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

Author(s): Biagio Ricciuti, MD, PhD¹; Francesca Fusco, MD²; Alissa Cooper, MD³; Edoardo Garbo, MD¹; Federica Pecci, MD¹; Mihaela Aldea, MD, PhD¹; Xinan Wang, PhD, MS¹; Maria Mayoral Penalva, MD⁴; Michelle Ginsberg, MD⁴; Lynette M. Sholl, MD⁵; Mizuki Nishino, MD⁶; Alessandro Di Federico, MD¹; Narek Shaverdian, MD³; Matthew Bott, MD³; Valentina Santo, MD¹; Erino Rendina, MD⁷; Rocco Trisolini, MD⁸; Sara Ramella, MD⁹; Filippo Gallina, MD²; Enrico Melis, MD²; Simonetta Buglioni, PhD²; Gabriele Minuti, MD²; Lorenza Landi, MD²; Paula A. Ugalde Figueroa, MD¹⁰; Alice T. Shaw, MD¹; Jamie Chaft, MD³; Mark M. Awad, MD, PhD¹; Federico Cappuzzo, MD²;

Source: DOI: 10.1001/jamaoncol.2025.1115

Dr. Anjan Patel's Thoughts

The phase II trial of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy in borderline resectable and unresectable stage III NSCLC showed a significant improvement in event-free survival (EFS) with the combination (24.1 vs 10.6 months) compared to chemotherapy alone, with a hazard ratio (HR) of 0.62. Major pathological response rates were higher with immunotherapy (44.7% vs 22.3%), and no new safety signals were noted. The regimen improved surgical resection rates (68% vs 52%) without increasing perioperative complications. This validates chemoIO in the neoadjuvant setting particularly in whom we wish to pursue resection or avoid chemoradiation. It would be great to see this compared to chemoradiation followed by immunotherapy rather than chemotherapy alone.

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.

Author Affiliations

¹Lowe Center of Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; ²IRCCS Regina Elena National Cancer Institute, Rome, Italy; ³Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; ⁴Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York; ⁵Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; ⁶Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts; ⁷Department of Thoracic Surgery, “Sapienza” University of Rome-“Sant’Andrea” Hospital, Rome, Italy; ⁸Interventional Pulmonology Division, Department of Neurosciences, Sense Organs and Thorax, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; ⁹Department of Radiation Oncology (Medicine and Surgery), Università Campus Bio-Medico di Roma, Rome, Italy; ¹⁰Division of Thoracic and Cardiac Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts;

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