Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: 5-year follow-up from the randomized phase III KEYNOTE-048 study
- PMID: 40262400
- DOI: 10.1016/j.ejca.2025.115395
Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: 5-year follow-up from the randomized phase III KEYNOTE-048 study
Abstract
Background: Pembrolizumab monotherapy and pembrolizumab-chemotherapy demonstrated superior overall survival (OS) versus cetuximab-chemotherapy (EXTREME) in the primary analysis of the phase III KEYNOTE-048 study of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the first-line setting. We report updated data with 5 years of follow-up.
Methods: Adults with previously untreated R/M HNSCC incurable by local therapy were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab plus chemotherapy, or EXTREME. The primary endpoints were OS and progression-free survival (PFS).
Results: Overall, 882 participants were assigned to pembrolizumab, pembrolizumab-chemotherapy, or EXTREME. Median study follow-up was 69.2 months (pembrolizumab) and 68.6 months (pembrolizumab-chemotherapy). Median OS remained longer for pembrolizumab versus EXTREME in the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20 (HR, 0.61; 95 % CI, 0.46-0.81) and CPS ≥ 1 populations (HR, 0.74; 95 % CI, 0.61-0.89), and similar in the total population (HR, 0.82; 95 % CI, 0.69-0.97). Pembrolizumab-chemotherapy prolonged median OS in the PD-L1 CPS ≥ 20 (HR, 0.63; 95 % CI, 0.47-0.84), CPS ≥ 1 (HR, 0.65; 95 % CI, 0.53-0.79), and total (HR, 0.72; 95 % CI, 0.60-0.86) populations. The 5-year OS rate in the total population was 14.4 % for pembrolizumab versus 6.5 % for EXTREME and 16.0 % for pembrolizumab-chemotherapy versus 5.2 % for EXTREME. There was no clinically meaningful difference in PFS among pembrolizumab, pembrolizumab-chemotherapy, or EXTREME groups in any populations.
Conclusions: These 5-year follow-up results support the use of pembrolizumab and pembrolizumab-chemotherapy as first-line standards of care for R/M HNSCC.
Clinical trial information: NCT02358031.
Prior presentation: Presented at the European Society for Medical Oncology Congress, September 9-13, 2022.
Keywords: Chemotherapy; Pembrolizumab; Programmed cell death ligand 1; Recurrent/metastatic head and neck squamous cell carcinoma.
Copyright © 2025. Published by Elsevier Ltd.
Conflict of interest statement
Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Makoto Tahara received honoraria from Bristol Myers Squibb, Eisai, Ono Pharmaceutical, MSD, Lilly, Bayer, Merck Serono, and Novartis; holds a consulting or advisory role for Ono Pharmaceutical, MSD, Pfizer, Bristol Myers Squibb, Rakuten Medical, Bayer, Lilly, Eisai, Boehringer Ingelheim, Genmab, Janssen, Nanobiotix, Astellas Pharma, GlaxoSmithKline, and Merck KgaA; and received research funding (institution) from Merck Sharp & Dohme, AstraZeneca, Ono Pharmaceutical, Novartis, Pfizer, Bristol Myers Squibb, Rakuten Medical, Bayer, GlaxoSmithKline, Lilly, and Merck Serono. Richard Greil owns stock and other stock ownership interests (institutional) in Novo Nordisk and Lilly; received honoraria from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, MSD, Sandoz, AbbVie, Gilead Sciences, Daiichi Sankyo, and Sanofi; holds a consulting or advisory role for Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Merck, Gilead Sciences, Daiichi Sankyo, and Sanofi; received research funding (institution) from Celgene, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, MSD, Sandoz, Gilead Sciences, Roche, Daiichi Sankyo Europe GmbH, and (personal) AbbVie; and received support for travel, accommodations, or expenses from Roche, Amgen, Janssen-Gilag, AstraZeneca, Novartis, MSD, Celgene, Gilead Sciences, Bristol Myers Squibb, AbbVie, and Daiichi Sankyo. Danny Rischin received research funding (institution) from Genentech/Roche, Merck, Regeneron, GlaxoSmithKline, Sanofi, Decibel Therapeutics, ALX Oncology, AstraZeneca, and Erasca, Inc; and has uncompensated relationships with Regeneron, Merck, GlaxoSmithKline, Sanofi, and Eisai. Kevin Harrington received honoraria (institution) from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Serono, MSD, RepImmune, Johnson and Johnson, Nanobiotix, ALX Oncology, BeiGene, GlaxoSmithKline, Bicara Therapeutics, Merus, PDS Biotechnology, Exelixis, Flamingo Pharma, PsiVac Ltd, and (personal) Scenic Biotech; holds a consulting or advisory role (institution) for AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Serono, MSD, RepImmune, and Nanobiotix; and served on a speaker’s bureau (institution) for Bristol Myers Squibb, Merck Serono, and MSD; received research funding (institution) from AstraZeneca, RepImmune, and Boehringer Ingelheim. Barbara Burtness holds a consulting or advisory role for Merck, CUE Biopharma, Macrogeneics, ALX Oncology, IO Biotech, Genentech/Roche, Kura Oncology, Merck KGaA, Coherus Biosciences, Arvinas, AbbVie, Vaccinex, Rakuten Medical, Eisai, Mirati Therapuetics, Orphagen Pharmaceuticals, Merus, Seagen, and Janssen Oncology; served on a speaker’s bureau for Clinical Education Alliance and Oncology Education; received research funding (institution) from Merck, Exelixis, CUE Biopharma, Merck, and IO Biotech; and has given expert testimony for Cel-Sci Corporation. Gilberto de Castro received honoraria from AstraZeneca, Pfizer, Merck Sharp & Dohme, Bristol Myers Squibb, Novartis, Roche, Amgen, Janssen, Merck Serono, Lilly, Takeda, and Daiichi Sankyo/UCB Japan; holds a consulting or advisory role for Boehringer Ingelheim, Pfizer, Bayer, Roche, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Yuhan, Merck Serono, Janssen, Libbs, Sanofi, Novartis, Lilly, Takeda, and Daiichi Sankyo/UCB Japan; served on a speaker’s bureau for AstraZeneca, Bayer, Novartis, Roche, Merck Serono, Bristol Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, Pfizer, Janssen, Amgen, Takeda, and Daiichi Sankyo/UCB Japan; and received support for travel, accommodations, or expenses from Merck Sharp & Dohme, Novartis, Pfizer, Roche, AstraZeneca, Boehringer Ingelheim, Bayer, Bristol Myers Squibb, Merck Serono, and Daiichi Sankyo/UCB Japan. Amanda Psyrri received honoraria from Merck Serono, Roche, Bristol Myers Squibb, MSD Oncology, Genesis Pharmaceuticals, Bayer, AstraZeneca, Pfizer, GlaxoSmithKline, Seagen, and Merus NV; holds a consulting or advisory role for AstraZeneca, MSD Oncology, Pfizer, Bristol Myers Squibb, Amgen, eTheRNA Immunotherapies, GlaxoSmithKline, Seagen, and Merus NV; received research funding from Kura Oncology, Bristol Myers Squibb, Roche, Amgen, Boehringer Ingelheim, Pfizer, Demo Pharmaceutical, and Pharmathen; received support for travel, accommodations, or expenses from Roche, MSD Oncology, Ipsen, and Bristol Myers Squibb; and has uncompensated relationships with AstraZeneca. Irene Brana holds a consulting or advisory role for Merck Sharp & Dohme, Sanofi, Achilles Therapeutics, eTheRNA Immunotherapies, Cancer Expert Now, Boehringer Ingelheim, Merus, Bristol Myers Squibb, Merck Serono, Roche, and MSD; served on a speaker’s bureau for Bristol Myers Squibb, Merck Serono, Roche, and MSD; received research funding (institution) from AstraZeneca, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Gliknik, Janssen Oncology, Kura Oncology, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Shattuck Labs, Nanobiotix, Seagen, Immutep, Debiopharm Group, Regeneron, Boehringer Ingelheim, ISA Pharmaceuticals, Merck Serono, Northern Biologics, VCN Biosciences, Tolremo, and Merus; and received support for travel, accommodations, or expenses from MSD Oncology. Prakash Neupane received honoraria from Merck and research funding from Merck Sharp & Dohme. Ase Bratland received honoraria from MSD Oncology, Bristol Myers Squibb, Sanofi, and Merck Serono; research funding (institution) from Bristol Myers Squibb and MSD Oncology; and support for travel, accommodations, or expenses from MSD Oncology. Thorsten Fuereder received honoraria from MSD, Bristol Myers Squibb/Celgene, Roche, Merck KGaA, Pfizer, Boehringer Ingelheim, and Amgen; holds a consulting or advisory role for Merck KGaA, MSD, Amgen, Boehringer Ingelheim, Janssen, Takeda, Invios, and Lilly; received research funding (institution) from MSD, Merck KGaA, Bristol Myers Squibb/Celgene, and Kura Oncology; and support for travel, accommodations, or expenses from MSD, Bristol Myers Squibb/Celgene, and Merck KGaA. Brett Hughes holds a consulting or advisory role for MSD Oncology, Bristol Myers Squibb, Roche, Pfizer, AstraZeneca, Eisai, Takeda, and Sanofi/Aventis and received research funding (institution) from Amgen. Ricard Mesia holds a consulting or advisory role for MSD, Merck KGaA, Roche, Seagen, Boehringer Ingelheim, GlaxoSmithKline, and PDS Biotechnology; served on a speaker’s bureau for Bristol Myers Squibb, Merck KGaA, MSD, and Boehringer Ingelheim; and received support for travel, accommodations, or expenses from Bristol Myers Squibb. Nuttapong Ngamphaiboon received research funding (institution) from MSD, Roche, Exelixis, RAPT Therapeutics, BeiGene, and Pfizer; honoraria from Roche, AstraZeneca, Amgen, MSD, and Taiho; and participates on an advisory board for MSD, Amgen, Novartis, Bayer, AstraZeneca, Claris, and Eli Lilly. Tamara Rordorf has no conflicts of interest. Wan Zamaniah Wan Ishak served as an invited speaker and on a speaker’s bureau and advisory board for Merck, Amgen, and Roche; served as an invited speaker and on an advisory board for AstraZeneca and Eisai; served as an invited speaker for Pfizer; received research funding from Merck; received funding from Amgen, Roche, AstraZeneca, and Eisai; provided expert testimony for Roche, and was involved in writing engagements for Roche and Merck. Jianxin Lin is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA owns stock in Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Burak Bumuscu is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and owns stock in Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Nati Lerman is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA owns stock in Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Denis Soulieres received honoraria from Merck, Novartis, Pfizer, AstraZeneca, Ipsen, Bristol Myers Squibb, Eisai, and Adlai Nortye; holds a consulting or advisory role for Merck, Pfizer, Ipsen, Adlai Nortye, and Eisai; and received research funding (institution) from Novartis, Pfizer, Merck, Roche/Genentech, Bristol Myers Squibb, Lilly, Adlai Norye, and GlaxoSmithKline.
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