Four-year outcomes with perioperative toripalimab plus chemotherapy in resectable stage III non-small cell lung cancer (NeoTAP01 study)

Introduction

According to the cancer statistics reported in 2022, lung cancer remains the leading cause of cancer-related death worldwide, and non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancer types (1,2). Different from the early-stage or late-stage NSCLC, which is mainly treated by radical surgery or palliative therapy, stage III NSCLC is a highly heterogeneous disease with a range of treatment options, determined by resectability, nodal extent, and molecular characteristics (3-5).

In the past few years, several trials have demonstrated that neoadjuvant immunotherapy in combination with platinum-based doublet chemotherapy is a promising treatment for resectable stage III NSCLC with negative driver mutations (6-8), which achieves unexpected effectiveness in tumor regression and nodal downstage. The pathologic complete response (pCR) rate and major pathologic response (MPR) rate vary from 18% to 41%, and 33% to 83%, respectively (6,9). The meta-analysis which included 43 eligible trials comprising 5,431 patients further indicates that pooled event-free survival (EFS) [hazard ratio (HR), 0.59; 95% confidence interval (CI): 0.52–0.67], and overall survival (OS) (HR, 0.65; 95% CI: 0.54–0.79) favor neoadjuvant chemoimmunotherapy over neoadjuvant chemotherapy (9). However, most of these trials have only limited follow-up duration and few of them report long-term outcomes over three years. Besides, immunotherapy-based adjuvant treatment is absent in the majority of earlier trials.

NeoTAP01 study, which is the leading trial of perioperative immunotherapy focused on resectable stage III NSCLC in Asia, firstly published the primary analysis in 2021 and proved the safety and feasibility (10). Besides, this trial prospectively designed the adjuvant toripalimab monotherapy, which is in accordance with current recommendations. In this report, we updated the 4-year follow-up results of NeoTAP01 study to confirm the long-term benefits of neoadjuvant chemoimmunotherapy in resectable stage III NSCLC patients, and analyzed the risk factors of recurrence or death from the aspects of pathological and genomic features. We present this article in accordance with the TREND reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2266/rc) (11,12).

Methods

Patient selection

Patients who were of at least 18 years of age, and diagnosed as resectable stage IIIA or T3–4N2 IIIB NSCLC [American Joint Committee on Cancer (AJCC) 8^th edition] (13) by multidisciplinary team, were eligible. All participants should have a measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (14,15). The evaluation of lymph nodes staging at baseline was determined via endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) or mediastinoscopy for clinically suspicious N2 patients. Genomic sequencing was essential for patients with adenocarcinoma, and those with EGFR exon 19 deletion (Ex19del) or L858R point mutation in exon 21, EML4-ALK mutation, or ROS1 mutation were excluded. Patients who had contraindications for immune checkpoint inhibitors, such as autoimmune diseases, or medication history of corticosteroid or other immunosuppressive treatment were also excluded. Eastern Cooperative Oncology Group (ECOG) performance status score should be 0 or 1. Additional eligibility criteria were listed in study protocol (appendix available at https://cdn.amegroups.cn/static/public/jtd-2024-2266-1.pdf).

Trial design, treatment, and end points

NeoTAP01 trial was an open-label, single-arm, phase II study conducted at Sun Yat-sen University Cancer Center. This clinical trial and post hoc analyses were pre-registered in ClinicalTrials.gov (NCT04304248), and the conductions were completely complied with the requirement in People’s Republic of China and abroad. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was acquired from the institutional review board of Sun Yat-sen University Cancer Center (No. 2019-FXY-084), and informed written consent was obtained from each participant prior to the enrollment.

Enrolled patients were assigned to receive three cycles of neoadjuvant treatment with intravenous toripalimab (240 mg), carboplatin (area under the curve 5), and pemetrexed (500 mg/m² for adenocarcinoma) or nab-paclitaxel (260 mg/m² for other subtypes) every 3 weeks (21 days). The clinical staging was re-evaluated by computed tomography (CT) or positron emission tomography (PET)/CT at 4 weeks after the last dose, and patients without N3 station and distant metastasis were regarded as being suitable for radical resection. Thoracotomy, video-assisted thoracoscopic surgery (VATS), or robot-assisted thoracoscopic surgery (RATS) was optional according to the preference of surgeons. Adjuvant toripalimab monotherapy was recommended for all resected patients, which began from 4 to 8 weeks after surgery, and a total of 12 cycles of adjuvant treatment were planned.

Primary endpoint was the MPR rate and secondary endpoints included the pCR rate, radical resection rate, EFS rate, OS rate, and safety. All outcomes were analyzed in both modified intention-to-treat (mITT) population, which involved patients who received at least one cycle of neoadjuvant treatment; and per-protocol (PP) population, which included the surgery cohort in the mITT population.

Outcomes assessments

The pre-treatment and pre-operation clinical staging were performed at 3 weeks before first dose of neoadjuvant treatment and 4 weeks after the last dose, respectively. The radiographic characteristics were evaluated by enhanced CT or PET/CT and reported according to RECIST guideline (version 1.1). Lymph nodes with enlargement (shortest diameter ≥10 mm) and/or elevated maximum standardized uptake value (SUVmax) were regarded as clinical metastasis. The methods of pathologically-confirmed N staging at baseline were mentioned above. In the post-operative period, enhanced CT was conducted every 3 months in the first 2 years, every 6 months in the following 3 years, and every 12 months afterward. EFS was defined as the time from enrollment until the date of first recurrence or death from any cause, OS as the time from enrollment until the date of death from any cause. For patients without any event, follow-up was censored at the latest disease evaluation performed according to the protocol.

Next-generation sequencing (NGS) or gene panel was compulsively conducted in all patients diagnosed with adenocarcinoma, and recommended for patients with other subtypes. Programmed cell death-ligand 1 (PD-L1) expression level was assessed by the pre-treatment biopsy of tumor tissue, using the Dako PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay, to calculate the tumor proportion score (TPS). The pathological assessment of the resected samples was followed by the IASLC neoadjuvant pathology recommendations, and the percentage of residual viable tumor (RVT) in the primary site was specified to report. pCR and MPR were defined as 0% and ≤10% RVT, respectively (16).

Treatment-related adverse events (TRAEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) guideline (version 4.0), and the adverse events caused by immunochemotherapy or surgery were recorded separately.

Statistical analysis

The sample size calculation followed the Simon’s optimal two-stage design, which assumed that the addition of toripalimab on the basis of chemotherapy in the neoadjuvant treatment would improve 25% of MPR rate from 20%. Therefore, 18 patients were about to enroll in the first stage, and only when more than four patients reached MPR outcome in the first cohort would allow the additional enrollment of the other 12 patients. Median and interquartile range (IQR) were used to present continuous variables with non-normal distributions. Categorical variables were described by frequencies and percentages. EFS and OS were estimated by Kaplan-Meier (K-M) method and log-rank test. The median follow-up and its IQR were calculated by reverse K-M method. Univariate and multivariate Cox regressions were used to analyze risk factors of follow-up outcomes. Firth’s penalized maximum likelihood bias reduction method was applied for Cox regression to optimize the cases of monotone likelihood.

For the post hoc analyses, comparisons were designed to perform between the following subgroups: histology, nodal status at diagnosis, PD-L1 expression, pCR, and MPR. Differences were analyzed by Chi-squared or Fisher exact test for categorical variables, and odds ratio (OR) and corresponding 95% CIs were performed for EFS and OS. Type I and type II error were set to 0.05 (two-sided) and 0.2. Statistical analyses were conducted by SPSS (version 22.0) and visualization was performed by R Statistical Software (version 4.2.2).

Results

Study population

From August 2019 through July 2020, a total of 33 patients were prospectively recruited from Sun Yat-sen University Cancer Center. All the participants accorded with the filtration criteria of the mITT population. Of those, 18 (54.5%) were squamous cell carcinoma, 13 (39.4%) were adenocarcinoma, and 2 (6.1%) were lymphoid epithelial-like carcinoma (LELC). For the baseline clinical staging, 20 (60.6%) patients were stage IIIA, and the other 13 (39.4%) were stage IIIB. Especially, among the 25 (75.8%) patients who diagnosed as clinical N2 metastasis, 10 underwent mediastinoscopy, 12 underwent EBUS-TBNA, and the other three were defined by PET/CT. As previously reported, 3 patients refused to received operation due to disease progression or Guillain-Barre syndrome in the period of neoadjuvant treatment. For the 30 patients who underwent definitive resection, sociodemographic and clinicopathological characteristics were listed (Table 1). The pCR and MPR rates were 45.5% and 60.6% in the mITT population, and 50.0% and 66.7% in the PP population. Lymph node clearance was observed in 70% (21/30) patients in the PP population. For the distribution of pathological staging revised by surgery, six were stage I, one was stage II, eight remained stage III, and the other reached pCR. The last patient received neoadjuvant treatment in January 2021. The median follow-up of the mITT cohort was 4.3 years (95% CI: 3.89–4.72).

Recurrence outcomes

In the mITT population, the EFS rate at 4 years was 63.6% (21/33; 95% CI: 46.6–77.8), with two experienced disease progression, nine experienced recurrence or metastasis, and one died. The EFS rate in the PP population was 66.7% (20/30; 95% CI: 48.8–80.8) (Figure S1A,S1B). The multivariate and univariate Cox regression further indicated that pCR was the protective factor against recurrence. The HR for presence of pCR was in the direction of improved EFS (HR, 0.09; 95% CI: 0.01–0.76; P=0.02; Figure 1). The MPR status (HR, 0.33; 95% CI: 0.09–1.24; P=0.10), squamous cell carcinoma (HR, 0.58; 95% CI: 0.22–1.55; P=0.28), PD-L1 TPS ≥1% (HR, 0.71; 95% CI: 0.13–3.86; P=0.69), VATS (HR, 0.85; 95% CI: 0.18–4.11; P=0.85), and adjuvant treatment (HR, 0.89; 95% CI: 0.33–5.98; P=0.55) trended toward improved EFS, but the statistical significance was not reached (Table S1).

Figure 1 EFS in the PP population. The K-M estimates of EFS for the patients with or without pCR in the PP population. CI, confidence interval; EFS, event-free survival; K-M, Kaplan-Meier; NR, not reached; pCR, pathologic complete response; PP, per-protocol.

We further analyzed the impact of baseline N staging on recurrence and metastasis. As our expected, patients without mediastinal lymph nodes metastasis (cN0 or cN1) had better EFS outcomes (HR, 0.45; 95% CI: 0.28–17.79; P=0.45), while no statistical significance was founded, according to the AJCC 9^th cancer staging system which suggested to divide N2 staging by single (N2a) or multiple stations (N2b) metastasis, we also explored the association between N2a/N2b and recurrence risk to validate its value in predicting survival benefits in neoadjuvant immunotherapy cohort. Among 24 patients diagnosed as cN2 in the PP cohort, 18 were defined as multiple stations metastasis, and the other six were single station metastasis. However, no EFS difference was observed between baseline N2a and N2b (HR, 1.08; 95% CI: 0.22–5.34; P=0.93).

Recurrence patterns

Of those 10 patients that experienced recurrence or metastasis within the follow-up period in the PP population, one was bone metastasis, and eight were intrathoracic recurrence, with five found N3 station lymph nodes metastasis and three found contralateral lung metastasis. The other one patient reached pCR but died at 7 months after surgery without cancer recurrence, which was secondary to a heart attack (Table 2).

In the PP population, 27 (90%) patients received adjuvant treatment, and the other three patients chose not to receive individually because of complete or MPR status. However, adjuvant treatment was not observed as a protective factor for whether pCR, MPR, or non-MPR pathologic response status. Specifically, two patients that reached pCR and missed adjuvant treatment still remained event-free (Figure 2).

Figure 2 Recurrence patterns in the PP population. Swimmer plot summarizes the follow-up and recurrence details for patients with or without pCR. pCR, pathologic complete response; PP, per-protocol.

Although all the adenocarcinoma cases had tumor genetic testing before enrollment, there were three patients confirmed with classical EGFR mutation (L858R or Ex19del) by re-analyzing the postoperative tumor samples, and all of them received osimertinib as adjuvant therapy instead of immunotherapy. Besides, one patient was with dual drive coexistence of EML4-ALK rearrangement and KRAS mutation, and received alectinib after surgery. For these four patients combined with driver gene mutations, two patients experienced recurrence, with one patient having EGFR Ex19del and one having ALK rearrangement. In addition, three patients who had non-classical EGFR mutations (exon 6, 17, and 18) were also observed disease-related events within 3 years after surgery. As known negative immune regulators, KEAP1 and STK11 were found in two non-MPR patients respectively, but recurrence or death was not observed at the time of analysis.

Survival and adverse effects outcomes

The 4-year OS rate was 81.8% (27/33; 95% CI: 65.6–91.4%) and 83.3% (25/30; 95% CI: 66.4–92.7%) in the mITT and PP population, respectively (Figure S2A,S2B). Of those six patients, five died of tumor progression, and one died of immunotherapy-related pneumonitis or infectious pneumonia. For those patients who reached pCR, OS benefit was not observed yet (HR, 0.67; 95% CI: 0.11–3.99; P=0.66) (Figure S3). The multivariate and univariate Cox regression further indicated that age, sex, pretreatment clinical stage, MPR, PD-L1 TPS level, tumor histology, surgical approaches, baseline N staging, and adjuvant treatment were not associated with survival outcomes (Table S2).

The TRAEs happened during the perioperative period were reported previously. In the following-up period of adjuvant treatment, three patients who received mono-immunotherapy experienced grade three pneumonitis. However, considering that the coronavirus disease 2019 (COVID-19) pandemic happened during the same period, whether the pneumonitis was caused by immunotherapy or infection was uncleared. No other grade 3–5 events were observed in long-term follow-up.

Discussion

This is one of the few perioperative immunotherapy trials that report the long-term outcomes in the population of resectable stage III NSCLC patients. In this 4-year analysis of NeoTAP01 trial, we concluded that perioperative toripalimab led to favorable clinical outcomes, with 4-year EFS rate of 66.7% and 4-year OS rate of 83.3% in the PP population. Post hoc analysis further indicated the protective and risk factors for the survival benefits of perioperative immunotherapy. In consideration of the paucity of long-term follow-up data, this 4-year analysis provides valuable details and key insights for clinical practice, especially in stage III NSCLC patients.

Before the era of immunotherapy, the standard treatment for resectable stage III NSCLC patients was surgery and adjuvant chemotherapy. However, according to the KINDLE study, which retrospectively collected 3,151 patients with stage III NSCLC (AJCC 7^th edition) and received different treatment strategies, subgroup analysis of resectable patients who received surgery and chemotherapy reported that the median progression-free survival (mPFS) and median OS were only 20.2 and 57.9 months, respectively (17). In addition, although neoadjuvant chemotherapy or adjuvant chemotherapy improved the mPFS, difference in OS was not observed (9). With the help of anti-programmed cell death-1 (PD-1)/PD-L1 inhibitors, the efficacy of adjuvant immunotherapy had proved robust benefits in disease-free survival (DFS) and OS. In the analysis of stage IIIA NSCLC patients from IMpower010 trial, the HR values of DFS in PD-L1 expression percentage of tumor cells (TCs) ≥1% subgroup and PD-L1 TC ≥50% subgroup were 0.66 and 0.42, and both of them reached statistical significances (18). However, DFS and OS benefits in PD-L1 TC 1–49% subgroup were still not observed. At present, the first-line recommended treatment for resectable stage III NSCLC patients had swapped to neoadjuvant or perioperative immunotherapy (19). As the first phase III randomized clinical trial (RCT) that evaluated the effectiveness of neoadjuvant immunotherapy in resectable NSCLC, the 4-year EFS and OS both presented significant benefits in CheckMate-816 (7). Perioperative immunotherapy showed similar trends of benefits. CheckMate-671 and NADIM study both demonstrated encouraging EFS and OS outcomes in long-term follow-up (20,21). In accordance with the trials mentioned above, the 4-year EFS and OS data of NeoTAP01 study further confirmed the clinical benefits of perioperative immunotherapy in resectable stage III NSCLC patients, especially in patients with multiple N2 station metastasis.

Although mono-immunotherapy after surgery is widely accepted in current treatment guidelines, its benefits in patients with different clinical characteristics such as stage, pathologic response status, and genomic mutations landscapes still need further analysis. A patient-level analysis that compared perioperative and neoadjuvant therapy observed landmark EFS benefit in perioperative immunotherapy group whether with PD-L1 <1% or ≥1% across clinical stages (IB/II or III) (22). However, the HR value in stage III subgroup of this retrospective study didn’t show statistical significance, which is consistent with the regressions analyses results of NeoTAP01 study that adjuvant immunotherapy couldn’t improve the recurrence or survival outcomes.

In addition to clinical stage, pathologic response levels were another critical factor to instruct adjuvant treatment. Zhao et al. recently proved that adjuvant immunotherapy could not improve survival in NSCLC patients who received neoadjuvant immunotherapy and reached pCR or MPR (23), while pCR subgroup in NeoTAP01 study also experienced better survival outcomes whether received adjuvant treatment or not. Unfortunately, for those eight patients who did not reach pCR or MPR and receive adjuvant immunotherapy, 75% (6/8) experienced recurrence during the period of adjuvant treatment. This result indicated that adjuvant immunotherapy may not reduce the recurrence risk, especially for non-MPR stage III NSCLC patients. Besides, grade 3 pneumonitis was observed in three cases during the adjuvant therapy period and were regarded as immunotherapy-related. Considering that stage III NSCLC patients mostly had multiple lymph node stations metastasis at baseline diagnosis (24), it is necessary to re-evaluate the definition of pCR and MPR, and its role in the prediction of adjuvant therapy effectiveness. Molecular biomarkers, such as minimal residual disease (MRD) should be conducted to better assess the tumor regression and clearance level, and to predict the benefit of adjuvant therapy (25,26).

The exploratory analysis among genome mutations, recurrence, and adjuvant treatment showed that the acknowledged negative immune regulators (STK11/LKB1 and KEAP1) could not effectively predict the benefit of adjuvant therapy. As previously reported, inactivation of STK11/LKB1 was associated with reduced infiltration of effector T cells, and patients with STK11-deficient tumor had worse survival benefit when receiving immune checkpoint inhibitor (27). KEAP1 loss-of function could activate NRF2 and also disrupt the efficacy of immunotherapy (28). However, the prediction value of these genes in the efficacy of adjuvant immunotherapy was still absent. In consideration that those patients had already undergone definitive resection and the tumor microenvironment was removed, tumor-specific gene mutation therefore could not effectively elucidate the differences of adjuvant therapy efficacy. Interestingly, this trial had involved three patients with non-classical EGFR mutations, with two cases reported non-MPR recurrence. Although there is no recommendation for patients with non-classical driver mutations to receive neoadjuvant targeted therapy (29), the benefit of perioperative immunotherapy should also be re-considered (30).

Conclusions

The 4-year analysis of perioperative toripalimab plus chemotherapy in resectable stage III NSCLC demonstrated a long-term sustained improvement of EFS and OS. However, the effectiveness of adjuvant immunotherapy in non-pCR patients is still limited and further therapeutic measures and prediction biomarkers should be developed in the future.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2266/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2266/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2266/prf

Funding: This work was supported by the Development Center for Medical Science & Technology National Health Commission of the People’s Republic of China (to H.L.) (No. WKZX2023CX020006).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2266/coif). H.L. reports the funding from the Development Center for Medical Science & Technology National Health Commission of the People’s Republic of China (No. WKZX2023CX020006). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was acquired from the institutional review board of Sun Yat-sen University Cancer Center (No. 2019-FXY-084), and informed written consent was obtained from each participant prior to the enrollment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent 2024;4:47-53. [Crossref] [PubMed]
2. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024;74:12-49. [Crossref] [PubMed]
3. Banna GL, Addeo A. Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. N Engl J Med 2024;391:1555. [Crossref] [PubMed]
4. Gray JE, Villegas A, Daniel D, et al. Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC-Update from PACIFIC. J Thorac Oncol 2020;15:288-93. [Crossref] [PubMed]
5. Guan S, Sun J, Wang Y, et al. Chemoradiotherapy versus surgery after neoadjuvant chemoimmunotherapy in patients with stage III NSCLC: a real-world multicenter retrospective study. Cancer Immunol Immunother 2024;73:120. [Crossref] [PubMed]
6. Cascone T, Awad MM, Spicer JD, et al. Perioperative Nivolumab in Resectable Lung Cancer. N Engl J Med 2024;390:1756-69. [Crossref] [PubMed]
7. Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med 2022;386:1973-85. [Crossref] [PubMed]
8. Provencio M, Nadal E, González-Larriba JL, et al. Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:504-13. [Crossref] [PubMed]
9. Sorin M, Prosty C, Ghaleb L, et al. Neoadjuvant Chemoimmunotherapy for NSCLC: A Systematic Review and Meta-Analysis. JAMA Oncol 2024;10:621-33. [Crossref] [PubMed]
10. Zhao ZR, Yang CP, Chen S, et al. Phase 2 trial of neoadjuvant toripalimab with chemotherapy for resectable stage III non-small-cell lung cancer. Oncoimmunology 2021;10:1996000. [Crossref] [PubMed]
11. Haynes AB, Haukoos JS, Dimick JB. TREND Reporting Guidelines for Nonrandomized/Quasi-Experimental Study Designs. JAMA Surg 2021;156:879-80. [Crossref] [PubMed]
12. Des Jarlais DC, Lyles C, Crepaz N, et al. Improving the reporting quality of nonrandomized evaluations of behavioral and public health interventions: the TREND statement. Am J Public Health 2004;94:361-6. [Crossref] [PubMed]
13. Detterbeck FC, Boffa DJ, Kim AW, et al. The Eighth Edition Lung Cancer Stage Classification. Chest 2017;151:193-203.
14. Schwartz LH, Litière S, de Vries E, et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer 2016;62:132-7. [Crossref] [PubMed]
15. Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18:e143-52. [Crossref] [PubMed]
16. Travis WD, Dacic S, Wistuba I, et al. IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens After Neoadjuvant Therapy. J Thorac Oncol 2020;15:709-40. [Crossref] [PubMed]
17. Jazieh AR, Onal HC, Tan DSW, et al. Real-World Treatment Patterns and Clinical Outcomes in Patients With Stage III NSCLC: Results of KINDLE, a Multicountry Observational Study. J Thorac Oncol 2021;16:1733-44. [Crossref] [PubMed]
18. Felip E, Altorki N, Zhou C, et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol 2023;34:907-19. [Crossref] [PubMed]
19. Riely GJ, Wood DE, Ettinger DS, et al. Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2024;22:249-74. [Crossref] [PubMed]
20. Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med 2023;389:491-503. [Crossref] [PubMed]
21. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol 2020;21:1413-22. [Crossref] [PubMed]
22. Forde PM, Peters S, Donington J, et al. PL02.08 perioperative vs neoadjuvant nivolumab for resectable NSCLC: patient-level data analysis of CheckMate 77T vs CheckMate 816. J Thorac Oncol 2024;19:S2.
23. Zhao ZR, Yan WP, Yu XY, et al. Adjuvant immunotherapy does not improve survival in non-small cell lung cancer with major/complete pathologic response after induction immunotherapy. J Thorac Cardiovasc Surg 2024; Epub ahead of print. [Crossref]
24. Rajaram R, Huang Q, Li RZ, et al. Recurrence-Free Survival in Patients With Surgically Resected Non-Small Cell Lung Cancer: A Systematic Literature Review and Meta-Analysis. Chest 2024;165:1260-70. [Crossref] [PubMed]
25. Xia L, Mei J, Kang R, et al. Perioperative ctDNA-Based Molecular Residual Disease Detection for Non-Small Cell Lung Cancer: A Prospective Multicenter Cohort Study (LUNGCA-1). Clin Cancer Res 2022;28:3308-17. [Crossref] [PubMed]
26. Zhang JT, Liu SY, Gao W, et al. Longitudinal Undetectable Molecular Residual Disease Defines Potentially Cured Population in Localized Non-Small Cell Lung Cancer. Cancer Discov 2022;12:1690-701. [Crossref] [PubMed]
27. Li A, Wang Y, Yu Z, et al. STK11/LKB1-Deficient Phenotype Rather Than Mutation Diminishes Immunotherapy Efficacy and Represents STING/Type I Interferon/CD8(+) T-Cell Dysfunction in NSCLC. J Thorac Oncol 2023;18:1714-30. [Crossref] [PubMed]
28. Romero R, Sánchez-Rivera FJ, Westcott PMK, et al. Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1. Nat Cancer 2020;1:589-602. [Crossref] [PubMed]
29. Zhou F, Guo H, Xia Y, et al. The changing treatment landscape of EGFR-mutant non-small-cell lung cancer. Nat Rev Clin Oncol 2025;22:95-116. [Crossref] [PubMed]
30. Robichaux JP, Le X, Vijayan RSK, et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature 2021;597:732-7. [Crossref] [PubMed]