First-line pembrolizumab ± chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048

Abstract

Background: Here, we report the results of the Japanese subgroup of the phase 3 KEYNOTE-048 study of pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil (pembrolizumab-chemotherapy), or cetuximab plus platinum and 5-fluorouracil (EXTREME) in previously untreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

Methods: Primary end points were overall survival (OS) and progression-free survival (PFS). Efficacy was evaluated in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1 and the total Japanese subgroup (n = 67).

Results: At data cutoff (25 February 2019), pembrolizumab led to longer OS versus EXTREME in the PD-L1 CPS ≥ 20 subgroup (median, 28.2 vs. 13.3 months; HR, 0.29 [95% CI 0.09-0.89]) and to similar OS in the total Japanese (23.4 vs. 13.6 months; HR, 0.51 [95% CI 0.25-1.05]) and CPS ≥ 1 subgroups (22.6 vs. 15.8 months; HR, 0.66 [95% CI 0.31-1.41]). Pembrolizumab-chemotherapy led to similar OS versus EXTREME in the PD-L1 CPS ≥ 20 (median, 18.1 vs. 15.8 months; HR, 0.72 [95% CI 0.23-2.19]), CPS ≥ 1 (12.6 vs. 15.8 months; HR, 1.19 [95% CI 0.55-2.58]), and total Japanese subgroups (12.6 vs. 13.3 months; unadjusted HR, 1.10 [95% CI 0.55-2.22]). Median PFS was similar for pembrolizumab and pembrolizumab-chemotherapy versus EXTREME in all subgroups. Grades 3-5 treatment-related adverse events occurred in 5 (22%), 19 (76%), and 17 (89%) patients receiving pembrolizumab, pembrolizumab-chemotherapy, and EXTREME, respectively. One patient receiving pembrolizumab-chemotherapy died because of treatment-related pneumonitis.

Conclusion: These results support the use of first-line pembrolizumab and pembrolizumab-chemotherapy for Japanese patients with R/M HNSCC. Clinical trial registry ClinicalTrials.gov, NCT02358031.

Keywords: Combined positive score; First-line treatment; Head and neck squamous cell carcinoma; Japan; PD-L1; Pembrolizumab.

Conflict of interest statement

Shunji Takahashi has received grants, honoraria, and personal fees from MSD, Eisai, Novartis, Taiho Pharmaceutical Co, Chugai, Bayer, and Daiichi-Sankyo and AstraZeneca. Nobuhiko Oridate has received honoraria from MSD K.K., Tokyo, Japan, Ono Pharmaceutical, Bristol Myers Squibb Japan, Merck Biopharma Japan, and Taiho Pharmaceutical Co. Kaoru Tanaka has received personal fees from AstraZeneca, Merck Biopharma, Eisai, Bristol Myers Squibb, Ono Pharmaceutical, MSD, and Kyowa Kirin. Yasushi Shimizu has received grants and other from MSD. Tomoya Yokota has received grants from AstraZeneca, Chugai Pharma, MSD, Syneos Health, Lilly, Incyte, Novartis, GlaxoSmithKline, and Adlai Nortye; and personal fees from Abbott Japan, Ono Pharmaceutical, Chugai Pharma, Bristol Myers Squibb, Merck Biopharma, MSD, Rakuten Medical, and Eisai. Tomoko Yamazaki has received grants from MSD, AstraZeneca, and GlaxoSmithKline plc. Masanobu Takahashi has received grants from Ono Pharmaceutical; and personal fees from Ono Pharmaceutical, MSD, Bristol Myers Squibb, Daiichi Sankyo, and Taiho Pharmaceutical Co. Tsutomu Ueda has received grants from Ono Pharmaceutical; and personal fees from Ono Pharmaceutical, Merck Biopharma, Mitsubishi Tanabe Pharma, Taiho Pharmaceutical Co, Bayer, and Bristol Myers Squibb. Hiroki Hara has received grants from AstraZeneca, Daiichi Sankyo, Dainippon Sumitomo Pharma, Merck Biopharma, MSD, Taiho Pharmaceutical Co, Chugai, Eisai, Incyte, Boehringer-Ingelheim, Beigene, Ono Pharmaceutical, Astellas, Bayer, Janssen, and Amgen; honoraria from Asahi Kasei, Bayer, Bristol Myers Squibb, Chugai Pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma, MSD, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical Co, Takeda, and Yakult Honsha; reports leadership roles for Bristol Myers Squibb, Boehringer-Ingelheim, Daiichi Sankyo, Dainippon Sumitomo Pharma, MSD, and Ono Pharmaceutical. Koji Matsumoto has received honoraria from Chugai Pharma and Kyowa Kirin and grants from MSD, Eisai, Chugai Pharma, and Eli Lilly and Company. Yasushi Fujimoto, Nobuhiro Hanai, Hironori Yamaguchi, Tomokazu Yoshizaki, Ryuji Yasumatsu, Masahiro Nakayama, Kenji Mitsugi, and Kiyoto Shiga declare they have no conflicts of interest. Takashi Fuji has received personal fees from Ono Pharmaceutical, Taiho Pharmaceutical Co, Bristol Myers Squibb, Olympus, Merck Biopharma, Eisai, Kyorin Pharmaceutical, and MSD. Kenichi Takahashi is an employee of MSD K.K., Tokyo, Japan and owns stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Nijiro Nohata is an employee of MSD K.K., Tokyo, Japan and owns stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Burak Gumuscu is an employee of Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Ramona F. Swaby was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, at the time the study was conducted and owns stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Makato Tahara has received grants and personal fees from MSD, Ono Pharmaceutical, Bristol Myers Squibb, Bayer, Eisai, Novartis, Pfizer, Rakuten Medical, Merck Biopharma, LOXO, Celgene, and Amgen.

© 2022. Merck & Co., Inc., Rahway, NJ, USA and its affiliates.

Figures

Fig. 1

Kaplan–Meier estimates of overall survival in the Japanese subgroup. Pembrolizumab monotherapy versus EXTREME in the a PD-L1 CPS ≥ 20, b PD-L1 CPS ≥ 1, and c total Japanese subgroups. aFrom product-limit (Kaplan–Meier) method for censored data. bBased on Cox regression model with Efron’s method of tie handling, with treatment as a covariate. CI, confidence interval; CPS, combined positive score; EXTREME, cetuximab plus platinum and 5-fluorouracil; HR, hazard ratio; NR, not reached; OS, overall survival; PD-L1, programmed death ligand 1

Fig. 2

Kaplan–Meier estimates of overall survival in the Japanese subgroup. Pembrolizumab–chemotherapy versus EXTREME in the a PD-L1 CPS ≥ 20, b PD-L1 CPS ≥ 1, and c total Japanese subgroups. aFrom product-limit (Kaplan–Meier) method for censored data. bBased on Cox regression model with Efron’s method of tie handling, with treatment as a covariate. CI, confidence interval; CPS, combined positive score; EXTREME, cetuximab plus platinum and 5-fluorouracil; HR, hazard ratio; NR, not reached; OS, overall survival; PD-L1, programmed death ligand 1

Fig. 3

Kaplan–Meier estimates of progression-free survival in the Japanese subgroup. Pembrolizumab monotherapy versus EXTREME in the a PD-L1 CPS ≥ 20, b PD-L1 CPS ≥ 1, and c total Japanese subgroups. aFrom product-limit (Kaplan–Meier) method for censored data. bBased on Cox regression model with Efron’s method of tie handling, with treatment as a covariate. CI, confidence interval; CPS, combined positive score; EXTREME, cetuximab plus platinum and 5-fluorouracil; HR, hazard ratio; NR, not reached; PD-L1, programmed death ligand 1; PFS, progression-free survival

Fig. 4

Kaplan–Meier estimates of progression-free survival in the Japanese subgroup. Pembrolizumab–chemotherapy versus EXTREME in the a PD-L1 CPS ≥ 20, b PD-L1 CPS ≥ 1, and c total Japanese subgroups. aFrom product-limit (Kaplan–Meier) method for censored data. bBased on Cox regression model with Efron’s method of tie handling with treatment as a covariate. CI, confidence interval; CPS, combined positive score; EXTREME, cetuximab plus platinum and 5-fluorouracil; HR, hazard ratio; NR, not reached; PD-L1, programmed death ligand 1; PFS, progression-free survival

Fig. 5

Treatment exposure and response duration in the Japanese subgroup receiving pembrolizumab monotherapy, pembrolizumab–chemotherapy, and EXTREME. aPatients in the EXTREME arm who were not included in the comparison analysis of pembrolizumab–chemotherapy versus EXTREME because they were enrolled in the EXTREME arm while enrollment in the pembrolizumab–chemotherapy arm was temporarily halted. CR, complete response; EXTREME, cetuximab plus platinum and 5-fluorouracil; PD, progressive disease; PR, partial response

Fig. 6

Change from baseline in target lesion size in the Japanese Subgroup receiving a pembrolizumab monotherapy (n = 23), b pembrolizumab with chemotherapy (n = 24),a and c EXTREME (n = 19). aTarget lesion size data with confirmation by blinded independent central review were not available for one patient in the pembrolizumab–chemotherapy arm. EXTREME, cetuximab plus platinum and 5-fluorouracil