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Randomized Controlled Trial
. 2021 Jul;32(7):881-895.
doi: 10.1016/j.annonc.2021.04.008. Epub 2021 Apr 22.

Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189

D Rodríguez-Abreu  1 , S F Powell  2 , M J Hochmair  3 , S Gadgeel  4 , E Esteban  5 , E Felip  6 , G Speranza  7 , F De Angelis  7 , M Dómine  8 , S Y Cheng  9 , H G Bischoff  10 , N Peled  11 , M Reck  12 , R Hui  13 , E B Garon  14 , M Boyer  15 , T Kurata  16 , J Yang  17 , M C Pietanza  17 , F Souza  17 , M C Garassino  18
Affiliations
Free article
Randomized Controlled Trial

Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189

D Rodríguez-Abreu et al. Ann Oncol. 2021 Jul.
Free article

Abstract

Background: In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab.

Patients and methods: Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators' choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed-platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS.

Results: After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed-platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed-platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed-platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed-platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed-platinum and 66.8% of patients receiving placebo plus pemetrexed-platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off.

Conclusions: Pembrolizumab plus pemetrexed-platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed-platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC.

Keywords: chemotherapy; nonsquamous non-small-cell lung cancer; pembrolizumab.

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Conflict of interest statement

Disclosure DR-A: Honoraria for lectures and consulting from BMS, MSD, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Roche, Novartis, and Pfizer. Study funding to institution from MSD. SFP: Study funding to institution from Bristol-Myers Squibb, Genentech, Incyte, Merck Sharp & Dohme, Pfizer, Novartis, Seattle Genetics, Actuate, and Vyriad. Consulting support to the institution from Bristol-Myers Squibb. MJH: Study funding to institution from MSD. SG: Received personal fees from Merck, AstraZeneca, Genentech/Roche, Takeda/Ariad, Boehringer Ingelheim, Novocure, Bristol-Myers Squibb, AbbVie, Xcovery, Janssen, Pfizer, and Jazz Pharmaceuticals. Study funding to institution from MSD. Research funding from Merck. EE: Study funding to institution from MSD. EF: Received personal fees as an advisor, consultant, and/or speaker from AbbVie, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Touchtime, BerGenBio, and Samsung; and is an independent member of the Board for Grífols. Study funding to institution from MSD. GS: Study funding to institution from MSD. FdA: Study funding to institution from MSD. MD: Received personal fees as an advisor and/or lecturer from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Pfizer, and Roche. Study funding to institution from MSD. SYC: Study funding to institution from MSD. HGB: Study funding to institution from MSD. NP: Received grants, personal fees, and/or honoraria as an advisor from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, NovellusDx, Foundation Medicine, and Guardant360. Study funding to institution from MSD. MR: Received personal fees/honoraria for consultancy and lectures from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Merck, MSD, Eli Lilly, Pfizer, AbbVie, Roche, and Novartis. Study funding to institution from MSD. RH: Received personal fees for advisory boards from MSD, AstraZeneca, BMS, Eli Lilly, Merck, Novartis, Oncosec, Pfizer, Roche, and Seagen; and speaker honoraria from MSD, Novartis, and Roche. Study funding to institution from MSD. EBG: Received grants and research support to the institution during the conduct of this study from Merck; has received grants from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, Merck, Novartis, Dynavax, Mirati Therapeutics, and Iovance Biotherapeutics; and payment for advisory boards/steering committees from Dracen Pharmaceuticals, EMD Serono, and Novartis. Study funding to institution from MSD. MB: Received grants and non-financial support from Merck Sharp & Dohme during the conduct of this study; has received grants and non-financial support from AstraZeneca and Genentech/Roche; and grants from Bristol-Myers Squibb, Amgen, Pfizer, and Novartis. Study funding to institution from MSD. TK: Received lecture fees, honoraria, or other fees from MSD, Ono, Bristol-Myers Squibb, AstraZeneca, Chugai, Eli Lilly, Boehringer Ingelheim; and research funds from MSD, AstraZeneca, Takeda, Bristol-Myers Squibb, and Novartis. Study funding to institution from MSD. JY: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. MCP: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. FS: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. MCG: Received grants and personal fees during the conduct of this study from MSD; has received grants and personal fees for clinical trials from AstraZeneca, Novartis, Bristol-Myers Squibb, Roche, Pfizer, Celgene, Bayer, and MSD; grants from Tiziana Life Sciences, Clovis, Merck Serono, GlaxoSmithKline, and Spectrum Pharmaceuticals; and personal fees from Eli Lilly, Boehringer Ingelheim, Otsuka Pharmaceutical Co., Ltd., Incyte, Inivata, Takeda, and Sanofi-Aventis. Study funding to institution from MSD.

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