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Randomized Controlled Trial
. 2018 Nov;125:273-281.
doi: 10.1016/j.lungcan.2018.08.019. Epub 2018 Aug 25.

Pembrolizumab and Platinum-Based Chemotherapy as First-Line Therapy for Advanced Non-Small-Cell Lung Cancer: Phase 1 Cohorts From the KEYNOTE-021 Study

Free PMC article
Randomized Controlled Trial

Pembrolizumab and Platinum-Based Chemotherapy as First-Line Therapy for Advanced Non-Small-Cell Lung Cancer: Phase 1 Cohorts From the KEYNOTE-021 Study

Shirish M Gadgeel et al. Lung Cancer. .
Free PMC article


Objectives: Platinum-based chemotherapy for advanced non-small-cell lung cancer (NSCLC) has modest benefit overall, but has the potential to amplify immune responses. In cohorts A-C of the multicohort phase 1/2 study KEYNOTE-021 (, NCT02039674), we evaluated combinations of platinum-doublet chemotherapy with the anti-programmed death 1 monocloncal antibody pembrolizumab.

Materials and methods: Patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations were randomized to pembrolizumab 2 or 10 mg/kg Q3W plus carboplatin area under the serum concentration-time curve (AUC) 6 mg/mL/min plus paclitaxel 200 mg/m2 (cohort A, any histology), carboplatin AUC 6 mg/mL/min plus paclitaxel 200 mg/m2 plus bevacizumab 15 mg/kg (cohort B, non-squamous), or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m2 (cohort C, non-squamous) for 4 cycles followed by maintenance pembrolizumab (cohort A), pembrolizumab plus bevacizumab (cohort B), or pembrolizumab plus pemetrexed (cohort C). Response was assessed by blinded independent central review.

Results: Overall, 74 patients were randomized; median follow-up was 21.4, 16.4, and 17.4 months in cohorts A, B, and C, respectively. No dose-limiting toxicities occurred in any cohort at either pembrolizumab dose. Most frequent treatment-related adverse events (AEs) were alopecia, fatigue, and nausea. Treatment-related grade 3/4 AEs occurred in 40%, 42%, and 46% of patients in cohorts A, B, and C, respectively; AEs with possible immune etiology occurred in 24%, 50%, and 38% of patients, respectively. Objective response rates were 48%, 56%, and 75% in cohorts A, B, and C, respectively.

Conclusion: Pembrolizumab in combination with carboplatin-paclitaxel and with pemetrexed-carboplatin yielded encouraging antitumor activity and toxicity consistent with known toxicities of platinum-based chemotherapy or pembrolizumab monotherapy.

Keywords: Antineoplastic agents; Bevacizumab; Carcinoma; Combination; Drug therapy; Non–small-cell lung; Pembrolizumab.

Conflict of interest statement

Author conflict of interest

Gadgeel: Honoraria from Genentech-Roche and AstraZeneca; consulting for Pfizer, AstraZeneca, Genentech-Roche, ARIAD, Bristol-Myers Squibb, and Novartis.

Stevenson: Research funding from Merck, Bayer, and Bristol-Myers Squibb.

Langer: Grants from Merck, Clovis, GSK, Genentech-Roche, Advantagene, and Inovio; personal fees from Lilly, AZ, Clovis, Bristol-Myers Squibb, Genentech-Roche, Synta, Abbvie, and Amgen.

Gandhi: Advisory boards for Genentech/Roche, Merck, AstraZeneca and Ignyta; paid consulting for Celldex and Eli Lilly; research funding from Bristol-Myers Squibb IION Foundation and Merck; current employee of Eli Lilly and Company as of June 25, 2018.

Borghaei: Advisory boards for Bristol-Myers Squibb, Lilly, Celgene, Genenetch, Novartis, Astra Zeneca, Trovagene, Merck, EMD-Serono, and Pfizer; research funding from Celgene, Merck, and Millennium; honoraria from Celgene; travel expenses from all companies listed here.

Patnaik: Research funding from Merck to institution.

Villaruz: None declared.

Gubens: Advisory boards for AbbVie, ARIAD, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Mersana, and Novartis; research funding from Celegne, Merck, Novartis, OncoMed, and Roche.

Hauke: Honoraria from Best Doctors, Inc; research funding by US Oncology, Bristol-Myers Squibb, Merck, Amgen, SOTIO, and Pharmacyclics; stock ownership for Aethlon; patent pending on an immunotherapeutic.

Yang: Personal fees from Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis Oncology, Celgene, Merrimack, Yuhan Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, and AstraZeneca.

Sequist: Advisory boards for AstraZeneca, Bristol-Myers Squibb, ARIAD, and Genentech; research funding from Clovis, Novartis, Boehringer Ingelheim, Merrimack, Merck, and AstraZeneca.

Bachman: employee of Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Saraf: employee of Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Raftopoulos: employee of Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Papadimitrakopoulou: Advisory boards for Bristol-Myers Squibb, AstraZeneca, Celgene, Janssen, Merck, OncLive, Genentech, Merck & Co, Araxes Pharma, LLC, Nektar Therapeutics, Takeda Pharmaceuticals, and Eli Lilly & Co.; speakers’ bureau for Creative Educational Concepts (CEC Oncology); research funding from Merck & Co., NIH/NCI, Bristol-Myers Squibb, Oregon Health Science University, Cancer Prevention & Research Institute of Texas (CPRIT), and American Association for Cancer Research (AACR).


Fig. 1.
Fig. 1.
Disposition of patients in the study. aOne patient in cohort B withdrew before receiving study treatment.
Fig. 2.
Fig. 2.
Kaplan-Meier analysis of progression-free survival by blinded independent central review and overall survival in patients enrolled the pembrolizumab and carboplatin-paclitaxel cohort (A) and (B), the pembrolizumab and carboplatin-paclitaxel-bevacizumab cohort (C) and (D), and the pembrolizumab and carboplatin-pemetrexed cohort (E) and (F). Outcomes are pooled for the pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W dose groups within each cohort. PFS, progression-free survival. NR, not reached. OS, overall survival.

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