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Review
. 2025 Jun 19;6(9):100866.
doi: 10.1016/j.jtocrr.2025.100866. eCollection 2025 Sep.

Phase 3 Trials of Neoadjuvant, Perioperative, and Adjuvant Chemoimmunotherapy for Resectable, Early-Stage NSCLC: Comprehensive Review and Detailed Analysis

Jay M Lee  1 , Alessandro Brunelli  2 , Amy L Cummings  1 , Enriqueta Felip  3 , Catherine A Shu  4 , Benjamin J Solomon  5 , Masahiro Tsuboi  6 , Heather Wakelee  7 , Anjali Saqi  8 , Yi-Long Wu  9 , Pao-Chen Li  10 , Barbara J Gitlitz  10
Affiliations
Review

Phase 3 Trials of Neoadjuvant, Perioperative, and Adjuvant Chemoimmunotherapy for Resectable, Early-Stage NSCLC: Comprehensive Review and Detailed Analysis

Jay M Lee et al. JTO Clin Res Rep. .

Abstract

Phase 3 trials of neoadjuvant, perioperative, and adjuvant immune checkpoint inhibitors combined with chemotherapy (ICI-CT) in resectable early-stage NSCLC (eNSCLC) have reported that all three approaches confer an event-free or disease-free survival benefit over CT alone, with acceptable safety profiles. All three strategies are approved standards of care for eNSCLC. This review provides a detailed analysis of these phase 3 ICI-CT trials and addresses the considerations regarding the selection of each approach, including protocol schema and baseline patient and tumor differences, preoperative staging, surgical outcomes, efficacy end points, safety, treatment disposition, and the programmed death-ligand 1 (PD-L1) efficacy biomarker. The differences between regimens and study populations among these ICI-CT trials hamper cross-trial comparisons and highlight the need for head-to-head trials. Patients achieving pathologic complete response with neoadjuvant ICI-CT have better survival outcomes irrespective of subsequent treatment, but the optimal number of preoperative ICI-CT cycles needed to achieve pathologic complete response has not been defined. The choice between a neoadjuvant or perioperative versus adjuvant treatment approach involves a risk-benefit assessment of the potential for preoperative attrition to surgery, postoperative attrition to ICI-CT, and the anticipated toxicity profile. Current limitations of invasive lymph node staging mean that adjuvant ICI remains an important treatment strategy, but preoperative node staging is imperative. Future studies that identify the safety and toxicity contributions of each treatment phase in perioperative trials will confirm whether a pre- or postoperative ICI approach is superior, whether there is added benefit to adjuvant after neoadjuvant ICI-CT, and which patients will benefit the most from each approach.

Keywords: Early-stage lung cancer; Immune checkpoint inhibitors plus chemotherapy; PD-1 and PD-L1 inhibitor therapy; Pre- and postoperative treatment; Treatment strategy.

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Conflict of interest statement

Dr. Lee has received advisory board and consulting fees from AstraZeneca, Bristol Myers Squibb, Foundation Medicine Institute, Genentech, Lilly, Merck, Novartis, Regeneron Pharmaceuticals, and Roche; has received research support from Bristol Myers Squibb, Genentech, Novartis, Roche, and Tempus; has served on steering committees for Genentech, Lilly, Merck, Novartis, and Roche; has participated in speakers bureaus for AstraZeneca, Bristol Myers Squibb, Genentech, and Roche; received payment or honoraria for lectures, presentations, and educational events from DAVA Oncology, eCancer, IDEOlogy, Medscape, Meetings Events and Conference Coordinators, OncLive, and Targeted Oncology; and holds patents with UCLA. Dr. Brunelli reports receiving personal consulting fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Ethicon, Medela, and Medtronic; receiving payment or honoraria for lectures, presentations, and educational events from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Ethicon, Medela, and Medtronic; serving as the International Director of the Society of Thoracic Surgeons; and being a Past President of the European Society of Thoracic Surgeons. Dr. Cummings has received consulting fees from AstraZeneca and Bristol Myers Squibb. Dr. Felip has received consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daichii, F. Hoffmann-La Roche, Gilead, GSK, Iteos Therapeutics, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point, and Daiichi Sankyo; honoraria for lectures, presentations, or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Gilead, Janssen, Johnson & Johnson, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, Novartis, Peervoice, Pfizer, Regeneron, Sanofi, Takeda, and Touch Oncology; and support for attending meetings from AstraZeneca, Janssen, and Roche; and serves on the Grifols Board as an independent member. Dr. Shu has received personal consulting fees from AstraZeneca, Janssen, Genentech, Takeda, Arcus Biosciences, and Mirati for participation in advisory boards; payment for participation in continuing medical education events from Curio, PER of MHJ Life Sciences, Plexus, and AiCME; and received payment from the US Department of Justice for providing expert testimony. Dr. Solomon has received consulting fees for advisory board participation from Pfizer, Roche, Genentech, AstraZeneca, Merck Sharp & Dohme, Bristol Myers Squibb, Eli Lilly, Janssen, Takeda, and D3 Bio; payment for lectures from Pfizer, Roche, Genentech, AstraZeneca, and Merck Sharp & Dohme; royalties from UptoDate; and holds leadership roles in the International Association for the Study of Lung Cancer, the Thoracic Oncology Group of Australasia, and Cancer Council Victoria. Dr. Tsuboi reports receiving honoraria from Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical Co. Ltd., Taiho Pharma, Medtronic Japan, Ono Pharmaceutical Ltd., Merck Sharp & Dohme, Bristol Myers Squibb KK, Daiichi Sankyo, and Amgen KK; participation on advisory boards or Data Safety Monitoring Boards for AstraZeneca KK, Chugai Pharmaceutical Ltd., Merck Sharp & Dohme, Novartis, and MiRXES; receiving research grant or funding to institution from Merck Sharp & Dohme, AstraZeneca KK, Ono Pharmaceutical Co. Ltd., Bristol Myers Squibb KK, Eli Lilly Japan, Novartis, MiRXES, and Johnson & Johnson Japan; and serving on the board of directors of the Japan Lung Cancer Society. Dr. Wakelee reports receiving research funding to her institution from Bayer, AstraZeneca, Bristol Myers Squibb, Genentech, Roche, Merck, Helsinn, SeaGen, and Xcovery; serving on compensated advisory boards for Mirati, IOBiotech, OncoC4, and Beigene, and on noncompensated advisory boards for GSK, Merck, Genentech, Roche, Bristol Myers Squibb, and AstraZeneca; serving as Past President of the International Association for the Study of Lung Cancer; and being a member of the executive committee of Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN). Dr. Saqi has received grants to the institution from Boehringer Ingelheim and Genentech; personal consulting fees from Genentech, Gilead, AbbVie, and Veracyte; payment or honoraria for lectures, presentations, and educational events from Medscape, Physician’s Education Resource, Memorial Sloan Kettering, Bronx Lebanon, and New York University; support for attending meetings or travel from the International Association for the Study of Lung Cancer and the College of American Pathologists; and holds patents for a device for cell blocks (issued or pending) and a major pathologic calculator tool (pending). Dr. Wu has received institutional grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Hengrui, and Roche; and payment or honoraria for lectures, presentations, speakers bureaus, or educational events from AstraZeneca, Beigen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi. Drs. Chen and Gitlitz are employees of Genentech, Inc. and report stock ownership in F. Hoffmann-La Roche.

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