Pembrolizumab With or Without Maintenance Olaparib for Metastatic Squamous Non–Small-Cell Lung Cancer That Responded to First-Line Pembrolizumab Plus Chemotherapy

Abstract

Introduction: Poly (adenosine diphosphate-ribose) polymerase inhibitors can up-regulate programmed cell deathligand 1 expression and promote immune-mediated responses and may improve efficacy of first-line anti-programmed cell death protein 1-based therapies in patients with metastatic squamous NSCLC. Methods: In this randomized, double-blind, phase 3 trial (NCT03976362), adults with previously untreated stage IV squamous NSCLC received four cycles of induction therapy (pembrolizumab 200 mg every 3 weeks plus carboplatin and paclitaxel or nab-paclitaxel). Patients with disease control were randomized to 31 cycles of pembrolizumab 200 mg every 3 weeks plus olaparib 300 mg orally twice daily or placebo. Dual primary end points were progression- free survival (PFS) and overall survival (OS). PFS was tested at interim analysis 2 (the final PFS analysis); OS was tested at final analysis. Results: A total of 851 patients received induction treatment; 296 were randomized to pembrolizumab plus olaparib and 295 to pembrolizumab plus placebo. At interim analysis 2, with median follow-up of 27.1 months, median (95% confidence interval [CI]) PFS was 8.3 (6.7-9.7) months in the pembrolizumab plus olaparib group and 5.4 (4.1-5.6) months in the pembrolizumab plus placebo group (hazard ratio = 0.77, 95% CI: 0.63-0.93, p = 0.0040 [not significant at a one-sided superiority boundary of p = 0.003]). At final analysis, with median follow-up of 33.4 months, median (95% CI) OS was 19.1 (15.9-22.2) and 18.6 (16.0-21.6) months, respectively (hazard ratio = 1.01, 95% CI: 0.83-1.24, p = 0.5481). Treatment-related adverse events occurred in 76.5% and 65.1% of patients, respectively. Conclusions: Adding olaparib to pembrolizumab as maintenance therapy for metastatic squamous NSCLC did not significantly improve PFS versus pembrolizumab plus placebo; neither PFS nor OS met the prespecified statistical significance boundary. No new safety signals were identified. Trial registration: ClinicalTrials.gov, NCT03976362. (c) 2024 Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and The Author(s). Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).