Pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced non-small cell lung cancer without tumor PD-L1 expression: A pooled analysis of 3 randomized controlled trials

Abstract

Background: Pembrolizumab plus platinum-based chemotherapy has demonstrated improved clinical outcomes over chemotherapy alone in patients with previously untreated advanced/metastatic non-small cell lung cancer (NSCLC), regardless of tumor programmed death ligand 1 (PD-L1) expression. This study pooled data from 3 randomized controlled trials to evaluate outcomes with pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced/metastatic NSCLC negative for PD-L1 (ie, a tumor proportion score < 1%).

Methods: Individual patient data were pooled from KEYNOTE-021 cohort G (nonsquamous; NCT02039674), KEYNOTE-189 (nonsquamous; NCT02578680 and NCT03950674), and KEYNOTE-407 (squamous; NCT02775435). Treatment comprised pembrolizumab plus chemotherapy (pemetrexed and platinum for nonsquamous histology and carboplatin and paclitaxel/nab-paclitaxel for squamous histology) or chemotherapy alone. Responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1 by blinded, independent, central review. No α was assigned to this descriptive, exploratory analysis.

Results: Four hundred forty-four of the 1328 patients (33.4%) who were enrolled across the 3 trials had PD-L1-negative tumors (256 on pembrolizumab plus chemotherapy [nonsquamous, n = 155; squamous, n = 94; other, n = 7] and 188 on chemotherapy alone [nonsquamous, n = 83; squamous, n = 99; other, n = 6]). The median time from randomization to the data cutoff was 28.0 months (range, 14.7-55.4 months). Pembrolizumab plus chemotherapy improved overall survival (OS; hazard ratio [HR], 0.63; 95% CI, 0.50-0.79) and progression-free survival (HR, 0.68; 95% CI, 0.56-0.83) over chemotherapy. Sixteen patients in the pembrolizumab plus chemotherapy arm completed 2 years of treatment; the objective response rate was 87.5% (95% CI, 61.7%-98.4%), and the 3-year OS rate was 100%. Adverse events (AEs) were experienced by 99.2% of the patients who received pembrolizumab plus chemotherapy and by 98.9% of the patients who received chemotherapy alone, with grade 3 or higher AEs occurring in 71.4% and 72.0%, respectively; immune-mediated AEs and infusion reactions were experienced by 29.0% and 12.4%, respectively.

Conclusions: Pembrolizumab plus chemotherapy demonstrated response and survival improvements with manageable safety in comparison with chemotherapy alone in PD-L1-negative advanced/metastatic NSCLC, and it is a standard-of-care first-line therapy for patients with advanced NSCLC, regardless of PD-L1 expression.

Lay summary: Some tumors produce a protein called programmed death ligand 1 (PD-L1), which interacts with the body's immune system and prevents an immune response against cancer. Antibody therapies such as pembrolizumab block interactions between tumor PD-L1 and the immune system and enable an immune response. Used alone, pembrolizumab provides benefit for patients with non-small cell lung cancer (NSCLC) tumors that produce PD-L1. However, when it is combined with chemotherapy, which can stimulate anticancer immune responses, pembrolizumab provides a benefit, regardless of tumor PD-L1 production. This article shows that among patients with NSCLC whose tumors produce no PD-L1, outcomes are better with pembrolizumab plus chemotherapy in comparison with chemotherapy alone.

Keywords: antineoplastic agents; combined drug therapy; non-small cell lung cancer; pembrolizumab; programmed cell death ligand 1 protein (human CD274 protein).

Conflict of interest statement

Hossein Borghaei receives partial support from the National Institutes of Health (P30 CA006927); has received clinical trial research support from Millennium Pharmaceuticals, Merck, Celgene, Bristol‐Myers Squibb, and Lilly; has served on an advisory board or as a consultant for Bristol‐Myers Squibb, Lilly, Genentech, Celgene, Pfizer, Merck, EMD Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, Takeda, Huya Bioscience International, GLG Pharma, and Daiichi‐Sankyo; has served on data and safety monitoring boards for the University of Pennsylvania chimeric antigen receptor T‐cell program, Takeda, and Incyte; has served on scientific advisory boards for Sonnet BioTherapeutics and Rgenix; owns stock in Sonnet BioTherapeutics and Rgenix; and is an employee of Fox Chase Cancer Center. Corey J. Langer has served as a consultant for/received honoraria from Boehringer Ingelheim, Novocure, AstraZeneca, Takeda, Genentech/Roche, Merck, Gilead Sciences, GlaxoSmithKline, OncLive, Takai, and RTP; has received research funding from Advantagene, AstraZeneca, Genentech/Roche, Lilly, Takai, Trizell, Merck, Takeda, and Inovio Pharmaceuticals; has received medical writing support from Novartis; and has served on data and safety monitoring committees for Lilly, Amgen, and SWOG. Luis Paz‐Ares reports honoraria (to him/spouse) for scientific advice or speaking from Advanced Accelerator Applications (Adacap), Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol‐Myers Squibb, Boehringer Ingelheim, Celgene, Incyte, Ipsen, Lilly, Merck, MSD, Novartis, PharmaMar, Pfizer, Roche, Sanofi, Servier, Takeda, and Sysmex; is a board member for Genomica and Altum Sequencing; and reports grants to his institution from AstraZeneca, Bristol‐Myers Squibb, MSD, and Pfizer. Delvys Rodríguez‐Abreu reports grants from Bristol‐Myers Squibb and has received honoraria for lectures and consulting from Bristol‐Myers Squibb, Genentech/Roche, MSD, AstraZeneca, Boehringer Ingelheim, Lilly, Roche, Novartis, and Pfizer. Balazs Halmos has received research funding from Amgen, Janssen, Advaxis, Merck, Bristol‐Myers Squibb, Boehringer‐Ingelheim, Lilly, Novartis, GlaxoSmithKline, Pfizer, AbbVie, AstraZeneca, Mirati Therapeutics, Takeda, and Guardant Health; has served as a consultant for Merck, Novartis, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Guardant Health, Spectrum, Bristol‐Myers Squibb, and Genentech; and has received personal fees from Amgen and TPT. Marina C. Garassino has received grants and personal fees for clinical trials from AstraZeneca, Novartis, Bristol‐Myers Squibb, Roche, Pfizer, Celgene, Bayer, and MSD; grants from Turning Point, Ipsen, MedImmune, Exelixis, Incyte, Lilly, Otsuka Pharmaceutical, Tiziana Life Sciences, Clovis Oncology, Merck Serono, Merck KGaA, Blueprint Medicine, GlaxoSmithKline, United Therapeutics Corporation, and Spectrum Pharmaceuticals; personal fees from Seattle Genetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Janssen, Boehringer Ingelheim, Blueprint Medicine, Otsuka Pharmaceutical, Incyte, Inivata, Spectrum Pharmaceuticals, Takeda, and Sanofi‐Aventis; and nonfinancial support from MSD, Pfizer, and Lilly. Takayasu Kurata has received honoraria from AstraZeneca, Boehringer‐Ingelheim, Bristol‐Myers Squibb, Chugai, Lilly, MSD, and Ono Pharmaceutical and reports grants from AstraZeneca, MSD, Bristol‐Meyers Squibb, Novartis, Takeda, and Chugai. Jianxin Lin is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA. M. Catherine Pietanza is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA and owns stock in Merck & Co., Inc., Kenilworth, New Jersey, USA. Bilal Piperdi is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA. and owns stock in Merck & Co, Inc., Kenilworth, New Jersey, USA. Shirish M. Gadgeel has received personal fees from AstraZeneca, Daichii‐Sankyo, Genentech/Roche, Takeda/Ariad, Boehringer Ingelheim, Merck, Novocure, Bristol‐Myers Squibb, AbbVie, Jazz Pharmaceuticals, and Xcovery. The other authors made no disclosures.

© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.

Figures

Figure 1

Summary of enrollment and patient disposition in the pooled analysis population of patients with advanced NSCLC and no PD‐L1 expression (TPS

Figure 2

Kaplan‐Meier estimates of OS among patients with no PD‐L1 expression (TPS

Figure 3

Kaplan‐Meier estimates of PFS among patients with no PD‐L1 expression (TPS