Background: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1–49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57–69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56–0·85, p=0·0003; ≥20% 0·77, 0·64–0·92, p=0·0020, and ≥1% 0·81, 0·71–0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4–24·9) for pembrolizumab versus 12·2 months (10·4–14·2) for chemotherapy, 17·7 months (15·3–22·1) versus 13·0 months (11·6–15·3), and 16·7 months (13·9–19·7) versus 12·1 months (11·3–13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation: The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding: Merck Sharp & Dohme.
Bibliographical noteFunding Information:
This study was funded by Merck Sharp & Dohme. We thank the patients and their families and caregivers for participating in this trial and all the investigators and site personnel. At Merck Sharp & Dohme, we thank Roger Dansey for critical review of the manuscript, Lu Xu for assistance with statistical analyses, Jim Betzel and Sara Sadowski for study support, and Melanie A Leiby for medical writing and editorial assistance.
TSKM is a member of the board of directors for AstraZeneca, Chi-Med, and Sanomics, has received grants or research support from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, and XCovery, speakers' fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Taiho, and Takeda Oncology, honoraria from ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Fishawack Facilitate, Ignyta, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, OncoGenex Pharmaceuticals, Pfizer, Roche/Genentech, SFJ Pharmaceuticals, Takeda Oncology, and Vertex Pharmaceuticals, is a major stockholder in Sanomics, and is an advisory board member for ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, ChiMed, Cirina, Clovis Oncology, Eli Lilly, Fishawack Facilitate, geneDecode Co, Ignyta, Janssen, Pfizer, Merck Serono, Merck Sharp & Dohme, Novartis, Roche/Genentech, SFJ Pharmaceuticals, Takeda, and Vertex Pharmaceuticals. Y-LW has received honoraria from AstraZeneca, Eli Lilly, Pfizer, Pierre Fabre, Roche, and Sanofi, has had a consulting or advisory role with AstraZeneca, Boehringer Ingelheim, Merck, and Roche, and has received research funding to his institution from Boehringer Ingelheim and Roche. BCC has received honoraria from AstraZeneca, Boehringer Ingelheim, and Roche, has acted as a consultant or adviser for AstraZeneca, Roche and Boehringer Ingelheim, been a member of the speakers' bureau for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis, and has received research funding from AstraZeneca, Bayer, Novartis, and Yuhan. GC has held consulting or advisory roles for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche, been a member of the speakers' bureau for AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis, and payment for travel, accommodation, and expenses from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Roche. KK has received research funding from Boehringer Ingelheim, Ono, and Taiho. GML, JZ and DK are employees of Merck Sharp & Dohme. GL has received research funding to the institution from AstraZeneca, EMD Serono, and Merck & Co. The other authors declare no competing interests.
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