriate corticosteroid use are crucial, with antifrotic agents such as nintedanib or pření-done administered as needed. The specific management by grade is outlined in Table 3.

The initial corticosteroid dose should be tailored to the patient's weight, severity of pneumonia, and comorbidities. With long-term or high-dose use, proton pump inhibitors should be given to protect the stomach, along with calcium and vitamin D to support bone health. Prevention of pneumocystis and fungal infections is also important. Blood glucose should be monitored closely, and hypoglycemic agents adjusted as needed. If symptoms worsen during steroid tapering, perform CT and pathogen tests to distinguish between disease progression and infection, then adjust treatment accordingly. Before starting targeted therapy, assess the risk of interstitial lung disease and choose agents with a lower pneumonia risk when possible.

4. Efficacy prediction and follow-up monitoring

Minimal residual disease (MRD) detection in solid tumors involves analyzing ctDNA to assess residual disease after curative-intent therapy. A study using CAPP-Seq ctDNA analysis in 65 stage III NSCLC patients treated with CRT (218 samples) found that ctDNA positivity detected recurrence a median of 4.1 months earlier than imaging [72]. Patients achieving ctDNA clearance during radiotherapy had significantly longer mPFS than those clearing it after radiotherapy (22.9 vs. 10.3 months, HR 0.29, p < 0.001). ctDNA-MRD status post-CRT predicted prognosis, with sustained negativity associated with excellent outcomes regardless of consolidation immunotherapy, suggesting potential cure and a basis for de-escalation [77]. MRD testing may be considered in patients who achieve complete response after chemoradiation to aid in prognostic evaluation and adaptive treatment planning. Further research is encouraged to explore the use of advanced detection technologies such as MRD for predicting treatment response and monitoring disease in patients with unresectable stage III driver-positive NSCLC, thereby guiding clinical decision-making.

Follow-up schedule: It is recommended to conduct follow-up every 2-3 months during the first 1-2 year, every 3-6 months during year 3-5, and every 6-12 months after year 5, with adjustments to the frequency based on clinical events. Systemic evaluations should include physical

examination, hematological tests, and imaging studies. Recommended imaging studies include enhanced CT scans of the neck, chest, and abdomen-pelvis, enhanced MRI of the brain (with enhanced CT as an alternative if MRI is contrained), and annual bone scans or PET-CT. Given that MRD is still in the clinical exploration stage, centers with available resources may consider MRD testing.

5. Summary and perspective

For patients with unresectable stage III driver gene-positive NSCLC, the importance of precision treatment and individualized management is increasingly paramount. This consensus systematically addresses the current treatment landscape and key challenges for this specific patient population. It integrates clinical research data and expert clinical experience to refine diagnostic and therapeutic pathways, clarify treatment principles, and provide evidence-based recommendations. The aim is to offer clinicians a scientific and comprehensive framework to guide the standardized management of treatment decisions for unresectable stage III driver gene-positive NSCLC.

5.1. Expert group members (in alphabetic order of last name)

Nan Bi (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese, Academy of Medical Sciences and Peking Union Medical College), Dawei Chen (Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences), Ming Chen (Sun Yat-sen University Cancer Center), Yu Chen (Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences), Yufeng Cheng (Qilu Hospital of Shandong University), Qian Chu (Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology), Tianqing Chu (Shanghai Chest Hospital), Xiaorong Dong (Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology), Jian Fang (Peking University Cancer Hospital), Hong Ge (Henan Cancer Hospital), Anxin Gu (Harbin Medical University Cancer Hospital), Xiao Han (Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences), Guang Han (Hubei Cancer Hospital), Xin Jiang (the First Hospital of Jilin University), Ou Jiang (The Second People's Hospital of Neijiang), Yongling Ji (Zhejiang Cancer Hospital), Hui Li (Inner Mongolia People's Hospital), Jiancheng Li (Fujian Cancer Hospital), Qin Lin (the First Affiliated Hospital of Xiamen University), Anwen Liu (the Second Affiliated Hospital of Nanchang University), Ningbo Liu (Tianjin Cancer Hospital), Yutao Liu (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese, Academy of Medical Sciences and Peking Union Medical College), Shun Lu (Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University), Kaihua Lu (Jiangsu Province Hospital), Xuezhen Ma (Qingdao Central Hospital of University of Health and Rehabilitation Sciences), Xiangjiao Meng (Shandong Cancer Hospital

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and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences), Xue Meng (Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences), Fangling Ning (Binzhou Medical University Hospital), Songbing Qin (the First Affiliated Hospital of Soochow University), Anhui Shi (Peking University Cancer Hospital), Jianhua Shi (Linyi Cancer Hospital), Meili Sun (Jinan Central Hospital), Pingping Song (Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences), Fengwei Tan (National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese, Academy of Medical Sciences and Peking Union Medical College), Hui Wang (Hunan Cancer Hospital), Jianbo Wang (Qilu Hospital of Shandong University), Lan Wang (the Fourth Hospital of Hebei Medical University), Huijuan Wang (Henan Cancer Hospital), Linlin Wang (Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences), Jun Wang (the Fourth Hospital of Hebei Medical University), Yuanuyan (Peking University Cancer Hospital), Guowu Wu (Meizhou People's Hospital), Conghua Xie (Zhongnan Hospital of Wuhan University), Congying Xie (the First Affiliated Hospital of Wenzhou Medical University), Ligang Xing (Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences), Benhua Xu (Fujian Medical University Union Hospital), Yaping Xu (Shanghai Pulmonary Hospital), Jianxin Xue (West China Hospital of Sichuan University), Fujun Yang (Waihai Municipal Hospital Affiliated to Shandong University), Kunning Yang (Weifang Second People's Hospital), Zhe Yang (Shandong Provincial Hospital Affiliated to Shandong First Medical University), Shucheng Ye (Jining Medical University Affiliated Hospital), Jinming Yu (Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences), Li Zhang (Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology), Xiaotao Zhang (Qingdao Central Hospital of University of Health and Rehabilitation Sciences), Wencheng Zhang (Tianjin Cancer Hospital), Yi Zhang (Qilu Hospital of Shandong University), Kaikai Zhao (Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences), Miaoqing Zhao (Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences), Guangging Zhuang (Yinging University Third Hospital), Bingwen Zou (West China Hospital of Sichuan University).

CRediT authorship contribution statement

Xiangjiao Meng: Writing – original draft, Methodology, Investigation, Funding acquisition. Nan Bi: Writing – original draft, Methodology, Investigation. Jun Wang: Writing – original draft, Methodology, Investigation. Xue Meng: Writing – original draft, Methodology, Investigation. Jianbo Wang: Writing – original draft, Methodology, Investigation. Ligang Xing: Writing – review & editing, Supervision. Yufeng: Cheng: Writing – review & editing, Project administration, Conceptualization. Shun Lu: Writing – review & editing, Supervision, Conceptualization. Ming Chen: Writing – review & editing, Supervision. Project administration. Jinming Yu: Writing – review & editing, Supervision, Project administration, Conceptualization.

Funding

This work was partly supported by the Collaborative Academic Innovation Project of Shandong Cancer Hospital (No. ZF003).

Declaration of competing interest

The authors declare that they have no known competing financial

interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

Non-small cell lung cancer (NSCLC), magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT), multidisciplinary team (MDT), progression-free survival (mPFS), concurrent chemoradiotherapy (cCRT), sequential chemoradiotherapy (sCRT), median overall survival (mOS), image-guided radiotherapy (IGRT), adaptive radiotherapy (ART), simultaneous integrated boost (SIB), adverse events (AEs), passive scattering proton therapy (PSPT), intensity-modulated proton therapy (IMPT), hypofractionated radiotherapy (Hypo-RT), tyrosine kinase inhibitor (TKI), Minimal residual disease (MRD).

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.canlet.2025.218223.

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