PD-1, an immunosuppressive transmembrane protein expressed on T cells, mediates immune inhibition upon binding its ligand PD-L1. Tumor cell-expressed PD-L1 engages PD-1, inducing tyrosine phosphorylation of cytoplasmic domain in T cell and subsequent recruitment of SHP-2 phosphatase. This cascade dephosphorylates TCR signaling molecules, suppressing downstream pathways and impairing T cell activation, cytokine secretion, and proliferation. PD-1/PD-L1 inhibitors block this interaction, reversing T cell suppression and restoring antitumor immunity^[8].

CTLA-4, an immune checkpoint receptor encoded by the CTLA-4 gene, is predominantly expressed on activated CD4+ and CD8+ T cells. It competes with cluster of differentiation 28 (CD28) for binding to shared ligands (CD80/CD86, collectively termed B7 molecules), exhibiting higher binding affinity. CTLA-4-B7 interaction competitively blocks CD28 co-stimulation, attenuating both TCR and CD28 signaling pathways. Additionally, CTLA-4 diminishes CD28 stimulation by either downregulating B7 expression on APCs or clearing these molecules through endocytosis. Moreover, CTLA-4 can induce dendritic cells (DCs) to express indoleamine 2,3-dioxygenase by binding to B7 on APCs, thereby inhibiting T cell function.

LAG-3 is primarily expressed on activated T cells, NK cells, and plasmacytoid dendritic cells. Its interaction with MHC class II molecules suppresses CD4+ T cell activation. Therapeutic LAG-3 blockade potentiates T cell activity, augmenting antitumor immunity^[9].

TIM-3 is another negative immune regulator and often acts in concert with PD-1 to maintain T cell tolerance. It is expressed on various immune cells, including effector T cells, regulatory T cells, and NK cells. It inhibits cell activation and proliferation by binding to specific ligands such as galectin-9 (Gal-9), carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1)^[10,11].

TIGIT is commonly co-expressed with CD226 on T cells and NK cells. It impairs antitumor function through CD155/CD112 binding. TIGIT inhibition enhances both NK cell cytotoxicity and T cell activation, demonstrating therapeutic potential in cancer immunotherapy^[12,13].

Neoadjuvant immunotherapy administered preoperatively when patients retain intact lymphatic systems, abundant tumor neoantigens, and optimal performance status, demonstrates enhanced antitumor immune activation with potential to eradicate micrometastases and reduce recurrence. Current approaches encompass immune monotherapy, dual checkpoint inhibition, chemoimmunotherapy, immuno-antiangiogenic combinations, and immuno-radiotherapy. Among these, the chemoimmunotherapy currently has the most substantial evidence.

For resectable EGFR/ALK-negative NSCLC (tumor ≥ 4 cm or node-positive) without ICI contraindications, neoadjuvant nivolumab plus platinum-based doublet chemotherapy is strongly recommended. For patients ineligible for ICIs, neoadjuvant platinum-based doublet chemotherapy is recommended.

Immune monotherapyThe phase II CheckMate-159 trial evaluated neoadjuvant nivolumab monotherapy in 21 resectable stage I-IIIA NSCLC patients, demonstrating a 45% MPR rate (9/20) in 20 surgically treated patients, with 18-month recurrence-free survival (RFS) and overall survival (OS) rates of 73% and 95% respectively^[18]. Updated 5-year follow-up data in 2023 showed 5-year RFS and OS rates of 60% and 80%, with better outcomes in MPR patients (HR = 0.61) and PD-L1-positive patients (TPS ≥ 1%, HR = 0.36), where 89% (8/9) of MPR patients achieved 5-year DFS without cancer-related deaths, while the non-MPR group (n = 11) had 6 recurrences and 3 deaths^[19]. Subsequent studies, including LCMC-3, IONESCO, PRINCEPS, and ChiCTR-OIC-17013726 have reported MPR rates of 6%-45% and pCR rates of 0%-15% with neoadjuvant immune monotherapy, showing relatively lower efficacy compared to combination approaches^[20-23]. Therefore, for patients without treatment contraindications, combination immunotherapy is recommended as the preferred neoadjuvant approach, with monotherapy remaining an alternative option.

Dual immunotherapyThe Phase II Neostar study evaluated neoadjuvant nivolumab vs. nivolumab plus ipilimumab in 44 patients with resectable stage I-IIIA NSCLC (single-station N2). The MPR rate were 22% (5/23) with monotherapy and 38% (8/21) with combination therapy. Among surgical subgroup, the MPR rates were 24% (5/21) and 50% (8/16) respectively. The study confirmed comparable surgical feasibility and safety of both regimens, while the combination therapy provided superior efficacy, with enhanced tumor immune infiltration and memory formation^[24].

Similarly, the Phase II NeoCOAST trial (n = 84, stage IA3-IIIA) revealed superior efficacy for durvalumab combinations vs. monotherapy: pCR rates increased from 3.7% (monotherapy) to 9.5-12.5% (combination with oleclumab/monalizumab/danvatirsen), while MPR rates improved from 11.1% to 19.0-31.3%, with comparable safety profiles^[25].Other ongoing studies such as the Phase II Neopredict-Lung trial (nivolumab plus relatlimab, a LAG-3 inhibitor) continue exploring the feasibility of neoadjuvant dual-immunotherapy. Given the current limitation to Phase II evidence, dual-immunotherapy regimens remain investigational in the perioperative setting^[26].

Immunotherapy combined with chemotherapyThe landmark Phase III CheckMate-816 trial established nivolumab plus platinum-doublet chemotherapy as the first FDA/NMPA-approved neoadjuvant regimen for resectable stage IB-IIIA/IIIB (T3N2) NSCLC (AJCC 7th, tumors ≥ 4 cm or node-positive), demonstrating superior pCR (24.0% vs. 2.2%; OR = 13.94, P < 0.001) and prolonged median event-free survival (EFS) (31.6 vs. 20.8 months; HR = 0.63, P = 0.005) vs. chemotherapy alone, with comparable grade 3-4 Treatment-Related Adverse Events(TRAEs) (33.5% vs. 36.9%)^[27]. Chinese subgroup analysis revealed even greater benefit (pCR: 25.0% vs. 1.9%, OR = 11.05; mEFS: not reach vs. 13.9 months, HR = 0.47) with favorable safety.

Similarly, the Phase II TD-FOREKNOW trial demonstrated that camrelizumab-chemotherapy significantly improved pCR rates (32.6% vs. 8.9%; OR = 4.95) and MPR rates (65.1% vs. 15.6%; OR = 10.13) vs. placebo-chemotherapy in resectable stage IIIA-IIIB (only T3N2 for Stage IIIB, AJCC 8th) NSCLC, with higher R0 resection rates (92.5% vs. 85.7%) and trending survival benefit (mEFS HR = 0.52)^[28].

Based on CheckMate-816 trial, neoadjuvant nivolumab-chemotherapy is strongly recommended for EGFR/ALK-negative resectable NSCLC (tumor ≥ 4 cm or node-positive) without immunotherapy contraindications.

Immunotherapy combined with anti-angiogenic therapyThe phase II EAST ENERGY trial investigated neoadjuvant pembrolizumab-ramucirumab in 24 PD-L1-positive (≥ 1% by 22C3 assay) stage IB-IIIA NSCLC patients. This two-cycle regimen achieved a 50% MPR rate (90% CI 31.9%-68.1%), meeting the primary endpoint, with 50% of MPR patients (6/12) attaining pCR. Grade 3 AEs occurred in 37.5% of patients, with no ramucirumab-related wound healing complications observed^[29].

Another phase II trial of camrelizumab-apatinib in stage IIA-IIIB (T3N2-eligible) NSCLC (n = 78) demonstrated 83% R0 resection, 57% MPR, and 23% pCR rates, with only 5% grade 3-4 TRAEs^[30].

While these immunotherapy-antiangiogenic combinations show promise, larger randomized trials are needed to confirm efficacy through larger-scale clinical trials.

Immunotherapy combined with radiotherapyThe single-arm phase II NCT04271384 trial (n = 25) demonstrated 80% MPR and 83% pCR rates with neoadjuvant nivolumab plus stereotactic ablative radiotherapy (SABR) in early-stage NSCLC, with 96% resection rates and favorable safety (4% grade 3-5 TRAEs)^[31].

Another phase II NCT02904954 study compared stereotactic body radiotherapy (SBRT) followed by durvalumab vs. durvalumab monotherapy in patients with potentially resectable stage I-IIIA NSCLC (n = 60). The results showed that the combination group had significantly higher MPR (53.3% vs. 6.7%, P < 0.0001) and pCR (30.7% vs. 0%) rates, with comparable resection rates (both 87%) and safety profiles(grade 3-4 AEs:20% vs. 17%)^[32]. Updated data in 2023 showed 3-year DFS of 65% (intent-to-treat population) and 3-year PFS of 76% (surgical cohort, n = 52), with a trend toward better PFS in the combination group (83% vs. 69%, P = 0.19)^[33].

The SACTION 01 study explored the efficacy and safety of SBRT followed by tislelizumab plus chemotherapy in EGFR wild-type, resectable stage II-III NSCLC (n = 46). Results showed strong efficacy (MPR: 76.1%, pCR: 52.2%, R0 resection: 95.7%) and manageable toxicity (grade ≥ 3 AEs: 26.1%)^[34]. Based on these promising results, the Phase III SACTION 2401 study is expected to commence.

While these phase II trials demonstrate promising efficacy signals in resectable NSCLC, their small sample sizes necessitate validation through larger randomized controlled studies to establish optimal treatment strategies and patient selection criteria.

Given the evidence for chemo-immunotherapy is the most compelling in the neoadjuvant setting, we recommend three cycles of PD-1/PD-L1 inhibitor plus platinum-doublet chemotherapy as the standard neoadjuvant approach for resectable NSCLC (tumors ≥ 4 cm or node-positive) without ICI contraindications, while other immune-based combinations remain investigational.

Adjuvant immunotherapy is administered postoperatively. It helps reverse the immune suppression caused by surgery and stress, enhances antitumor immune memory, eradicates micrometastases, and reduces the risk of recurrence and metastasis.

The IMpower010 study is the first Phase III clinical trial demonstrating adjuvant immunotherapy benefit in early-stage NSCLC. The trial randomized 1,280 patients with completely resected stage IB (≥ 4 cm)-IIIA NSCLC (AJCC 7th) to receive 1-4 cycles of adjuvant chemotherapy followed by either 16 cycles of atezolizumab or best supportive care (BSC). In PD-L1 ≥ 1% subgroup, atezolizumab significantly improved DFS (median NR [Not Reached] vs. 35.3 months; HR = 0.66) with 3-year DFS rates of 60.0% vs. 48.2%. OS also showed a favorable trend (HR = 0.71), with 5-year OS rate of 76.8%^[35,36]. Based on these findings, the FDA and NMPA approved atezolizumab for adjuvant immunotherapy in PD-L1 ≥ 1%, stage II-IIIA NSCLC in 2021 and 2022 respectively.

The Phase III KEYNOTE-091 study evaluated adjuvant pembrolizumab in patients with completely resected stage IB (≥ 4 cm) - IIIA NSCLC (AJCC 7th edition). Pembrolizumab met its primary endpoint, significantly improving DFS in the overall population (53.6 vs. 40.2 months; HR = 0.76) with enhanced effect in chemotherapy-treated subgroups (HR = 0.73), while maintaining an acceptable safety profile. Based on these findings, the FDA approved this regimen in 2023 for adjuvant therapy following platinum-doublet chemotherapy^[37].

The aforementioned studies support adjuvant immunotherapy. For resectable NSCLC, it is recommended that patients receive 1-year ICI maintenance therapy following adjuvant chemotherapy.

Building upon neoadjuvant/adjuvant immunotherapy success, emerging perioperative ‘sandwich’ regimens demonstrate efficacy in resectable NSCLC. For stage IIIA-IIIB, we recommend neoadjuvant toripalimab-chemotherapy followed by adjuvant toripalimab. For tumors ≥ 4 cm or node-positive disease, neoadjuvant pembrolizumab-chemotherapy with adjuvant pembrolizumab is preferred. For stage II-IIIA, neoadjuvant tislelizumab-chemotherapy plus adjuvant tislelizumab is recommended, all recommended for ICI-eligible patients after exclusion of immunotherapy contraindications.

Immune monotherapyThe Phase II LCMC3 trial (n = 181) evaluated perioperative atezolizumab with optional postoperative chemo/radiotherapy in resectable stage IB-IIIB NSCLC, demonstrating 3-year DFS and OS rates of 72% and 82% respectively in the MPR-evaluable population, Stratified analysis by disease stage revealed that the 3-year DFS rates for stage I-II and stage III were 75% and 70% respectively, while the OS rates were 82% and 81%. Adjuvant atezolizumab demonstrated superior outcomes compared to observation (3-year DFS: 83% vs. 64%, HR = 0.44; 3-year OS: 89% vs. 77%, HR = 0.48), with similar patterns in non-MPR patients (DFS HR = 0.48; OS HR = 0.50)^[20].

Immunotherapy combined with chemotherapyThe KEYNOTE-671 study, which achieved dual positive endpoints in EFS and OS, evaluated perioperative pembrolizumab vs. placebo plus chemotherapy (3 neoadjuvant + 13 adjuvant cycles) in resectable stage II-IIIB NSCLC (n = 797). At a median follow-up of 36.6 months, result showed pembrolizumab significantly improved median EFS by 28.9 months (47.2 vs. 18.3 months; HR = 0.59, 95% CI 0.48-0.72), while OS showed similar improvement regardless of PD-L1 status (median OS NR vs. 52.4 months; HR = 0.72, 95% CI 0.56-0.93). Secondary endpoints also demonstrated substantial improvement in pathological responses (MPR: 32.0% vs. 11.0%, 95% CI: 13.9-24.7, P < 0.0001; pCR: 18.1% vs. 4.0%, 95% CI: 10.1-18.7, P < 0.0001). Based on these, the FDA approved pembrolizumab plus platinum-based chemotherapy as neoadjuvant therapy followed by adjuvant pembrolizumab monotherapy for resectable NSCLC (tumor ≥ 4 cm or lymph node-positive) in October 2023. This approval marked the first perioperative immunotherapy indication in early-stage NSCLC^[38].

The Phase III NEOTORCH study evaluated perioperative toripalimab vs. placebo in resectable stage II-III NSCLC (EGFR/ALK wild-type for nonsquamous), using a novel “3 + 1 + 13” regimen (3 neoadjuvant chemoimmunotherapy cycles, 1 adjuvant combination, 13 maintenance monotherapy cycles). As of November 30, 2022, toripalimab met the primary endpoint (median EFS: not evaluable vs. 15.1 months; HR = 0.40, 95%CI 0.28-0.57; P < 0.001) and achieved better pathological responses, with 6-fold higher MPR (48.5% vs. 8.4%) and 25-fold higher pCR (24.8% vs. 1.0%). The R0 resection rate reached 95.8% with manageable safety^[39]. These results led to NMPA approval of toripalimab in 2023 as the first China-approved and second globally-approved perioperative immunotherapy for stage IIIA-IIIB NSCLC.

The RATIONALE-315 study evaluated neoadjuvant tislelizumab or placebo plus chemotherapy (3-4 cycles) followed by adjuvant tislelizumab or placebo monotherapy (8 cycles) in EGFR/ALK wild-type, resectable stage II-IIIA NSCLC(n = 453). Results showed that tislelizumab achieved significantly higher MPR (56.2% vs. 15.0%) and pCR (40.7% vs. 5.7%) rates (both P < 0.0001), with consistent benefits across subgroups regardless of stage, histology, or PD-L1 expression^[40].Updated interim analyses demonstrated significant improvement in EFS with tislelizumab (HR = 0.56, P = 0.0003) and a clinically meaningful OS trend (HR = 0.62, P = 0.0193), though OS data remain immature^[41]. ELCC 2024 data further revealed comparable surgical outcomes (resection rates: 84.1% vs. 76.2%; R0 rates: 95.3% vs. 93.1%), similar operative duration or hospitalization time, and favorable safety (grade ≥ 3 postoperative complications: 11.1% vs. 15.6%) between arms^[42]. Following acceptance of its perioperative indication by China’s Center for Drug Evaluation (CDE) on 2024, tislelizumab represents a promising treatment option for resectable NSCLC.

The phase III CheckMate-77T trial(n = 461) in resectable stage II-IIIB NSCLC demonstrated that perioperative nivolumab (4 neoadjuvant cycles with chemotherapy + 13 adjuvant monotherapy cycles) significantly improved EFS vs. placebo (median NR vs. 18.4 months; HR = 0.58, P = 0.00025), with consistent benefit across subgroups except never-smokers. Enhanced efficacy was observed in stage III and PD-L1-positive subgroup. Pathological responses favored nivolumab (pCR: 25.3% vs. 4.7%; MPR: 35.4% vs. 12.1%), while maintaining surgical feasibility and safety^[43].

The phase III AEGEAN trial (n = 802) in resectable stage IIA-IIIB[N2] NSCLC demonstrated perioperative durvalumab (4 neoadjuvant cycles with chemotherapy + 12 adjuvant monotherapy cycles) significantly improved EFS (NR vs. 25.9 months; HR = 0.68, P = 0.0039) and pathological responses (pCR: 17.2% vs. 4.3%; MPR: 33.3% vs. 12.3%; both P < 0.0001) vs. placebo, while maintaining comparable safety. Notably, surgical feasibility remained high (R0 resection: 94.7% vs. 91.3%) despite 50% of patients having stage IIIN2 disease. This confirmed durvalumab’s dual benefit of efficacy and surgical feasibility in N2 populations^[44].

The data above demonstrate that the chemo-immunotherapy significantly enhances both MPR and pCR rates, bringing substantial clinical benefits in resectable NSCLC patients.

Immunotherapy combined with anti-angiogenic therapyThe phase II ALTER-L043 trial evaluated penpulimab-based neoadjuvant/adjuvant therapy in 49 patients with resectable stage IIB-IIIB(N2) NSCLC lacking targetable gene mutations. Patients were stratified into three cohorts: Group A (neoadjuvant penpulimab + chemotherapy + anlotinib, adjuvant penpulimab + anlotinib), Group B (neoadjuvant penpulimab + chemotherapy, adjuvant penpulimab alone), and Group C (neoadjuvant penpulimab + anlotinib, adjuvant penpulimab + anlotinib). As of August 3, 2023, surgical resection rates were 87.5% (A), 87.5% (B), and 76.5% (C). Pathological responses were notable, with MPR rates of 70.0% (A), 37.5% (B), and 80.0% (C), and pCR rates of 50.0% (A), 37.5% (B), and 60.0% (C). The objective response rate (ORR) to neoadjuvant therapy was 50.0% (A), 37.5% (B), and 47.06% (C). These findings support the potential of combining PD-1 inhibition with antiangiogenic therapy as a perioperative strategy for resectable locally advanced NSCLC(LA-NSCLC)^[45].

Immunotherapy combined with radiotherapyOne Phase Ib dose-escalation study (n = 9) evaluated neoadjuvant durvalumab plus chemotherapy with low-dose radiotherapy (three dose cohorts: 10 Gy/5fx, 20 Gy/10fx, 30 Gy/15fx) followed by adjuvant durvalumab in EGFR/ALK wild-type, potentially resectable stage III NSCLC. All patients achieved tumor downstaging post-neoadjuvant therapy, with an overall ORR of 66.7% and R0 resection rate of 77.8% (7/9). Pathological responses varied by cohort: Cohort 1 (10 Gy) showed 33.3% MPR and pCR; Cohort 2 (20 Gy) achieved 66.7% MPR but 0% pCR; Cohort 3 (30 Gy) attained 100% MPR and 66.7% pCR. The regimen demonstrated favorable safety with no dose-limiting toxicities (DLTs), treatment-related surgical delays, or deaths. Grade 3 AEs occurred in 33.3% of patients. The study preliminarily identified 30 Gy/15 fractions as the optimal radiotherapy dose, though further validation is needed to confirm the safety and efficacy of this combination^[46].

The Phase II SAKK 16/18 trial evaluated neoadjuvant durvalumab plus chemotherapy with three radiotherapy regimens (Group A: 20 × 2 Gy; Group B: 5 × 5 Gy; Group C: 3 × 8 Gy) followed by adjuvant durvalumab in resectable cT1-4N2M0 NSCLC (n = 31). Interim analysis (data cutoff: October 8, 2022) showed an 81% surgical rate (25/31), with pCR achieved in 20% (5/25; Group B:3, C:2) and MPR in 76% (19/25; Group A:4, B:8, C:7) of resected patients. TRAEs occurred in 97% of patients, with 4% attributed to durvalumab and 4% to radiotherapy. These preliminary findings support the potential of neoadjuvant immunoradiotherapy while awaiting mature data from SAKK 16/18^[47].

Notably, ongoing trials, such as IMpower030 and NCT03694236, are expected to refine immunotherapy strategies for early-stage NSCLC^[48,49].

In summary, for resectable stage II–III NSCLC, current evidence (NEOTORCH, KEYNOTE-671, RATIONALE-315, CheckMate-77T, AEGEAN) supports 3-4 cycles of neoadjuvant ICI plus platinum-based chemotherapy, followed by adjuvant ICI monotherapy or one cycle of chemotherapy plus ICIs for one year.

Immunotherapy recommendations for resectable NSCLC are summarized in Table 5.

The Phase III PACIFIC trial (n = 731) established consolidation durvalumab as standard care for unresectable stage III NSCLC without progression after concurrent CRT(CCRT), demonstrating significant survival benefits vs. placebo (median OS: 47.5 vs. 29.1 months, HR = 0.72; median PFS: 16.9 vs. 5.6 months, HR = 0.52), with 5-year OS and PFS rates of 42.9% and 33.1%, respectively. Safety profiles were comparable between arms(grade 3-4 AEs: 29.9% vs. 26.1%; grade ≥ 3 pneumonitis: 3.4% vs. 2.6%)^[50]. These results supported the FDA (2018) and NMPA (2019) approvals of consolidation durvalumab for unresectable stage III NSCLC without progression post-CCRT.

For patients intolerant to CCRT, sequential chemotherapy followed by radiotherapy represents an alternative approach. The Phase III GEMSTONE-301 (n = 381) showed consolidation sugemalimab significantly improved PFS vs. placebo (10.5 vs. 6.2 months; HR = 0.65), with consistent benefits in concurrent (15.7 vs. 8.3 months; HR = 0.71) and sequential CRT subgroups (8.1 vs. 4.1 months; HR = 0.57). While OS data remain immature, sugemalimab showed favorable survival trends with a manageable safety profile (grade ≥ 3 TRAEs: 11.4% vs. 5.6%)^[51]. Based on these results, the NMPA approved consolidation sugemalimab in 2022 for unresectable stage III NSCLC without progression after concurrent or sequential CRT.

The Pacific series, including PACIFIC-R and PACIFIC-6, further validated consolidation immunotherapy in unresectable LA-NSCLC. Additionally, for patients with poor PS, chemotherapy-free regimes are under investigation in trials such as DUART (NCT04249362) and TRADE-hypo (NCT04351256)^[52-55]. Meanwhile, intensified consolidation strategies are under exploration to improve outcomes. The COAST study demonstrated enhanced efficacy with durvalumab combinations (10-month PFS rates: 72.7% [monalizumab combination], 64.8% [oleclumab combination] vs. 39.2% [durvalumab alone]) without new safety signals^[56]. Other ongoing trials exploring combinations of PD-1/PD-L1 inhibitors with CTLA-4i, CD73i, PARPi, and anti-angiogenic agents are also underway.

The AFT-16 study evaluated neoadjuvant/adjuvant atezolizumab plus CCRT in unresectable stage III NSCLC(n = 64). With a median follow-up of 25.1 months, results showed a median PFS and OS of 23.7 months and NR, with 18-month PFS and OS rate of 57% and 84% respectively. The regimen exhibited a manageable safety profile, supporting the feasibility of this combination for unresectable stage III NSCLC^[57].

The retrospective EP05.01-004 study further validated that two cycles of induction chemoimmunotherapy followed by definitive CRT is feasible for bulky LA-NSCLC, showing significant tumor volume reduction and disease control^[58].

Notably, disease progression during induction immunotherapy may preclude definitive CRT in some patients, highlighting the need for prospective trials to optimize induction strategies and define their clinical utility.

The Phase II NICOLAS trial evaluated nivolumab plus CCRT followed by nivolumab consolidation in LA-NSCLC(n = 79). With a median follow-up of 21 months, nivolumab gained a median PFS of 12.7 months and median OS of 38.8 months^[59].

The Phase II KEYNOTE-799 study investigated pembrolizumab plus CCRT followed by pembrolizumab consolidation in unresectable stage III NSCLC. At median follow-up of 18.5 months (Cohort A, squamous/nonsquamous) and 13.7 months (Cohort B, nonsquamous), ORR were 71.4% and 75.5% with median PFS of 30.6 months and NR, respectively, demonstrating consistent benefit across PD-L1 expression levels and histological subtypes. The regimen showed manageable toxicity, supporting concurrent immunotherapy-CCRT as a potential standard^[60].

A phase II trial (NCT03110978) compared immunotherapy plus SABR (I-SABR) vs. SABR alone in stage I-IIB(T ≤ 7 cm, N0M0) or isolated lung parenchymal recurrent NSLCLC(T ≤ 7 cm). At a median 33 months’ follow-up, I-SABR significantly improved 4-year EFS (77% vs. 53%; HR = 0.38, P = 0.0056), particularly in tumors ≤ 2cm (HR = 0.35, P = 0.023). Treatment-related toxicity was acceptable (no grade ≥ 3 SABR-related events; two grade 2 pneumonitis cases), supporting I-SABR as a viable option for unresectable early-stage patients, especially with small tumors (T ≤ 2 cm)^[61].

Ongoing studies such as DETERRED, KEYLYNK-012, AdvanTIG-301 and CheckMate-73L are actively exploring the potential of concurrent immunotherapy in LA-NSCLC^[62-65]. They will provide more evidence for protocol optimization.

In summary, for unresectable stage III NSCLC patients who have not progressed after definitive CRT, PD-L1 inhibitor consolidation therapy for 1-2 years is recommended. However, induction or concurrent immunotherapy with CRT is not currently recommended as standard practice due to insufficient evidence.

Immunotherapy recommendations for unresectable LA-NSCLC are summarized in Table 6.

First-line treatmentya) Immune monotherapyCurrent guidelines recommend pembrolizumab, atezolizumab, or cemiplimab monotherapy as first-line treatment for advanced NSCLC patients with high PD-L1 expression (TPS ≥ 50%) and no targetable genomic alterations.

The IMPOWER110 study demonstrated that atezolizumab monotherapy significantly improved PFS (HR = 0.63) and OS (HR = 0.59) in EGFR/ALK wild-type stage IV non-squamous or squamous NSCLC patients with high PD-L1 expression (TPS ≥ 50% or IPS ≥ 10%)^[67].

Similarly, KEYNOTE-024 showed pembrolizumab monotherapy significantly prolonged PFS (HR = 0.50) and OS (HR = 0.63) compared to chemotherapy in treatment-naive NSCLC with PD-L1 TPS ≥ 50% and no EGFR/ALK aberrations, while demonstrating fewer grade 3-5 TRAEs (31.2% vs. 53.3%)^[68,69]. KEYNOTE-042 study expanded enrollment to include patients with PD-L1 ≥ 1%. The results demonstrated that pembrolizumab provided survival benefits across all PD-L1 expression levels (HR = 0.68 for ≥ 50%, HR = 0.75 for ≥ 20%, and HR = 0.79 for ≥ 1%), with the greatest benefit observed in the PD-L1≥ 50% subgroup^[70]. These results established pembrolizumab as the preferred first-line option for advanced NSCLC with PD-L1 TPS ≥ 50% and PD-L1 TPS 1%-49%.

The EMPOWER-Lung 1 study further demonstrated cemiplimab’s superiority over chemotherapy in PD-L1 ≥ 50% NSCLC (squamous/nonsquamous), with significant improvements in median OS (26.1 vs. 13.3 months; HR = 0.57) and PFS (8.1 vs. 5.3 months; HR = 0.51) at 35-month follow-up (both P < 0.0001). Notably, sequential cemiplimab-chemotherapy after progression on cemiplimab monotherapy yielded meaningful survival benefit (median OS: 15.1 months; median PFS: 6.6 months), offering a viable salvage strategy^[71].

b) Immunotherapy combined with chemotherapyFor treatment-naïve metastatic NSCLC without targetable alterations, PD-1/PD-L1 inhibitors(pembrolizumab, tislelizumab, cemiplimab, atezolizumab, camrelizumab, sugemalimab, penpulimab, sintilimab, or serplulimab) combined with platinum-based chemotherapy as first-line treatment is recommended regardless of histology or PD-L1 status.

The efficacy of immune-chemotherapy combinations is also strongly supported by clinical evidence. The KEYNOTE-407 study demonstrated that first-line pembrolizumab plus chemotherapy significantly prolonged median PFS (6.4 vs. 4.8 months, HR = 0.56, P < 0.001) and OS (15.9 vs. 11.3 months, HR = 0.64, P < 0.001) with 5-year OS reaching 18.4% and consistent benefits across all PD-L1 subgroups^[72,73]. Similarly, the RATIONALE-307 trial in advanced sq-NSCLC showed superior outcomes with tislelizumab-chemotherapy combinations (platinum plus either paclitaxel [arm A] or nab-paclitaxel [arm B]) vs. chemotherapy alone [arm C]), with significantly prolonged PFS by IRC assessment (7.6 months in both arm A and B vs. 5.5 months in arm C, P < 0.001 for both comparisons), along with higher ORR (72.5%/74.8% vs. 49.6%) and longer DOR (8.2/8.6 vs. 4.2 months)^[74].

The CameL-sq study demonstrated significant benefits with camrelizumab plus chemotherapy vs. chemotherapy in advanced sq-NSCLC, including improved median PFS (8.5 vs. 4.9 months, P < 0.0001) and OS (NR vs. 14.5 months, P < 0.0001)^[75].Updated results showed durable efficacy in combination group, with median OS reaching 27.4 months (vs. 15.5 months; HR = 0.57, P < 0.0001) and 4-year follow-up confirmed sustained survival advantages (OS 33.9%; PFS 20.5%) regardless of PD-L1 expression level^[76,77]. The GEMSTONE-302 study established sugemalimab-chemotherapy’s efficacy across all histological types and PD-L1 expression levels (median OS 25.4 vs. 16.9 months, HR = 0.65), with particularly pronounced benefits in squamous histology (OS 23.3 vs. 12.2 months, HR = 0.56; ORR 70.5% vs. 46.0%)^[78]. The AK105-302 trial demonstrated penpulimab’s clinical value in sq-NSCLC, improving median PFS by 2.8 months (7.0 vs. 4.2 months, HR = 0.40) without increasing grade ≥ 3 TEAEs (69% vs. 68%)^[79]. The ORIENT-12 study showed that sintilimab plus gemcitabine and platinum significantly extended the median PFS (5.5 vs. 4.9 months, P < 0.00001) assessed by the Independent Review Committee (IRC). Despite 48.9% of the patients in the chemotherapy group crossed over to the sintilimab group after progression, the OS showed benefit trend (HR = 0.567, P = 0.01701) and comparable grade ≥ 3 TEAE incidence (86.6% vs. 83.1%)^[80]. The ASTRUM-004 trial further expanded options with serplulimab-chemotherapy’s superior PFS (8.28 vs. 5.72 months, HR = 0.55) and manageable safety profile (grade ≥ 3 TRAEs: 35.2% vs. 32.4%)^[81].

The EMPOWER Lung 3 trial confirmed cemiplimab-chemotherapy’s histology-agnostic efficacy (OS 21.1 vs. 12.9 months, HR = 0.65; PFS 8.2 vs. 5.5 months, HR = 0.55)^[82].Together with the EMPOWER Lung 1 study, cemiplimab has become the second PD-1 inhibitor (after pembrolizumab) to demonstrate efficacy in both monotherapy and combination therapy for squamous and non-squamous NSCLC, leading to FDA approval for first-line advanced NSCLC^[83]. Updated data revealed durable 5-year outcomes with cemiplimab monotherapy and meaningful survival benefits when adding chemotherapy after progression on cemiplimab monotherapy, providing a viable sequential treatment strategy^[84].

c) Dual blockade immunotherapyDual blockade immunotherapy with or without chemotherapy has also demonstrated promising therapeutic efficacy in advanced NSCLC and can be considered as a first-line or subsequent treatment option.

The CheckMate-9LA trial demonstrated superior outcomes with first-line nivolumab-ipilimumab-chemotherapy vs. chemotherapy alone in stage IV NSCLC (median OS 15.6 vs. 10.9 months, HR = 0.66; PFS 6.7 vs. 5.0 months, HR = 0.70), with benefits observed across all PD-L1 levels and histologies^[85]. In 2020, the FDA approved this regimen for first-line treatment of EGFR/ALK wild-type advanced NSCLC, although it has not yet been approved by NMPA. Similarly, the trial evaluated first-line durvalumab ± tremelimumab in metastatic NSCLC without targetable alterations. Compared to chemotherapy alone, both durvalumab-tremelimumab (D + T) and durvalumab-tremelimumab-chemotherapy (D + T + CT) significantly improved PFS (6.2 vs. 4.8 months, HR = 0.72; 5.5 vs. 4.8 months, HR = 0.74) and OS (14.0 vs. 11.7 months, HR = 0.70; 13.3 vs. 11.7 months, HR = 0.86). The limited-course tremelimumab to durvalumab-chemotherapy demonstrated meaningful clinical benefit with manageable toxicity^[86]. Based on these findings, NCCN guidelines have incorporated this approach as a category 1 recommendation for advanced NSCLC. Further clinical trials of dual checkpoint inhibitor strategies are warranted to optimize treatment paradigms.

d) Patients with PS ≥ 2The aforementioned data primarily apply to patients with PS 0-1. For NSCLC patients with PS 2, standard treatment is chemo-monotherapy or platinum-based chemotherapy. When considering immunotherapy, atezolizumab monotherapy is recommended. The IPSOS study, representing the first and only global phase III trial specifically designed for NSCLC patients ineligible for platinum-based doublet chemotherapy, established atezolizumab monotherapy as a valuable treatment option for PS 2 patients. Atezolizumab showed superior OS (10.3 vs. 9.2 months; HR = 0.78, P = 0.028) and better tolerability (grade 3/4 TRAEs: 16% vs. 33%) vs. chemotherapy, along with improved quality of life measures，such as cancer-related symptom scales. These benefits were consistent across all histology and PD-L1 subgroups^[87]. Based on these findings, this consensus recommends atezolizumab monotherapy as a first-line immunotherapy option for PS 2 patients ineligible for platinum-based regimens.

Treatment strategies after first-line therapy failureTreatment strategies after first-line therapy failure require careful evaluation of drug exposure duration, best response, and response duration of prior immunotherapy to determine resistance patterns (primary vs. secondary resistance) and progression patterns (oligoprogressive vs. widespread progression).

For oligoprogression after immunotherapy, the multidisciplinary team (MDT) consultation is recommended. If the patient has good PS, continuation of ICIs combined with local therapies (radiotherapy/ablation) may be considered.

A retrospective study in 2022 included 1,536 advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. Among them, 20% (n = 312) achieved initial response and 9% (n = 143) developed secondary resistance, of whom 56% (80/143) experienced oligoprogression. Patients receiving local therapy (n = 57, 56 continuing ICIs) showed significantly improved OS vs. no local therapy (HR = 0.48, P = 0.04), with 13 patients remaining progression-free ≥ 2 years post-progression^[88]. In 2023, another retrospective study further classified the progression patterns based on the European Organization for Research and Treatment of Cancer consensus into four types: repeat oligoprogression (oligoprogression with a history of oligometastatic disease), induced oligoprogression (oligoprogression with a history of polymetastatic disease), de-novo polyprogression (polyprogression with a history of oligometastatic disease), and repeat polyprogression (polyprogression with a history of polymetastatic disease). Result showed that patients with repeat oligoprogression benefited from local ablative therapy (next-line PFS, 6.8 vs. 3.3 months; P = 0.0135; OS, NR vs. 24.5 months; P = 0.0337), while those with induced oligoprogression benefited from continued immunotherapy (next-line PFS: 6.1 vs. 4.1 months, P = 0.0264; OS: 45.4 vs. 32.3 months, P = 0.0348)^[89]. Currently, the exploration of treatment patterns for oligoprogression after immunotherapy in NSCLC is mostly based on retrospective studies^[88-91]. Ongoing prospective studies, including NCT04405401, NCT03693014, and NCT04492969, are expected to provide more evidence for the optimal management of oligoprogression post-ICI therapy.

For widespread progression post-immunotherapy, the current standard treatment is second-line chemotherapy, such as docetaxel or paclitaxel. Based on relevant clinical and retrospective studies, the combination of chemotherapy and anti-angiogenic therapy can be considered. The VARGADO trial demonstrated that docetaxel plus nintedanib in patients progressing after first-line chemoimmunotherapy yielded a DCR of 72.5%, ORR of 37.5%, and PFS of 4.8 months with manageable toxicity^[92]. Pooled analysis from the ALTER-L016 and ALTER-L018 studies showed that superior outcomes with anlotinib-docetaxel vs. docetaxel monotherapy (ORR: 25.0% vs. 12.9%; DCR: 82.5% vs. 45.2%; median PFS: 5.4 vs. 2.3 months; P < 0.001)^[93]. A retrospective study in 2024 further suggested survival benefit with anti-angiogenic therapy post-ICI progression (HR = 0.275, P = 0.013)^[90].

Currently, there is insufficient evidence to support immunotherapy rechallenge for secondary immune resistance. Studies suggest that patients with good PS (PS ≤ 1), initial ICI duration ≥ 3 months, planned ICI discontinuation and chemotherapy between ICI courses may benefit from immunotherapy rechallenge^[90,94-98]. However, robust evidence identifying optimal candidates is deficient. The mechanisms of acquired resistance to ICIs are primarily categorized into six types: loss of neoantigens, defects in antigen processing, abnormalities in the interferon (IFN)-γ signaling pathway, formation of an immunosuppressive TME, expression of co-inhibitory receptors, and other signaling pathway abnormalities^[99]. These resistance mechanisms inform potential therapeutic strategies including chemoimmunotherapy combination, oncolytic virus injections or neoantigen vaccines to increase antigen release; adoptive T-cell/CAR-T/CAR-NK therapies to enhance antigen recognition and T-cell infiltration; TLR9 agonists or drug targeting the IFN-γ pathway to restore IFN-γ signaling; anti-angiogenic therapy to remodel the TME, and novel ICIs to overcome co-inhibitory receptor expression^[99,100].

Emerging clinical data demonstrate promising approaches in NSCLC patients who progressed after chemotherapy and ICIs. BTCRC-LUN15-029 study showed pembrolizumab plus second-line chemotherapy (gemcitabine/docetaxel/pemetrexed) extended the median PFS to 5.1 months and the median OS to 26.8 months^[101]. A Phase I clinical study explored the efficacy of tumor-infiltrating lymphocytes (TILs) plus nivolumab in nivolumab-resistant NSCLC. Among 13 evaluable patients, 3 had confirmed responses (median best change, 35%), 11 experienced tumor burden reduction, and 2 achieved durable CR for 1.5 years. This autologous TIL cell therapy was found to be relatively safe and clinically active, potentially representing a new treatment strategy for metastatic lung cancer^[102]. The Phase Ib study demonstrated that intratumoral injection of Vidutolimod (a TLR agonist) plus pembrolizumab had the potential to overcome PD-1 inhibitor resistance in advanced melanoma. Among 44 patients, 11 achieved ORR, with a median DOR of 19.5 months and a median PFS of 2.8 months^[103]. The Phase II S1800A study combining ramucirumab with pembrolizumab showed median OS of 14.5 vs. 11.6 months (HR = 0.69) in ICI-resistant NSCLC (prior ICI ≥ 84 days)^[104]. The Phase II TACTI-002 study (Part B) showed that second-line eftilagimod alpha (soluble LAG-3 protein) plus pembrolizumab achieved an ORR of 8.3% and a DCR of 33% (iRECIST). The study also reported a 50% reduction in tumor growth rate, with a median PFS of 2.1 months and a median OS of 9.9 months^[105].

However, since most studies are Phase I/II trials, conclusive evidence for immunotherapy rechallenge remain premature. Therefore, for patients progressing on immunotherapy, genetic testing and MDT consultations are recommended to develop the optimal treatment strategy, with strong encouragement for clinical trial participation when available.

For ICI-naive patients, treatment selection should be guided by biomarker and genetic testing result. Nivolumab, atezolizumab, tislelizumab, or pembrolizumab (for PD-L1 TPS ≥ 1%) can be considered as subsequent treatment. Additionally, enrollment in clinical trials is strongly recommended. The CheckMate-078 trial established nivolumab’s superiority over docetaxel in chemotherapy-pretreated advanced NSCLC, demonstrating significant improvements in both median OS (12.0 vs. 9.6 months; P = 0.0006) and ORR (16.6% vs. 4.2%; P < 0.0001)^[106]. Similarly, the Phase III RATIONALE-303 trial showed that tislelizumab significantly prolonged OS and PFS compared to docetaxel (median OS 16.9 vs. 11.9 months, HR = 0.66, P < 0.0001, median PFS 4.2 vs. 2.6 months, HR = 0.63, P < 0.0001) in chemotherapy-pretreated NSCLC, with manageable safety profile^[107]. The KEYNOTE-010 study indicated that in PD-L1 TPS ≥ 1%, advanced NSCLC patients, subsequent-line pembrolizumab provided significant OS benefits, with 5-year OS rates of 25.0% (TPS ≥ 50%) and 15.6% (TPS ≥ 1%) vs. 8.2% and 6.5% with docetaxel, respectively^[108,109]. The OAK trial subgroup analysis demonstrated atezolizumab’s superior efficacy and safety in sq-NSCLC, showing significant OS benefit (13.8 vs. 9.6 months; HR = 0.73, P = 0.0003) regardless of PD-L1 status, with fewer grade 3-4 AEs (15% vs. 43%) compared to docetaxel^[110].

For patients with poor PS (PS = 3-4), best supportive care is recommended.

First-line treatmenta) Immune monotherapyCurrently, pembrolizumab, atezolizumab, and cemiplimab monotherapy are recommended as first-line treatment for advanced NSCLC patients with high PD-L1 expression and no targetable genomic alterations.

The IMpower110 study demonstrated atezolizumab’s superiority over chemotherapy in PD-L1-high (TC ≥ 50% or IC ≥ 10%) EGFR/ALK wild-type NSCLC, with significant PFS (HR = 0.63) and OS benefits (20.2 vs. 13.1 months; HR = 0.59, P = 0.01) at 15.9-month median follow-up, leading to FDA (2020) and NMPA (2021) approvals for this indication^[67].

Similarly, The KEYNOTE-024 study showed pembrolizumab’s durable efficacy in PD-L1 TPS ≥ 50% NSCLC with 59.9-month follow-up data revealing superior median OS (26.3 vs. 13.4 months; HR = 0.62) and unprecedented 5-year survival rates (31.9% vs. 16.3%)^[69,111]. This study was the first to report 5-year survival outcomes for first-line immunotherapy in advanced NSCLC. This trial was the first to report 5-year survival outcomes for first-line immunotherapy in advanced NSCLC. These findings were extended in KEYNOTE-042, where pembrolizumab demonstrated OS benefits across PD-L1 ≥ 1%^[70]. Evidence from EMPOWER-Lung 1 further supports cemiplimab’s role in PD-L1-high disease^[71].

b) Immunotherapy combined with chemotherapyIn the first-line treatment of advanced nsq-NSCLC, multiple landmark clinical trials including KEYNOTE-189, CAMEL, ORIENT-11, RATIONALE-304, GEMSTONE-302, IMpower132, and CHOICE-01 have consistently demonstrated that combining ICI with platinum-based chemotherapy significantly prolongs PFS compared to chemotherapy^[78,112-119]. Based on these robust clinical data, chemotherapy combined with pembrolizumab, camrelizumab, sintilimab, tislelizumab, sugemalimab, atezolizumab, or toripalimab is recommended as a priority first-line treatment for advanced nsq-NSCLC without targetable genomic alterations.

The IMpower130 trial showed atezolizumab plus nab-paclitaxel/carboplatin significantly improved both median PFS (7.0 vs. 5.5 months; HR = 0.64, P < 0.0001) and OS (18.6 vs. 13.9 months; HR = 0.79, P = 0.033) compared to chemotherapy alone, with a manageable safety profile^[120]. Additionally, the IMpower150 study demonstrated that in advanced patients without targetable genomic alterations, the combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) significantly prolonged median PFS (8.3 vs. 6.8 months, HR = 0.62, P < 0.001) and OS (19.2 vs. 14.7 months, HR = 0.78, P = 0.02) compared to the combination of bevacizumab, carboplatin, and paclitaxel (BCP)^[66]. Based on these findings, the FDA approved both atezolizumab-carboplatin-paclitaxel (ACP) and ABCP as first-line treatment for metastatic nsq-NSCLC. The EMPOWER Lung 3 study regarding chemo-immunotherapy combinations in sq-NSCLC (as detailed previously) provide additional supporting evidence for this treatment paradigm.

c) Dual blockade immunotherapyThe CheckMate-9LA study demonstrated nivolumab plus ipilimumab and two cycles of chemotherapy provides clinically meaningful benefit, regardless of PD-L1 expression levels or histological type^[85]. In 2020, the FDA approved this combination as first-line treatment for advanced NSCLC.

In 2023, the 6-year follow-up data from CheckMate-227 further demonstrated durable survival advantages with nivolumab-ipilimumab dual immunotherapy in EGFR/ALK wild-type advanced NSCLC, regardless of PD-L1 expression levels: in PD-L1 < 1% patients, 6-year OS rates were 16% (HR = 0.65) for dual therapy, 10% (HR = 0.79) for nivolumab monotherapy, and 5% for chemotherapy; while in PD-L1 ≥ 1% patients, the corresponding rates were 22% (HR = 0.78), 15% (HR = 0.91), and 13% respectively^[121].

These findings are complemented by the POSEIDON study results (detailed previously) supporting dual checkpoint inhibition strategies. For PS 2 patients intolerant to chemotherapy, the IPSOS trial data (discussed earlier) suggest atezolizumab monotherapy represents a viable option.

Treatment strategies after first-line therapy failureFor patients with PS 0-2, treatment strategies should be individualized through comprehensive clinical assessment, with strong recommendation for clinical trial participation at any line of therapy upon disease progression. For patients who received immunotherapy, the treatment strategy is consistent with the approach as outlined previously for advanced nsq-NSCLC following first-line treatment failure. For patients who progressed after first-line chemotherapy, re-biopsy for biomarker testing is recommended. Based on the CheckMate-078, RATIONALE-303, KEYNOTE-010, and OAK studies, subsequent-line treatment may include nivolumab or tislelizumab, pembrolizumab (limited to patients with PD-L1 TPS ≥ 1%), and atezolizumab. Camrelizumab also represents a viable alternative, with a phase II study demonstrating that camrelizumab plus apatinib achieved an ORR of 30.9%, median PFS of 5.7 months, and OS of 15.5 months^{[106,107,109,110]}. This combination showed benefits across all PD-L1 subgroups and also in patients with STK11/KEAP1 mutations^[122].

Combination therapies with different immune checkpoint inhibitorsRecent advances in understanding the tumor immune microenvironment and immunotherapy resistance mechanisms have spurred development of novel ICIs targeting LAG-3, TIGIT, and TIM-3.

Eftilagimod alpha (E) is a soluble LAG-3 protein that binds to MHC II molecules, mediating the activation of APCs and CD8 T cells. The Phase II TACTI-002 study explored the combination of Eftilagimod alpha with pembrolizumab in two parts: Part A evaluated first-line treatment for metastatic NSCLC, while Part B assessed second-line treatment for PD-1/L1-inhibitor-resistant NSCLC. In Part A(n = 114), the ORR by iRECIST was 28.1% for PD-L1-negative patients, 45.5% for PD-L1 ≥ 1%, 41.7% for PD-L1 1%-49%, and 52.6% for PD-L1 ≥ 50%, along with median PFS of 6.9 months (all patients), 8.4 months (PD-L1 ≥ 1%), and 11.8 months (PD-L1 ≥ 50%)^[123].The second-line cohort (Part B) achieved more modest outcomes (ORR 8.3%, DCR 33%, median PFS 2.1 months, OS 9.9 months)^[105,124]. In 2022, the FDA granted Fast Track designation to Eftilagimod alpha plus pembrolizumab for first-line treatment of stage IIIB/IV NSCLC with PD-L1 TPS ≥ 1%. Other LAG-3 antibodies, such as relatlimab and LAG-525, are also undergoing Phase I/II clinical trials in melanoma and solid tumors.

TIGIT is an immune checkpoint molecule primarily expressed on T/NK cells. It inhibits immune responses by binding to its ligands. Phase I trial of vibostolimab (anti-TIGIT) demonstrated limited single-agent activity (ORR 3%) in PD-1/L1-resistant advanced NSCLC in the MK-7684-001 trial^[125]. However, the phase II CITYSCAPE trial revealed significantly enhanced efficacy when combining tiragolumab (anti-TIGIT) with atezolizumab vs. atezolizumab monotherapy in PD-L1-positive disease, with improved ORR (31% vs. 16%) and PFS (5.42 vs. 3.58 months)^[126]. Based on these findings, the FDA granted Breakthrough Therapy designation in 2021 to tiragolumab plus atezolizumab as first-line therapy for EGFR/ALK wild type metastatic NSCLC with high PD-L1 expression. Additional TIGIT inhibitors, including BMS-986207 and domvanalimab (AB-154), remain under investigation in preclinical and early-phase clinical development.

TIM-3, expressed across multiple immune cell subsets including T cells and innate immune cells (dendritic cells, NK cells, monocytes, and macrophages), serves as a regulator of T-cell exhaustion and tumor immune evasion. The phase I NCT03099109 trial evaluating LY3321367 (anti-TIM-3) with or without PD-L1 blockade in PD-1/L1-resistant patients showed modest clinical activity (ORR 4%, DCR 42%) but demonstrated mechanistic proof-of-concept through increased CD8+ T-cell infiltration in 50% of paired tumor biopsies^[127]. This finding supports TIM-3’s role in overcoming PD-1 resistance, with several TIM-3 inhibitors (cobolimab, sabatolimab) currently in development as potential components of immunotherapy combinations for NSCLC.

Bispecific antibody immunotherapyRecent advances in bispecific antibody development have yielded promising results across multiple targets in NSCLC, including PD-1/VEGF, PD-1/CTLA-4, PD-L1/TGF-β, and PD-L1/CTLA-4.

Ivonescimab (AK112) is a PD-1/VEGF bispecific antibody that simultaneously targets PD-1 and VEGF-A, inhibiting tumor angiogenesis and modulating the TME to achieve antitumor effects. The AK112-201 study evaluated AK112 plus chemotherapy in treatment-naïve advanced NSCLC without targetable genomic alterations (Cohort 1), immunotherapy-progressed advanced NSCLC without targetable genomic alterations (Cohort 3), and EGFR-TKI-resistant advanced NSCLC with targetable genomic alterations (Cohort 2). Results showed that the ORR were 53.5% (23/43) in Cohort 1, 68.4% (13/19) in Cohort 2, and 40.0% (8/20) in Cohort 3. The median PFS was NR, 8.5 months and 7.5 months correspondently^[128]. The HARMONi-A study further showed AK112 plus chemotherapy reduced progression risk by 54% (median PFS 7.1 vs. 4.8 months) and death risk by 20% (median OS 17.1 vs. 14.5 months) vs. chemotherapy alone in EGFR-mutant NSCLC post-TKI failure^[128,129]. Notably, the phase III HARMONi-2 trial presented at 2024 WCLC showed ivonescimab monotherapy significantly outperformed pembrolizumab in PD-L1 ≥ 1% NSCLC (mPFS 11.1 vs. 5.8 months, HR = 0.51, P < 0.0001), representing the first immune agent to demonstrate superiority over pembrolizumab in a head-to-head phase III trial. Although not yet globally approved for NSCLC, Ivonescimab has shown significant potential in this area^[130].

Other promising bispecifics include QL1706 (PD-1/CTLA-4), KN046 (PD-L1/CTLA-4) and SHR-1701 (PD-L1/TGF-β). A Phase II study showed QL1706 plus chemotherapy ± bevacizumab in treatment-naïve advanced NSCLC patients without targetable genomic alterations achieved an ORR of 45% and a median PFS of 6.8 months, with enhanced activity in EGFR-TKI resistant patients (ORR 54.8%, mPFS 8.5 months)^[131]. Another Phase II clinical trial showed KN046 plus chemotherapy as first-line treatment for metastatic NSCLC achieved an ORR of 46.0%, a median PFS of 5.8 months, and a median OS of 26.6 months^[132]. A Phase I study explored SHR-1701 in advanced NSCLC patients in three cohorts: treatment-naïve patients with PD-L1 TPS ≥ 1% (Cohort 1), EGFR-mutant patients with TKI resistance (Cohort 2), and immunotherapy-refractory patients with ≤ 3 prior lines of therapy (Cohort 3). The study showed promising antitumor activity across all cohorts, with ORR of 36.8%, 19.5%, and 9.1%, respectively. The median PFS was 5.3 months, 1.4 months, and 2.1 months, and the median OS was 24.2 months, 14.4 months, and 16.1 months, respectively. The safety profile was favorable, providing new treatment insights for treatment-naïve, EGFR-TKI resistance, and immunotherapy resistance NSCLC^[133]. Ongoing investigations like the TRAILBLAZE study continue to explore bispecific antibodies in unresectable stage III NSCLC, further expanding the therapeutic landscape.

Immunotherapy combined with antiangiogenic therapy/targeted therapyBy reversing the immunosuppressive TME, antiangiogenic agents demonstrate synergistic potential when combined with ICIs, yielding enhanced clinical outcomes beyond additive effects (1 + 1 > 2). In addition to the IMpower150 and ORIENT-31 studies, multiple clinical trials continue to investigate this strategic combination^[66,134].

The phase II S1800A study demonstrated this potential in ICI-resistant NSCLC, with ramucirumab plus pembrolizumab improving median OS to 14.5 vs. 11.6 months for standard of care (HR = 0.69)^[104]. Similarly, updated results from COSMIC-021 showed cabozantinib-atezolizumab outperformed cabozantinib alone in ICI-pretreated nsq-NSCLC (median PFS 4.5 vs. 3.4 months; OS 13.8 vs. 9.4 months), with tumor shrinkage observed in 76% of patients and responses across all PD-L1 subgroups^[135]. Additional promising combinations under investigation include JVDF (ramucirumab/pembrolizumab), NCT03083041 (apatinib/camrelizumab) and NCT03628521 (anlotinib/sintilimab)^[136-138]. These findings align with earlier successes in IMpower150 (atezolizumab/bevacizumab/chemotherapy) and ORIENT-31 (sintilimab/bevacizumab/chemotherapy), supporting continued exploration of this strategy^[66,134].

Despite promising results, not all combinations have succeeded. High-profile trials such as CONTACT-01 (atezolizumab/cabozantinib), LEAP-006/008 (pembrolizumab/lenvatinib ± chemotherapy), SAPPHIRE (sitravatinib/nivolumab), and KN046-302 (KN046/lenvatinib) failed to meet primary endpoints in ICI-pretreated NSCLC^[139-142]. These mixed outcomes highlight the need for refined patient selection, optimized dosing, and predictive biomarkers to identify responders.

Immunotherapy combined with an ADCRecent advancements in antibody-drug conjugate (ADC) therapeutics have revolutionized treatment paradigms for NSCLC, with Trophoblast cell surface antigen 2 (TROP2) and HER2 ADC being most extensively studied.

TROP2, a transmembrane glycoprotein critically involved in tumor cell self-renewal and proliferation, demonstrates significant overexpression across multiple epithelial malignancies including NSCLC (64% of adenocarcinomas, 75% of squamous cell carcinomas), breast, cervical, and urothelial cancers^[143,144]. Its elevated expression correlates with ICI resistance in advanced NSCLC, driving the clinical development of TROP2 ADC such as sacituzumab govitecan, datopotamab deruxtecan (Dato-DXd), and SKB264^[145].

Promising results from the EVOKE-02 trial demonstrated first-line sacituzumab govitecan plus pembrolizumab achieved ORRs of 69% (PD-L1 ≥ 50%) and 44% (PD-L1 < 50%), with 6-month DoR rate of 88% in advanced NSCLC^[146]. These findings are being further evaluated in the phase III EVOKE-03 study for PD-L1-high metastatic NSCLC (TPS ≥ 50%). Similarly, the TROPION-Lung02 showed Dato-DXd combinations achieved ORRs of 38% (doublet with pembrolizumab) and 49% (triplet with chemotherapy), with median PFS of 8.3 and 7.8 months respectively, in advanced NSCLC without targetable genomic alterations. Notably, Dato-DXd combinations also showed promising benefit in first-line treatment, with the ORR of 50% and 57% respectively^[147]. Based on these findings, the TROPION-Lung07 and TROPION-Lung08 studies are ongoing to explore this regime (Dato-DXd + pembrolizumab ± chemotherapy) in advanced NSCLC with PD-L1 TPS < 50% and ≥ 50%, respectively^[148,149]. The phase Ib TROPION-Lung04 study further validated this approach, showing ORRs of 47.4% (Dato-DXd + durvalumab) and 71.4% (triplet with chemotherapy) in treatment-naïve or previously treated, EGFR/ALK wild type advanced NSCLC, leading to the ongoing phase III AVANZAR trial comparing this regimen against pembrolizumab-chemotherapy in first-line treatment of advanced NSCLC^[150]. Meanwhile, the phase II OPTITROP-Lung01 trial of SKB264 plus KL-A167 (anti-PD-L1) also showed impressive activity and manageable safety profile, with a phase III evaluation (NCT06170788) now underway^[151].

For HER2-altered NSCLC, trastuzumab deruxtecan (T-DXd) has established a new standard of care in later-line settings based on DESTINY-Lung01/02/05 trials, with current investigations (DESTINY-Lung03, NCT04042701) exploring its potential in first-line combinations with durvalumab/chemotherapy or pembrolizumab for HER2-overexpressing or HER2-mutant disease^{[122,152,153]}. These developments collectively underscore the potential of ADCs in NSCLC therapeutics across multiple molecular subsets and treatment lines.

The recommended immunotherapy options for stage IV NSCLC without targetable genomic alterations are presented in Table 7.

For EGFR-mutant NSCLC, tyrosine kinase inhibitors (TKIs) remain the standard first-line therapy due to the tumors’ low immunogenicity and non-inflammatory microenvironment, which limit immunotherapy efficacy. Early studies have explored various immunotherapy strategies, including ICI monotherapy, ICI-chemotherapy, and ICI-TKI combinations. However, these strategies have shown limited benefits in treatment-naive patients. In CheckMate-012 study, nivolumab monotherapy (ORR 14%, mPFS 1.8 months, mOS 18.8 months) and nivolumab-chemotherapy (ORR 17%, mPFS 4.8 months, mOS 20.5 months) showed modest activity but higher toxicity (21% vs. 12% discontinuation rates) in EGFR-mutant NSCLC(n = 13)^[155]. The TATTON trial (durvalumab-osimertinib) was halted due to safety concerns, with a 35% incidence of interstitial lung disease (ILD) vs. 2%-3% with osimertinib or durvalumab alone. In terms of efficacy, the ORR was 82% in 11 treatment-naive patients and 43% in 23 patients who had previously received EGFR-TKIs^[156]. Multiple studies have shown that ICI monotherapy or ICI-chemotherapy are far less effective than standard EGFR-TKI therapy in treatment-naive NSCLC. Moreover, In ICI-TKI combinations, the significant toxicity risk, particularly pulmonary toxicity, often outweighs the marginal efficacy gains. Thus, ICI-TKI combinations are not recommended, and EGFR-TKIs remain the preferred first-line approach.

Although EGFR-TKIs demonstrate remarkable efficacy in EGFR-mutant NSCLC, acquired resistance inevitably develops, necessitating re-biopsy to identify resistance mechanisms and guide subsequent therapy. For EGFR-TKI resistant patients with oligoprogression or central nervous system progression, continuation of the EGFR-TKIs with local treatment may be considered. For widespread progression, in the absence of effective targeted therapies or traditional treatments, re-biopsy, MDT consultation and ICI-based strategies may be considered.

Emerging evidence suggests potential roles for various immunotherapy approaches in the EGFR-TKI-resistant NSCLC, including combinations of ICIs with chemotherapy, ICIs with antiangiogenic agents, or ICI monotherapy, though optimal sequencing and patient selection criteria require further investigation.

The IMpower150 study demonstrated improved outcomes with atezolizumab-bevacizumab-chemotherapy (ABCP) vs. bevacizumab-chemotherapy (BCP) in EGFR-mutant NSCLC (mOS 29.4 vs. 18.1 months; HR = 0.60), including TKI-pretreated subgroups (mOS 27.8 vs. 18.1 months; HR = 0.74)^[157].

Subsequent ORIENT31 trial further supported the potential benefit of immunotherapy-antiangiogenic-chemotherapy combinations in EGFR-TKI-pretreated patients, showing sintilimab-IBI305-chemotherapy significantly prolonged mPFS vs. chemotherapy (6.9 vs. 4.3 months; HR = 0.46, P < 0.0001)^[134]. A meta-analysis indicated that the immunotherapy-antiangiogenic-chemotherapy triplet regimen showed the best PFS outcomes compared to immunotherapy-chemotherapy (HR 0.71, 95% CI: 0.59-0.85), immunotherapy alone (HR 0.30, 95% CI: 0.22-0.41), and non-immunotherapy strategies including antiangiogenic-chemotherapy (HR 0.76, 95% CI: 0.58-1.00) or chemotherapy alone (HR 0.54, 95% CI: 0.45-0.64). However, triplet regimen showes increased toxicity compared to chemotherapy^[158]. These findings collectively suggest potential clinical benefit of chemotherapy-antiangiogenic-immunotherapy combinations in EGFR-TKI-resistant patients.

Additionally, the MARIPOSA and MARIPOSA2 studies further expand therapeutic options with amivantamab-lazertinib (first-line) and amivantamab-chemotherapy (second-line) regimens for EGFR-sensitive mutant NSCLC^[159,160].

In summary, while immunotherapy is not recommended as first-line treatment for EGFR-mutant NSCLC, it may be considered in specific clinical scenarios following comprehensive evaluation. When targeted therapies are unavailable or upon development of widespread resistance to EGFR-TKIs, management should commence with tissue re-biopsy to characterize resistance mechanisms. Subsequent treatment planning requires multidisciplinary assessment incorporating tumor molecular profiling, immune microenvironment biomarkers, patient performance status, treatment tolerance, and socioeconomic considerations. The selection of immunotherapy-based regimens (including ICI-chemotherapy-antiangiogenic combinations, ICI-platinum doublets, or ICI-antiangiogenic therapy) should be guided by molecular resistance patterns and determined through MDT discussion to optimize therapeutic outcomes while mitigating toxicity risks.

EGFR exon 20 insertion mutations (EGFR exon20ins) represent 5% to 12% of all EGFR mutations, demonstrating a distinct geographic distribution with lower prevalence in Chinese (4.8%-5.1%) vs. Western populations (9%-12%)^[161]. These mutations exhibit remarkable molecular heterogeneity, with over 100 identified variants primarily clustering in the 761-775 peptide segment. This localization disrupts critical C-helix and loop structures, conferring intrinsic resistance to conventional EGFR TKIs^[162].

Current treatment strategies for EGFR exon20ins mutations primarily involve platinum-based chemotherapy. ICI monotherapy has shown limited efficacy, while the combination of ICIs and chemotherapy appears promising but remains controversial. Kirchner et al. found that TME with EGFR exon20ins mutations are more likely to be “cold” microenvironment, characterized by a lack of cytotoxic T cells and Th1 cells^[163]. Liu et al. also demonstrated that a more immunosuppressive TME in EGFR exon20ins mutations compared to wild-type, showing reduced infiltrating CD8+ FOXP3- T cells, tumor-promoting T cell phenotypes with enhanced epithelial-mesenchymal transition (EMT) capacity, and predominant M2-like macrophage infiltration^[164]. This suggests that immune monotherapy may be insufficient, and combination immunotherapy could be a better option^[164].

These biological features may explain the limited efficacy observed with ICI monotherapy (ORR 4%, mPFS 2.6 months) compared to chemotherapy (ORR 39%, mPFS 6.9 months)^[165]. While platinum-based chemotherapy remains the therapeutic cornerstone, recent evidence suggests potential benefits from chemoimmunotherapy combinations, with one 2024 study reporting superior PFS (10.3 vs. 6.3 months, P = 0.013) and ORR (33.3% vs. 15%, P = 0.0168) vs. chemotherapy alone^[166]. However, the clinical utility of ICIs remains controversial, as demonstrated by Choudhury et al. who found no significant improvement in time to treatment discontinuation (TTD) with ICIs compared to chemotherapy^[167].

Moreover, the therapeutic landscape has evolved significantly with the development of mutation-specific agents. Frontline options now include amivantamab-chemotherapy (PAPILLON trial) and sunvozertinib (WU-KONG1/15), while later-line settings feature sunvozertinib (WU-KONG6) and amivantamab monotherapy (CHRYSALIS trial)^[168-171].

In summary, according to the 2024 NCCN guidelines, treatment for advanced NSCLC with EGFR exon20ins mutations still refers to the strategies for advanced NSCLC without targetable genomic alteration^[172]. Platinum-based chemotherapy combinations remain the cornerstone of first-line therapy, with sunvozertinib representing a viable alternative when accessible. For subsequent-line treatment, sunvozertinib is the preferred option when available. The incorporation of immunotherapy should be determined through MDT evaluation, incorporating comprehensive assessment of individual patient characteristics, tumor biomarker profiles, and immune microenvironment features to optimize therapeutic decision-making.

Treatment-naïve ALK (Anaplastic Lymphoma Kinase)-rearranged NSCLC is characterized by low tumor mutational burden (TMB), sparse TILs in the TME, and diminished expression of immunostimulatory biomarkers, collectively predicting poor response to ICIs. The ImmunoTarget study reported complete lack of efficacy for ICI monotherapy in ALK-positive patients (ORR 0%)^[173]. Similar to observations in EGFR-mutant NSCLC, combining ICIs with ALK-TKIs showed only marginal efficacy benefits while significantly increasing toxicity risks, particularly with crizotinib or ceritinib-based combination^[174]. Therefore, ICIs are not recommended for the treatment of ALK-positive NSCLC. Moreover, the immunomodulatory effects of ALK-TKIs on the TME remain incompletely understood, though evidence suggests ALK fusions are associated with inherently low tumor immunogenicity and non-inflammatory microenvironments that may be further suppressed by ALK-TKI treatment^[158]. Current data on immunotherapy for ALK-TKI-resistant patients, derived primarily from small retrospective studies, demonstrate consistently poor outcomes: ICI monotherapy yields ORRs of 0%-3.6% with PFS of 2-3 months, while ICI-chemotherapy combinations show modest improvement (ORR 28%, PFS 2.9 months)^{[172,175-177]}. These findings collectively indicate limited clinical benefit. Therefore, immunotherapy is not recommended for treatment-naïve or TKI-resistant ALK-positive NSCLC^[174].

ROS1 (c-ros oncogene 1) fusion-positive NSCLC exhibits low immunogenicity. Although ROS1 shares high homology with ALK, the efficacy of PD-1/PD-L1 inhibitors in ROS1-positive patients differs from that in ALK-positive patients. Studies have shown that ROS1 fusion tumors have higher PD-L1 positivity rates compared to driver-negative NSCLC (46.7% vs. 36.6%), suggesting that ROS1-positive NSCLC may potentially benefit from immunotherapy^[173]. The ImmunoTarget study reported an ORR of 17% with ICI monotherapy in seven ROS1-positive patients while a larger multicenter retrospective analysis (n = 184) observed an ORR of 13% and median TTD of 2.1 months among 28 patients receiving ICI monotherapy. Notably, the combination of ICIs with chemotherapy (n = 11) demonstrated significantly improved efficacy (ORR 83%, TTD 10 months), indicating that chemoimmunotherapy may offer greater clinical benefit in this population^[173]. However, given the limited and retrospective nature of current evidence, immunotherapy is not routinely recommended for treatment-naïve or TKI-resistant ROS1-positive NSCLC. First-line therapy should prioritize ROS1-targeted agents such as crizotinib or entrectinib, while platinum-based chemotherapy (with or without bevacizumab) remains the standard approach after TKI failure^[174]. Patients are also encouraged to participate in clinical trials to explore new therapeutic options.

MET (Mesenchymal-Epithelial Transition factor) aberrations in NSCLC primarily occur as three distinct molecular subtypes: MET exon 14 skipping mutations, MET gene amplification, and protein overexpression. MET exon 14 skipping mutations occur in 3%-4% of lung cancer, while primary MET amplification is observed in 1%-5% of cases, and secondary MET amplification varies between 5%-50% of EGFR-TKI-resistant tumors depending on the TKI generation^[173,179]. Currently, 4 MET-TKIs (glumetinib, bozitinib, tepotinib, and savolitinib) are approved in China exclusively for MET exon 14 skipping mutations, with no targeted therapies available for other MET alterations.

Clinical evidence demonstrates that MET-TKIs achieves ORR of 66.7%-68% in treatment-naïve patients and 41%-51.9% in in pretreated populations with MET exon 14 skipping mutations, while patients with high-copy MET amplification (≥ 10) may benefit from crizotinib, capmatinib, or tepotinib^{[172,180-182]}.

Preliminary research has revealed that MET exon 14 skipping mutation tumors exhibit lower TMB compared to unselected NSCLC, along with higher TME heterogeneity that may partially demonstrate inflammatory characteristics, with PD-L1 expression levels being independent of TMB^{[154,183,184]}.

Current evidence for immunotherapy in MET-altered NSCLC derives predominantly from retrospective analyses. The IMMUNOTARGET study involving 36 MET-altered patients (23 with exon 14 skipping mutations) demonstrated an ORR of 16%, median PFS of 3.4 months, and median OS of 18.4 months with subsequent-line ICI monotherapy^[173]. Another study of 24 patients with MET exon 14 skipping mutation reported 17% ORR and 1.9-month median PFS with ICIs ± chemotherapy^[183]. Notably, in MET-amplified NSCLC (n = 278), ICI monotherapy showed superior efficacy vs. chemotherapy (median OS 19 vs. 8 months, P < 0.0001), particularly in cases with copy number < 10^[185].

Based on current evidence, MET-TKIs remains the first-line standard for MET-altered NSCLC. Upon development of TKI resistance or when targeted therapies are inaccessible, MDT consultation is recommended to guide subsequent treatment based on the resistance mechanisms. When no effective options exist, immunotherapy may be cautiously considered after comprehensive evaluation of patient’s physical condition, financial situation, and preferences, Subsequent therapies could refer to the treatment strategy of stage IV NSCLC with or without targetable genomic alteration.

RET (Rearranged during Transfection) genomic alterations include RET mutations and fusions, with RET fusions being more common in lung cancer, accounting for 1%-2% of lung adenocarcinomas^[186]. Currently approved targeted therapies for RET fusions in China include pralsetinib and selpercatinib. Like other oncogenic fusions, RET fusions demonstrate low immunogenicity^[174]. A study by Lee et al. evaluating various systemic therapies in 59 RET fusion NSCLC(using the multikinase inhibitor vandetanib as targeted therapy) showed pemetrexed-based chemotherapy achieved better outcomes (ORR 63.0%, mPFS 9.0 months [95% CI: 6.9-11.2], mOS 24.1 months [95% CI: 15.2-33.0]), while PD-1/PD-L1 inhibitors demonstrated limited efficacy (ORR 7.7%, mPFS 2.1 months [95% CI: 1.6-2.6], mOS 12.4 months [95% CI: 2.9-21.8])^[187]. A phase 3 clinical trial demonstrated superior efficacy of selpercatinib compared to chemotherapy ± immunotherapy, with significantly prolonged PFS (24.8 vs. 11.2 months; HR 0.46; P < 0.001) and higher ORR (84% vs. 65%) among advanced RET fusion-positive NSCLC^[188]. Given these data, the efficacy of first-line immunotherapy RET fusion-positive NSCLC requires further validation. When available, targeted therapy should be prioritized. If access to RET inhibitors is limited, platinum-based chemotherapy with pemetrexed may be considered^[189]. The role of ICIs in this population remains undefined due to insufficient evidence, underscoring the need for additional clinical investigations to establish evidence-based therapeutic approaches^[174].

KRAS(Kirsten Rat Sarcoma Viral Oncogene Homolog)-mutant NSCLC represents a distinct molecular subset with available targeted therapies including KRAS G12C inhibitors (sotorasib, adagrasib, garsorasib) and emerging KRAS G12D inhibitors (HRS-4642, MRTX-1133)^[190,191]. Comparative analysis of 4,017 targetable genomic alteration-positive NSCLC samples revealed that KRAS-mutant tumors exhibit higher TMB (median 7.8 mut/Mb, n = 2,240), increased PD-L1 expression, and greater TIL levels vs. EGFR-mutant or ALK-fusion patients. Further analysis of 231 surgical specimens demonstrated KRAS-mutant tumors had enhanced T-cell infiltration (P = 0.003) and higher PD-L1+/TIL+ co-positivity rates (P = 0.007) compared to KRAS wild-type tumors, indicating KRAS mutations correlate with heightened tumor immunogenicity and an inflammatory microenvironment that may confer potential benefit from ICIs^[192]. Multiple clinical and retrospective studies have demonstrated that KRAS-mutated patients can benefit from ICIs monotherapy or in combination with chemotherapy. Clinical evidence from trials including IMpower150, KEYNOTE-189, and KEYNOTE-042 support the efficacy of first-line ICIs in KRAS-mutated NSCLC^[193-195]. The CheckMate 057 (n = 62) and OAK (n = 59) trials specifically showed ICI monotherapy improved OS vs. docetaxel in previously treated KRAS-mutant NSCLC^{[110,192,196]}.

Current treatment paradigms for KRAS-mutant NSCLC primarily incorporate immunotherapy-based approaches, either as monotherapy or combined with chemotherapy, with emerging evidence suggesting KRAS mutational status significantly influences therapeutic outcomes. A retrospective analysis by Amanam et al. involving 60 NSCLC patients (87% stage IV adenocarcinoma, 78% KRAS exon 12 mutations) demonstrated numerically improved median OS in the immunotherapy-treated subgroup (33 vs. 22 months, P = 0.31)^[197]. However, the relationship between KRAS mutations and immunotherapy response is complex as highlighted by Dong et al.^[198]. KRAS mutations coexpressed with other types of gene mutations may affect the efficacy of immunotherapy.

Specifically, KRAS frequently co-occurs with TP53 or STK11 mutations in lung adenocarcinoma, creating distinct biological and clinical phenotypes.

KRAS/TP53 co-mutated tumors exhibit elevated PD-L1 expression and may benefit from anti-PD-1 therapy (ORR ~ 30%). Conversely, when KRAS co-mutates with STK11, the efficacy of immunotherapy may be suboptimal^[199]. A retrospective study analyzed the outcomes of immunotherapy in 174 patients with KRAS-mutated lung adenocarcinoma. The findings indicated that patients with only KRAS mutations had better responses to immunotherapy. Patients with KRAS/TP53 co-mutations had the greatest OS benefit (with an ORR of approximately 30%), while those with KRAS/STK11 co-mutations had the least benefit^[200]. This suggests that KRAS/TP53 co-mutation may serve as a potential predictive biomarker for guiding immunotherapy. Additionally, STK11 plays a crucial role in cellular metabolism, growth, and the regulation of cell polarity. STK11 mutations are associated with the formation of an immunologically “cold” TME. Clinical data demonstrate KRAS/STK11 co-mutated adenocarcinoma have shorter PFS and OS following ICIs vs. STK11 wild-type^[201]. Animal studies further confirmed that STK11 deficiency promotes resistance to PD-1/PD-L1 inhibitors. Ricciuti et al.^[202] and Jeong et al.^[203] also demonstrated that STK11 mutations are associated with poorer outcomes in immunotherapy for KRAS-mutated lung adenocarcinoma. Moreover, KRAS mutations encompass multiple subtypes, and the correlation between each subtype and immunotherapy efficacy is inconsistent. Further advancements in basic and clinical research are anticipated to elucidate these relationships.

In summary, the relationship between KRAS mutations and the PD-1 signaling pathway in NSCLC is complex. Most scholars currently believe that KRAS-mutated NSCLC have higher PD-L1 expression levels and they may derive better outcomes from immunotherapy compared to KRAS wild-type NSCLC. This suggests that KRAS mutations could be an important predictive biomarker for immunotherapy in NSCLC. Optimal treatment selection should involve comprehensive genomic profiling and multidisciplinary evaluation to integrate molecular findings with clinical factors, particularly for patients with STK11 co-mutations or other biomarkers of immunosuppression. As the understanding of KRAS biology evolves, ongoing clinical trials are expected to further refine precision immunotherapy approaches for this molecular subset.

BRAF alterations (including mutations, deletions, and fusions) occur in 1%-5% of NSCLC cases and are classified into three functional categories based on their signaling mechanisms and kinase activity: Class I (V600D/E/K/R mutations with monomeric kinase activity, where V600E accounts for > 90% of V600 variants); Class II (G464E/V/R, G469A/V/S, L597Q/R/S/V mutations with dimer-independent kinase activity; and Class III (impaired kinase activity mutations that signal through C-RAF dimerization).

While targeted therapies have demonstrated efficacy for Class I BRAF mutations, no prospective studies have specifically evaluated immunotherapy in BRAF-mutant NSCLC. Notably, BRAF mutations, particularly BRAF non-V600 mutations, are associated with elevated TMB and PD-L1 expression^[157]. Several retrospective studies have suggested that these patients may benefit from ICIs^[204-206]. For BRAF V600E-mutant patients, clinical trials including NCT01336634 and PHAROS support first-line use of BRAF/MEK inhibitor combinations (dabrafenib plus trametinib or encorafenib plus binimetinib)^[207,208]. Upon disease progression, MDT consultation is recommended to guide subsequent therapy, which may follow treatment guidelines for NSCLC without targetable genomic alterations. For BRAF non-V600 mutations, where neither targeted therapies nor immunotherapies have been prospectively evaluated, treatment decisions should be made through MDT discussion may consider referring to therapeutic strategies for advanced NSCLC without targetable genomic alterations.

HER2 (Human Epidermal Growth Factor Receptor 2) alterations primarily include HER2 mutations (1.6%-3%), gene amplifications (2%-4%), and protein overexpression (7.7%-15.4%). While no targeted therapies are currently approved for HER2-altered NSCLC, the FDA granted approval in August 2022 to trastuzumab deruxtecan (T-DXd, DS-8201) for previously treated HER2-mutant cases based on Phase II trial results demonstrating an ORR of 55%, a median PFS of 8.2 months, and a median OS of 17.8 months^[153]. Notably, DS8201 has not yet been approved for NSCLC indications in China.

HER2-mutant tumors exhibit high immunogenicity with complex, heterogeneous TME^[209]. While several small retrospective studies suggest that HER2-mutant NSCLC may benefit from ICIs-based treatment strategies, prospective studies with more robust evidence is needed to validate the conclusion^[173]. ccording to the 2024 NCCN guidelines, for HER2-mutant NSCLC, we recommend referring to the treatment strategies for stage IV NSCLC without targetable genomic alterations, while incorporating MDT consultations to optimize therapeutic decision-making^[171].

NeuroTrophin Receptor Kinase (NTRK), a member of the tyrosine receptor kinase family, comprises NTRK1, NTRK2, and NTRK3 genes, which encode TRKA, TRKB, and TRKC proteins respectively^[152]. NTRK gene fusions, occurring in less than 5% of NSCLC cases, represent a rare but clinically important molecular subset due to their remarkable sensitivity to targeted therapies^[210,211]. The fusion partners are highly diverse, and NTRK fusions are mutually exclusive with other major targetable genomic alterations^[212]. Currently, entrectinib and larotrectinib constitute first-line standard of care for NTRK fusion-positive NSCLC based on their demonstrated efficacy, though detection challenges persist given the complexity of NTRK fusion identification^[212,213].

The immunological characteristics and responsiveness to immunotherapy in this population remain poorly defined due to extreme rarity, with available evidence limited to case reports and small series. Dudnik et al. reported limited activity of ICIs in two NTRK-mutant patients (median PFS NR [range 3.2-NR] and the OS from diagnosis was only 4.8 months)^[214]. Zhang et al. described one patient with an NCOR2-NTRK1 fusion who had high TMB (58.58 mut/Mb) and PD-L1 expression (20%-0%). The patient progressed on first-line camrelizumab but achieved significant tumor shrinkage and eventual disappearance of lesions after switching to larotrectinib^[215]. The retrospective analysis by Rosen et al. (n = 76, across 17 tumor types) demonstrated modest efficacy of non-TRK inhibitor therapies (median PFS 9.6 months), with chemotherapy showing superior activity (ORR 63%) compared to ICIs, Notably, among 12 patients treated with ICIs, only one with MSI-H colorectal cancer responded^[216]. Gatalica et al. suggested that TRK inhibitors alone or in combination with ICIs could be a viable treatment option^[217]. Suh et al. found that larotrectinib may offer substantial gains in life expectancy and quality-adjusted life years (QALY) compared to ICIs^[218].

Given this evidence, targeted therapy remains the first-line recommendation for patients with NTRK fusions. In cases where targeted therapies are unavailable or resistance develops, MDT consultation is recommended and treatment strategies should follow the guidelines for stage IV NSCLC without targetable genomic alterations, as outlined in the 2024 NCCN guidelines^[218]. Following comprehensive MDT discussion, immunotherapy combined with chemotherapy may be considered cautiously as part of antitumor strategy.

Neuregulin 1 (NRG1), a neuroregulatory growth factor capable of binding HER3 and HER4 to activate the ErbB signaling pathway, belongs to the EGF ligand family and represents a rare molecular target. The incidence of NRG1 fusions in NSCLC is 0.3%, with a rate of 0.26% in lung adenocarcinoma and 0.21% in squamous cell carcinoma. Notably, in mucinous adenocarcinoma (a rare subtype of lung adenocarcinoma), the incidence of NRG1 fusions is significantly higher, reaching up to 7%^[213]. Current targeted therapies under investigation for advanced pan-cancer NRG1 fusions include afatinib, pyrotinib, zenocutuzumab (MCLA-128), and seribantumab, with preliminary data showing promising efficacy^[219].

Zenocutuzumab (MCLA-128), a bispecific antibody targeting HER2 and HER3, has demonstrated an ORR of 34%, with tumor shrinkage observed in up to 70% of patients and a median DOR of 14.9 months (95% CI: 7.4-20.4). The 12-month DOR rate was 57% (95% CI: 34-75%)^[220]. The immunological characteristics of NRG1 fusion-positive tumors appear unfavorable for immunotherapy, as evidenced by a global retrospective study (n = 110) reporting low PD-L1 expression (median 28%) and TMB (median 0.9 mut/Mb), with correspondingly poor outcomes to ICIs (median PFS 3.3 months) or chemoimmunotherapy combinations (median PFS 3.6 months)^[221].

In summary, for NRG1 fusion NSCLC, EGFR/HER2-TKIs (e.g. afatinib, pyrotinib, neratinib, tarloxitinib) or HER2/HER3-targeted monoclonal antibodies/ADCs (e.g. trastuzumab, margetuximab) are recommended. If targeted therapies are unavailable, treatment strategies should follow the guidelines for stage IV NSCLC without targetable genomic alterations, as outlined in the 2024 NCCN guidelines^[171].

The fibroblast growth factor receptor (FGFR) family, comprising FGFR1-4, represents a subfamily of transmembrane tyrosine kinase receptors implicated in various malignancies, including lung squamous cell carcinoma, urothelial carcinoma, and breast cancer. FGFR aberrations predominantly manifest as amplifications (most commonly FGFR1 and FGFR4), followed by mutations, rearrangements, and fusions, with FGFR1 amplifications occurring in approximately 22% of lung squamous cell carcinomas compared to only 3% of adenocarcinomas, where they may correlate with prolonged survival^[222,223]. Although FGFR inhibitors (e.g., erdafitinib, pemigatinib, futibatinib, infigratinib) have demonstrated efficacy in FGFR-altered urothelial carcinoma and cholangiocarcinoma, none are currently approved for lung cancer, despite emerging signals of activity - such as pemigatinib’s promising response rates in lung cancer cohorts within pan-solid tumor trials^[224]. The relationship between FGFR alterations and ICI efficacy remains controversial, with conflicting evidence across tumor types. While FGFR alterations in gastric cancer, melanoma, and NSCLC have been associated with enhanced ICI responses in some studies, others report inferior outcomes, including shorter OS in FGFR-altered melanoma and urothelial carcinoma treated with PD-1 inhibitors^[225-229]. Notably, a study of 240 NSCLC patients revealed that FGFR4 alterations correlated with significantly improved ORR (50.0% vs. 19.4%; P = 0.057) and median PFS (13.17 vs. 3.17 months; P = 0.04) following PD-1/PD-L1 inhibition compared to wild-type counterparts^[230]. Preclinical data suggest that combining FGFR inhibitors with ICIs may enhance antitumor immunity by increasing T-cell infiltration and inducing immunogenic cell death^[231,232], though the clinical applicability of these findings requires further validation.

Given the current lack of definitive evidence supporting FGFR-directed therapies in lung cancer, the 2024 NCCN guidelines recommend managing advanced FGFR-altered NSCLC according to strategies for advanced NSCLC without targetable genomic alterations, with ongoing clinical trials expected to clarify the therapeutic potential of FGFR inhibition - either alone or in combination with immunotherapy - in this molecular subset^[171].

Recommendations for immunotherapy in NSCLC with targetable genomic alterations are shown in Table 8. Clinical trials related to NSCLC are listed in Supplementary Table 1.