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Multicenter Study
. 2025 Jul 1;11(7):735-741.
doi: 10.1001/jamaoncol.2025.1115.

Neoadjuvant PD-1 and PD-L1 Blockade With Chemotherapy for Borderline Resectable and Unresectable Stage III Non-Small Cell Lung Cancer

Biagio Ricciuti  1 , Francesca Fusco  2 , Alissa Cooper  3 , Edoardo Garbo  1 , Federica Pecci  1 , Mihaela Aldea  1 , Xinan Wang  1 , Maria Mayoral Penalva  4 , Michelle Ginsberg  4 , Lynette M Sholl  5 , Mizuki Nishino  6 , Alessandro Di Federico  1 , Narek Shaverdian  3 , Matthew Bott  3 , Valentina Santo  1 , Erino Rendina  7 , Rocco Trisolini  8 , Sara Ramella  9 , Filippo Gallina  2 , Enrico Melis  2 , Simonetta Buglioni  2 , Gabriele Minuti  2 , Lorenza Landi  2 , Paula A Ugalde Figueroa  10 , Alice T Shaw  1 , Jamie Chaft  3 , Mark M Awad  1 , Federico Cappuzzo  2
Affiliations
Multicenter Study

Neoadjuvant PD-1 and PD-L1 Blockade With Chemotherapy for Borderline Resectable and Unresectable Stage III Non-Small Cell Lung Cancer

Biagio Ricciuti et al. JAMA Oncol. .

Abstract

Importance: Patients with borderline resectable or unresectable stage III non-small cell lung cancer (NSCLC) with T4 and/or N2-N3 involvement face limited treatment options and poor outcomes. Neoadjuvant chemoimmunotherapy has shown promise in improving resectability and pathological responses.

Objective: To evaluate the efficacy of neoadjuvant programmed cell death 1 protein (PD-1) or programmed cell death 1 ligand 1 (PD-L1) blockade combined with chemotherapy in enhancing surgical outcomes and pathological responses in patients with T4 and/or N2-N3 stage III NSCLC.

Design, setting, and participants: This multicenter cohort study analyzed data from patients treated between February 2018 and January 2024 with neoadjuvant PD-1/PD-L1 inhibitors plus chemotherapy at academic and tertiary care centers across the US and Italy. Pathological and survival outcomes were assessed. Patients with stage III NSCLC and T4 and/or N2-N3 involvement were included. Data were collected from February 2018 to January 2024.

Exposures: Neoadjuvant PD-1/PD-L1 blockade combined with platinum-based chemotherapy.

Main outcomes and measures: Pathological complete response (pCR), major pathological response, surgical resectability, and event-free survival (EFS).

Results: Of 112 patients, 58 (51.8%) were female, and the median (range) age was 66 (41-84) years. A total of 84(75.0%) underwent surgical resection, achieving a pCR rate of 29.0% (24 of 83 with available final pathology) and a major pathological response rate of 42.2% (35 of 83). Patients with both PD-L1 expression of 50% or more and high tumor mutational burden achieved the highest pCR rate (4 of 9 [44.4%]; P = .03). Conversely, covariants in KRAS/STK11 or KRAS/KEAP1 were associated with lack of pCR. Patients with single-station or multistation N2/N3 disease exhibited comparable pathological outcomes. The median EFS for all resected patients was 52.6 months (95% CI, 27.8 to not reached), and this was significantly longer in patients with pCR (not reached vs 27.8 months [95% CI, 19.5 to not reached]; P < .001).

Conclusions and relevance: In this study, neoadjuvant PD-1/PD-L1 blockade combined with chemotherapy resulted in high pathological response rates and surgical resectability in patients with T4 and/or N2-N3 stage III NSCLC. This approach offers a viable treatment option for patients with borderline resectable or unresectable NSCLC but requires further validation through prospective studies.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ricciuti reported personal fees from AstraZeneca, Regeneron, Bristol Myers Squibb, Bayer, AbbVie, Amgen, SITC, and Targeted Oncology outside the submitted work. Dr Cooper reported personal fees from MJH Life Sciences, Ideology Health, Intellisphere LLC, MedStar Health, CancerGRACE, Gilead Sciences, Daiichi/AstraZeneca, and Regeneron as well as grants from Merck, Monte Rosa, AbbVie, Daiichi-Sankyo, and Amgen paid to her institution outside the submitted work. Dr Garbo reported support from an American-Italian Cancer Foundation Post-Doctoral Research Fellowship. Dr Aldea reported institutional grants from Amgen, AstraZeneca, Sandoz, and Owkin outside the submitted work. Dr Sholl reported personal fees from Genentech and Lilly as well as grants from Bristol Myers Squibb outside the submitted work. Dr Nishino reported grants from Canon and Konica outside the submitted work. Dr Di Federico reported personal fees from Hanson-Wade, IQVIA, Novartis, and SITC as well as nonfinancial support from Johnson & Johnson outside the submitted work. Dr Shaverdian reported research support from Amgen, AstraZeneca, and Novartis outside the submitted work. Dr Bott reported personal fees from AstraZeneca and Merck as well as grants from Obsidian Therapeutics outside the submitted work. Dr Ramella reported grants, personal fees, and nonfinancial support from AstraZeneca, Roche, and Merck MSD; personal fees from Tema Sinergie and Amgen; and nonfinancial support from Elekta outside the submitted work. Dr Minuti reported personal fees from Bristol Myers Squibb, AstraZeneca, Novartis, MSD, Roche, Amgen, Johnson & Johnson, Sanofi, Daiichi-Sankyo, and Gilead Sciences outside the submitted work. Dr Landi reported personal fees from AstraZeneca, Pfizer, MSD, Bristol Myers Squibb, Sanofi, Thermo Fisher Scientific, Lilly, Novartis, Amgen, and Roche and serves as consultant for AbbVie outside the submitted work. Dr Shaw reported personal fees from Novartis and Pfizer during the conduct of the study as well as personal fees from Nuvalent and Tango outside the submitted work. Dr Chaft reported grants from the National Institutes of Health during the conduct of the study; institutional grants from Bristol Myers Squibb, AstraZeneca, Beigene, Merck, and Genentech; and personal fees from AstraZeneca, Boehringer Ingelheim, Merck, Genentech, Lilly, and Guardant Health outside the submitted work. Dr Awad reported grants from Bristol Myers Squibb, Lilly, Genentech, AstraZeneca, and Amgen as well as personal fees from Bristol Myers Squibb, Lilly, AstraZeneca, Merck, Genentech, Blueprint Medicine, Synthekine, AbbVie, Gritstone, Mirati, Regeneron, AffiniT, EMD Serono, Novartis, Janssen, Coherus, D3Bio, Pfizer, Seagen, and Gilead Sciences outside the submitted work. Dr Cappuzzo reported personal fees from Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, Pharmamar, Novocure, Mirati, Galecto, OSE Immunotherapeutics, Illumina, Thermo Fisher Scientific, Beigene, and MSD during the conduct of the study; personal fees from Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, Pharmamar, Novocure, Mirati, Galecto, OSE Immunotherapeutics, Illumina, Thermo Fisher Scientific, Beigene, and MSD outside the submitted work. No other disclosures were reported.

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