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Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy of neoadjuvant ICIs remains unclear. We report the influence of AGAs on treatment failure (TF) in patients with resectable NSCLC treated with neoadjuvant ICIs., Methods: Tumor molecular profiles were obtained from patients with stage I-IIIA resectable NSCLC (American Joint Committee on Cancer seventh edition) treated with either neoadjuvant nivolumab (N, n=23) or nivolumab+ipilimumab (NI, n=21) followed by surgery in a previously reported phase-2 randomized study (NCT03158129). TF was defined as any progression of primary lung cancer after neoadjuvant ICI therapy in patients without surgery, radiographic and/or biopsy-proven primary lung cancer recurrence after surgery, or death from possibly treatment-related complications or from primary lung cancer since randomization. Tumors with AGAs (n=12) were compared with tumors without AGAs and non-profiled squamous cell carcinomas (non-AGAs+NP SCC, n=20)., Results: With a median follow-up of 60.2 months, the overall TF rate was 34.1% (15/44). Tumor molecular profiling was retrospectively obtained in 47.7% (21/44) of patients and select AGAs were identified in 12 patients: 5 epidermal growth factor receptor (EGFR) , 2 KRAS , 1 ERBB2 , and 1 BRAF mutations, 2 anaplastic lymphoma kinase (ALK) and 1 RET fusions. The median time to TF in patients with AGAs was 24.7 months (95% CI: 12.6 to 40.4), compared with not reached (95% CI: not evaluable (NE)-NE) in the non-AGAs+NP SCC group. The TF risk was higher in AGAs (HR: 5.51, 95% CI: 1.68 to 18.1), and lower in former/current smokers (HR: 0.24, 95% CI: 0.08 to 0.75). The odds of major pathological response were 4.71 (95% CI: 0.49 to 45.2) times higher in the non-AGAs+NP SCC group, and the median percentage of residual viable tumor was 72.5% in AGAs compared with 33.0% in non-AGS+NP SCC tumors., Conclusions: Patients with NSCLC harboring select AGAs, including EGFR and ALK alterations, have a higher risk for TF, shorter median time to TF, and diminished pathological regression after neoadjuvant ICIs. The suboptimal efficacy of neoadjuvant chemotherapy-sparing, ICI-based regimens in this patient subset underscores the importance of tumor molecular testing prior to initiation of neoadjuvant ICI therapy in patients with resectable NSCLC., Competing Interests: Competing interests: NZ reports consulting fee, travel, dining expenses from Ethicon. WW reports consulting fees, speaker fees and/or honoraria from Amgen, AstraZeneca, Genentech/Roche, Astellas, Boehringer Ingelheim, Merck, Eli Lilly, BMS, MSD, Bayer, Pfizer, Janssen, Sanofi-Aventis, Takeda, Novartis, United Medical; and research grants (to institution) from Amgen, AstraZeneca, Genentech/Roche, Astellas, Boehringer Ingelheim, Eli Lilly, BMS, MSD, Pfizer, Janssen, Sanofi-Aventis. GRB reports grants or contracts from Amgen, Bayer, Adaptimmune, Exelixis, Daiichi Sankyo, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, Torque, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, MedImmune, Merck, Novartis, Roche, Sanofi, Xcovery, Tmunity Therapeutics, Regeneron, BeiGene, Repertoire Immune Medicines, Verastem. CytomX Therapeutics, Duality Biologics, Mythic Therapeutics, Takeda, Aulos Bioscience, Seagen, Nuvalent, Turning Point Therapeutics; Consulting fees from AbbVie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Genzyme, Gilead, Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Sanofi, Tyme Oncology, Xcovery, Virogin Biotech, Maverick Therapeutics, BeiGene, Regeneron, CytomX Therapeutics, Intervenn Biosciences, Onconova Therapeutics, Seagen, Scorpion Therapeutics, Immunocore. Advisory board for Virogin Biotech SAB, Beigene, Immunocore, Regeneron. XL reports consulting/advisory fees from Eli Lilly, EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Regeneron, Boehringer Ingelheim, Hengrui Therapeutics, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint Medicines, Sensei Biotherapeutics, SystImmune, ArriVent, Abion, and AbbVie; Research Funding to Institution from Eli Lilly, EMD Serono, ArriVent, Dizal, Teligene, Regeneron, Janssen, ThermoFisher, Takeda, and Boehringer Ingelheim; Travel support from EMD Serono, Janssen, and Spectrum Pharmaceutics. MA reports research funding from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Labs, Gilead; Consulting fees from GlaxoSmithKline, Shattuck Labs, Bristol Myers Squibb, AstraZeneca, Insight; Speaker fees from AstraZeneca, Nektar Therapeutics, SITC; and participation of safety review committee for Nanobiotix-MDA Alliance, Henlius. JAR reports consulting fee, stock, patents issued and pending with Genprex. MVN reports receiving research funding to institution from Mirati, Novartis, Checkmate, Alaunos, AstraZeneca, Pfizer, Genentech, Navire; a consultant or advisory role for Mirati, Merck/MSD, Novartis, Genentech, Sanofi, Pfizer; and other support from Ziopharm Oncology, ApotheCom, Ashfield Healthcare. HTT reports consulting fee for Abion Bio. JZ reports grants from Merck, Helius, grants and personal fees from Johnson and Johnson and Novartis, personal fees from Bristol Myers Squibb, AstraZeneca, GenePlus, Innovent, Varian, Catalyst and Hengrui outside the submitted work. DLG has served on scientific advisory committees for Menarini Ricerche, 4D Pharma, Onconova, and Eli Lilly and has received research support from Takeda, Astellas, NGM Biopharmaceuticals, Boehringer Ingelheim and Mirati. JVH reports Advisory Committees—AbbVie, AnHeart Therapeutics, AstraZeneca, BioNTech AG, BI, BMS, DAVA Oncology, Eli Lily Research Support—AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb and Takeda; Licensing/Royalties—Spectrum. BS reports consulting fees from AstraZeneca, BMS, Medscape; dining from AstraZeneca. BMS; Speaker fees from AstraZeneca, Medscape, Peer View; advisory board from AstraZeneca, BMS. TC reports (over the past 24 months) speaker fees/honoraria (including travel/meeting expenses) from ASCO Post, AstraZeneca, Bio Ascend, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Medical Educator Consortium, Medscape, OncLive, PEAK Medicals, PeerView, Physicians' Education Resource, Targeted Oncology; advisory role/consulting fees (including travel/meeting expenses) from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Merck, oNKo-innate, Pfizer, RAPT Therapeutics, Regeneron; institutional research funding from AstraZeneca and Bristol Myers Squibb., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Advances in the multidisciplinary care of early stage resectable NSCLC (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and reorganization of care pathways. Perhaps, most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the International Association for the Study of Lung Cancer commissioned a diverse multidisciplinary international expert panel to evaluate the current landscape and provide diagnostic, staging, and therapeutic recommendations for patients with rNSCLC, with particular emphasis on patients with American Joint Committee on Cancer-Union for International Cancer Control TNM eighth edition stages II and III disease. Using a team-based approach, we generated 19 recommendations, of which all but one achieved greater than 85% consensus among panel members. A public voting process was initiated, which successfully validated and provided qualitative nuance to our recommendations. Highlights include the following: (1) the critical importance of a multidisciplinary approach to the evaluation of patients with rNSCLC driven by shared clinical decision-making of a multispecialty team of expert providers; (2) biomarker testing for rNSCLC; (3) a preference for neoadjuvant chemoimmunotherapy for stage III rNSCLC; (4) equipoise regarding the optimal management of patients with stage II between upfront surgery followed by adjuvant therapy and neoadjuvant or perioperative strategies; and (5) the robust preference for adjuvant targeted therapy for patients with rNSCLC and sensitizing EGFR and ALK tumor alterations. Our primary goals were to provide practical recommendations sensitive to the global differences in biology and resources for patients with rNSCLC and to provide expert consensus guidance tailored to the individualized patient needs, goals, and preferences in their cancer care journey as these are areas where physicians must make daily clinical decisions in the absence of definitive data. These recommendations will continue to evolve as the treatment landscape for rNSCLC expands and more knowledge is acquired on the best therapeutic approach in specific patient and disease subgroups., Competing Interests: Disclosure Dr. Spicer reports receiving grants or contracts from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Amgen, Roche, Regeneron, and Pfizer; consulting fees from AstraZeneca, Bristol-Myers Squibb, Eisai, Daiichi Sankyo, and Merck Sharp & Dohme; honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, and Pfizer; meeting support from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme; data safety monitoring board for AstraZeneca; and receipt of other services from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme, outside the submitted work. Dr. Cascone reports receiving speaker fees and/or honoraria from the American Society for Clinical Oncology Post, AstraZeneca, Bio Ascend, Bristol-Myers Squibb, Clinical Care Options, IDEOlogy Health, Medical Educator Consortium, Medscape, OncLive, PEAK Medical, PeerView, Physicians' Education Resource, Society for Immunotherapy of Cancer, and Targeted Oncology; advisory role/consulting fees from Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Mark Foundation for Cancer Research, Merck, oNKo-innate, Pfizer, RAPT Therapeutics, and Regeneron; and institutional research funding from AstraZeneca and Bristol-Myers Squibb, outside the submitted work. Dr.Ahn reports receiving consulting fees from AstraZeneca, Alpha Pharmaceuticals, Genxin, and Pfizer; and honoraria from Takeda, Roche, Merck, Merck Sharp & Dohme, AstraZeneca, Amgen, Boronoi, Arcus, Daiichi Sankyo, Bayer, and Janssen, outside the submitted work. Dr.Dacic reports receiving consulting fees from AstraZeneca, Genentech, and Medscape, outside the submitted work. Dr. Felip reports receiving consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point, and Daiichi Sankyo; honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda, and Touch Oncology; travel support from AstraZeneca, Janssen, and Roche; and other from Grifols as an independent member of the board, outside the submitted work. Dr. Forde reports receiving grants or contracts from AstraZeneca, Bristol-Myers Squibb, Novartis, Regeneron, and BioNTech; consulting fees from Ascendis, AstraZeneca, Bristol-Myers Squibb, Curevac, Novartis, Regeneron, G1, Genlux, Genentech, Gritstone, Merck, Janssen, F Star, Sanofi, Amgen, Fosun, Teva, Synthekine, Flame, Iteos, and Tavotek. Dr. Higgins reports receiving grants or contracts from Jazz Pharmaceuticals, RefleXion Medicalx; consulting fees from AstraZeneca and Janssen; positions on the NRG Oncology Board of Directors and RTOG Foundation Board of Directors; and stock or stock options in Picture Health. Dr. Kris reports receiving grant or contracts from BerGenBio, Merus, AstraZeneca, Mirati, Pfizer, Janssen, Sanofi, and Novartis; honoraria from Pfizer and AstraZeneca; and personal fees from AstraZeneca and Roche/Genentech, outside the submitted work. Dr. Mitsudomi reports receiving grants or contracts from Boehringer Ingelheim, AstraZeneca, Chugai, Pfizer, Ono, Daiichi Sankyo, and Eli Lilly; consulting fees from AstraZeneca, Novartis, Chugai, Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Thermo Fisher, Roche Diagnostics, Bristol-Myers Squibb, Ono Pharmaceuticals, Taiho, Takeda, Janssen, Daiichi Sankyo, and Regeneron; honoraria from AstraZeneca, Chugai, Boehringer Ingelheim, Pfizer, Taiho, Eli Lilly, Daiichi Sankyo, Thermo Fisher, Merck Sharp & Dohme, Bristol-Myers Squibb, Ono Pharmaceuticals, Invitae, Guardant, Novartis, Amgen, Merck biopharma, and Kyorin; data safety monitoring board for Taiho Pharmaceutical, outside the submitted work. Dr. Provencio reports receiving grants or contracts from Bristol-Myers Squibb, AstraZeneca, Roche, Janssen, and Takeda; consulting fees from Bristol-Myers Squibb, Roche, AstraZeneca, Merck Sharp & Dohme, and Takeda; honoraria from Bristol-Myers Squibb, Takeda, Roche, AstraZeneca, and Merck Sharp & Dohme; and meeting attendance support from Merck Sharp & Dohme, Roche, and Bristol-Myers Squibb, outside the submitted work. Dr. Senan reports receiving grants or contracts from AstraZeneca, Merck Sharp & Dohme, and Bristol-Myers Squibb; consulting fees from AstraZeneca and Bristol-Myers Squibb; honoraria from AstraZeneca; advisory board participation for AstraZeneca and Merck Sharp & Dohme; and membership on ETOP scientific committee, outside the submitted work. Dr. Solomon reports receiving travel support from IASLC to attend meeting related to manuscript; consulting fees from AstraZeneca, Bristol-Myers Squibb, Eli Lily, Merck Sharp & Dohme, Pfizer, Roche, GlaxoSmithKline, Janssen, and Amgen; honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, and GlaxoSmithKline; unpaid leadership roles at the IASLC, Thoracic Oncology Group of Australasia, and Cancer Council of Victoria. Dr. Tsao reports receiving travel support from IASLC to attend meeting related to manuscript; grants or contracts from AstraZeneca, Bayer, and Lily; consulting fees from AstraZeneca, Bayer, Amgen, AbbVie, Regeneron, Sanofi, Daiichi Sankyo, and Lily; honoraria from AbbVie and Sanofi; and board of directors for IASLC. Dr. Tsuboi reports receiving grant from AstraZeneca KK, Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb KK, Novartis Japan, BMG KK, MiRXES, and Johnson & Johnson Japan; honoraria from Amgen KK, Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical Co., Ltd., Taiho Pharma, Medtronic Japan, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme KK, Bristol-Myers Squibb KK, Daiichi Sanko KK, and Novalis; advisory committee participation for Chugai Pharmaceutical Co., Ltd., and AstraZeneca KK; and Board of Directors for Japan Lung Cancer Society (JLCS), Bronchology Committee Chair for JLCS, and Educational Committee working group chair for IASLC, outside the submitted work. Dr. Wakelee reports receiving grants or contracts from ACEA Biosciences, Arrys Therapeutics, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Genentech/Roche, Merck, Novartis, SeaGen, Xcovery, and Helsinn; advisory board participation for AstraZeneca, Blueprint, Mirati, Merck, and Genentech/Roche; and leadership positions on the IASLC Board of Directors and ECOG-ACRIN executive committee. Dr. Wu reports receiving grants and contracts form AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Henqrui, and Roche; honoraria from AstraZeneca, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi; and unpaid leadership role for Chinese Thoracic Oncology Group. Dr. Yang reports receiving personal fees and other from Amgen, Bayer Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Merck KGaA, Merck Sharp & Dohme, Novartis, Roche/Genentech, Takeda Oncology, and Yuhan Pharmaceuticals; grants, personal fees, and other from AstraZeneca; other from Eli Lilly; personal fees from Ono Pharmaceuticals and Pfizer; and other from JNJ, Puma Technology, Gilead, and GlaxoSmithKline, outside the submitted work. Dr. Zhou reports receiving consulting fees from Innovent Biologics, Hengrui, Qila, and TopAlliance Biosciences; honoraria from Lily China, Sanofi, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, LUYE Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart. Dr. Kelly reports receiving grants from AstraZeneca, during the conduct of the study; grants and personal fees from Genentech and Bristol-Myers Squibb; and personal fees from AstraZeneca, outside the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC., Methods: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R 2 with 95% confidence interval were calculated by the bootstrapping approach., Results: Seven randomized clinical trials were identified for a total of 2385 patients. At the patient level, the R 2 of pCR and MPR with 2-year EFS were 0.82 (0.66-0.94) and 0.81 (0.63-0.93), respectively. The OR of 2-year EFS rates by response status was 0.12 (0.07-0.19) and 0.11 (0.05-0.22), respectively. For the 2-year OS, the R 2 of pCR and MPR were 0.55 (0.09-0.98) and 0.52 (0.10-0.96), respectively. At the trial level, the R 2 for the association of OR for response and HR for EFS was 0.58 (0.00-0.97) and 0.61 (0.00-0.97), respectively., Conclusions: Our analyses reveal a robust correlation between pCR and MPR with 2-year EFS but not OS. Trial-level surrogacy was moderate but imprecise. More mature follow-up and data to assess the impact of study crossover are needed., Competing Interests: Disclosure Drs. Hines and Cameron were supported by the National Institute for General Medical Sciences (T32 GM07019). Dr. Bestvina reports receiving institutional research funding from AstraZeneca and Bristol Myers Squibb; and advisory board membership/consulting for Amgen, AstraZeneca, Bristol Myers Squibb, CVS, Daiichi Sankyo, EMD Serono, Gilead, JNJ, Mirati, Novocure, Regeneron, Sanofi, Takeda, and Tempus. Dr. Garassino reports receiving personal financial support from AstraZeneca, Abion, Merck Sharp & DohmeInternational GmbH, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Incyte, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Blueprint, Janssen, Sanofi, AbbVie, BeiGenius, Oncohost, and Medscape; received institutional financial support from Eli Lilly, Merck Sharp & Dohme, Pfizer (MISP), AstraZeneca, Merck Sharp & Dohme International GmbH, Bristol-Myers Squibb, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, GlaxoSmithKline, and Spectrum pharmaceuticals; received other forms of support from AIRC, AIFA, Italian Moh, and Transcan; and received research funding from Horizon 2020. Dr. Veronesi has received honoraria from Ab Medica Spa, AstraZeneca, Roche, and Merck Sharp & Dohme outside the submitted work. Dr. Cascone reports receiving speaker fees/honoraria from ASCO Post, AstraZeneca, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Mark Foundation for Cancer Research, Medscape, OncLive, PeerView, Physicians’ Education Resource, Roche, and Society for Immunotherapy of Cancer; has advisory role/consulting fees from Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Genentech, Merck & Co., Pfizer, and Regeneron; and received institutional research funding from AstraZeneca and Bristol Myers Squibb. Dr. Taube reports having an advisory role or have received consulting fees from Akoya Biosciences, AstraZeneca, Bristol Myers Squibb, Merck & Co., Genentech, Lunaphore, Compugen, Elephas, and Regeneron; received institutional research funding from Bristol Myers Squibb and Akoya Biosciences; and received reagents and equipment loan and has stock options from Akoya Biosciences. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Standard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes., Methods: In this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to IIIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response according to blinded independent review, overall survival, and safety., Results: At this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; P<0.001). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group., Conclusions: Perioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.)., (Copyright © 2024 Massachusetts Medical Society.)

Importance: To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in randomized and nonrandomized settings. In addition, there exists controversy concerning the efficacy of neoadjuvant chemoimmunotherapy for patients with NSCLC with programmed cell death 1 ligand 1 (PD-L1) levels less than 1%., Objective: To compare neoadjuvant chemoimmunotherapy with chemotherapy by adverse events and surgical, pathological, and efficacy outcomes using recently published randomized clinical trials and nonrandomized trials., Data Sources: MEDLINE and Embase were systematically searched from January 1, 2013, to October 25, 2023, for all clinical trials of neoadjuvant chemoimmunotherapy and chemotherapy that included at least 10 patients., Study Selection: Observational studies and trials reporting the use of neoadjuvant radiotherapy, including chemoradiotherapy, molecular targeted therapy, or immunotherapy monotherapy, were excluded., Main Outcomes and Measures: Surgical, pathological, and efficacy end points and adverse events were pooled using a random-effects meta-analysis., Results: Among 43 eligible trials comprising 5431 patients (4020 males [74.0%]; median age range, 55-70 years), there were 8 randomized clinical trials with 3387 patients. For randomized clinical trials, pooled overall survival (hazard ratio, 0.65; 95% CI, 0.54-0.79; I2 = 0%), event-free survival (hazard ratio, 0.59; 95% CI, 0.52-0.67; I2 = 14.9%), major pathological response (risk ratio, 3.42; 95% CI, 2.83-4.15; I2 = 31.2%), and complete pathological response (risk ratio, 5.52; 95% CI, 4.25-7.15; I2 = 27.4%) favored neoadjuvant chemoimmunotherapy over neoadjuvant chemotherapy. For patients with baseline tumor PD-L1 levels less than 1%, there was a significant benefit in event-free survival for neoadjuvant chemoimmunotherapy compared with chemotherapy (hazard ratio, 0.74; 95% CI, 0.62-0.89; I2 = 0%)., Conclusion and Relevance: This study found that neoadjuvant chemoimmunotherapy was superior to neoadjuvant chemotherapy across surgical, pathological, and efficacy outcomes. These findings suggest that patients with resectable NSCLC with tumor PD-L1 levels less than 1% may have an event-free survival benefit with neoadjuvant chemoimmunotherapy.

Introduction: The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade., Methods: Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73)., Results: NCT was associated with increased infiltration of cytotoxic CD8 + T cells and CD20 + B cells. Moreover, NCT was associated with increases in CD8 + CD103 + and CD4 + CD103 + PD-1 + TIM3 - tissue resident memory T cells. Gene expression profiling supported memory function of CD8 + and CD4 + T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery., Conclusions: Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8 + and CD4 + memory helper T cells., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: We have suggested that major pathologic response (MPR) could serve as a surrogate endpoint for survival and provide rapid means of comparing different neoadjuvant treatment regimens. Here, we confirm that MPR is predictive of long-term overall survival (OS) in patients with non-small-cell lung cancer (NSCLC) who underwent neoadjuvant chemotherapy and surgical resection, to assess agreement on MPR between 2 observers, and to determine the minimum number of slides needed to obtain an accurate determination of MPR., Patients and Methods: We identified 151 patients with NSCLC who had been treated with neoadjuvant chemotherapy followed by complete surgical resection from 2008 to 2012. Tissue specimens were retrospectively evaluated by 2 pathologists who had been blinded to patients' treatment and outcome. We assessed the relationships between MPR and OS, the levels of agreement between the pathologists, and determined the number of slides needed to obtain an accurate determination of MPR., Results: Our results reveal that MPR examined by either observer 1 (experienced) or by observer 2 (trained) was significantly predictive of long-term OS after neoadjuvant chemotherapy. MPR was associated with long-term OS in patients with NSCLC undergoing neoadjuvant chemotherapy on multivariable analysis (hazard ratio 2.68; P = .01). The levels of agreement between 2 pathologists were high after direct in-person training by one pathologist or the other (R 2  = 0.994). Our data suggest that at least 3 slides should be read to accurately determine MPR., Conclusions: MPR is significantly predictive of long-term OS in neoadjuvant chemotherapy-treated patients with NSCLC. MPR may serve as a surrogate endpoint for evaluating novel chemotherapies and immunotherapy response in biomarker-driven translational clinical trials., (Published by Elsevier Inc.)

Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years. The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response., (Copyright © 2020. Published by Elsevier Inc.)

Background: The clinical efficacy observed with inhibitors of programed cell death 1/programed cell death ligand 1 (PD-L1/PD-1) in cancer therapy has prompted studies to characterize the immune response in several tumor types, including lung cancer. However, the immunological profile of non-small cell lung carcinoma (NSCLC) treated with neoadjuvant chemotherapy (NCT) is not yet fully characterized, and it may be therapeutically important. The aim of this retrospective study was to characterize and quantify PD-L1/PD-1 expression and tumor-associated immune cells (TAICs) in surgically resected NSCLCs from patients who received NCT or did not receive NCT (non-NCT)., Methods: We analyzed immune markers in formalin-fixed, paraffin-embedded tumor tissues resected from 112 patients with stage II/III NSCLC, including 61 non-NCT (adenocarcinoma [ADC] = 33; squamous cell carcinoma [SCC] = 28) and 51 NCT (ADC = 31; SCC = 20). We used multiplex immunofluorescence to identify and quantify immune markers grouped into two 6-antibody panels: panel 1 included AE1/AE3, PD-L1, CD3, CD4, CD8, and CD68; panel 2 included AE1/AE3, PD1, granzyme B, FOXP3, CD45RO, and CD57., Results: PD-L1 expression was higher (> overall median) in NCT cases (median, 19.53%) than in non-NCT cases (median, 1.55%; P = 0.022). Overall, density of TAICs was higher in NCT-NSCLCs than in non-NCT-NSCLCs. Densities of CD3+ cells in the tumor epithelial compartment were higher in NCT-ADCs and NCT-SCCs than in non-NCT-ADCs and non-NCT-SCCs (P = 0.043). Compared with non-NCT-SCCs, NCT-SCCs showed significantly higher densities of CD3 + CD4+ (P = 0.019) and PD-1+ (P < 0.001) cells in the tumor epithelial compartment. Density of CD68+ tumor-associated macrophages (TAMs) was higher in NCT-NSCLCs than in non-NCT-NSCLCs and was significantly higher in NCT-SCCs than in non-NCT-SCCs. In NCT-NSCLCs, higher levels of epithelial T lymphocytes (CD3 + CD4+) and epithelial and stromal TAMs (CD68+) were associated with better outcome in univariate and multivariate analyses., Conclusions: NCT-NSCLCs exhibited higher levels of PD-L1 expression and T-cell subset regulation than non-NCT-NSCLCs, suggesting that NCT activates specific immune response mechanisms in lung cancer. These results suggest the need for clinical trials and translational studies of combined chemotherapy and immunotherapy prior to surgical resection of locally advanced NSCLC.