Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial.

Background: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC.
Methods: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m ² ) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting.
Findings: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1-52·3). Median event-free survival was not reached (95% CI 44·7 months-not reached) in the pembrolizumab group and 46·6 months (27·5-not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68-1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis).
Interpretation: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches.
Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
Competing Interests: Declaration of interests J-PM, YT, LL, BBu, MTah, DR, GA, IPFL, BGMH, YP, SA, SL, RG, MB, MH, J-PD, RM, MTab, JNW, CS, VG, KJH, and LLS report funding to their institution from Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co, Rahway, NJ, USA to support conduct of this study. J-PM, YT, LL, BBu, MTah, DR, GA, IPFL, BGMH, YP, SA, SL, RG, MB, MH, J-PD, RM, MTab, JNW, CS, VG, KJH, RFS, YZ, BG, BBi, and LLS received medical writing and editorial support for the preparation of this manuscript from MSD. J-PM additionally reports receiving consulting fees managed by the institution for serving as an advisory board member or speaker from Pfizer, Roche, Bayer, Merck Serono, Boehringer, Bristol Myers Squibb (BMS), Novartis, Incyte, Cue Biopharma, ALX Oncology, iTEOS, eTheRNA, NEKTAR, F-Star, Seagen, Genmab, Astellas, CureVac, MSD, GSK, and Merus; receiving travel support managed by the institution from Amgen, BMS, Pfizer, MSD, Gilead, and Sanofi; participating on a data safety monitoring board or advisory board for Psioxus; and serving as the Chair of the EORTC Head and Neck group. YT additionally reports payment or honoraria to themselves from MSD, Merck Serono, and Beigene, and travel support from MSD and Merck Serono. LL additionally reports study funding to their institution from Adlai Nortye, AstraZeneca, BMS, Debiopharm International, Eisai, Eli Lilly and Company, Exelixis, F Hoffman-La Roche, Isa Therapeutics, Kura Oncology, Merck Serono, MSD, Nektar Therapeutics, Novartis, Regeneron, Roche, Sanofi, Syneos, Sun Pharmaceutica, Incyte Biosciences International, Gilead Sciences, Genmab, and Merck Healthcare; consulting fees from MSD IT, Merck Serono Spa Healthcare Professional, Merck Healthcare, GSK, F Hoffman-La Roche, GroupH, ALX Oncology, EMD Serono Research & Development Institute, and Boehringer Ingelheim International; payment or honoraria from Merck Serono Spa, MSD IT, Merck Healthcare, Adlai Nortye, BMS, and ALTIS Omnia Pharma Service; travel support from TAE Life Science; and receiving occasional fees for participation as a speaker at conferences or as a scientific consultant for advisory boards from Merck Healthcare, Neutron Therapeutics, Merck & Co, AstraZeneca, MSD IT, EMD Serono Research & Development Institute, Mirati Therapeutics, F Hoffman-La Roche, Novartis Farma Spa, Janssen Research & Development, Seagen International, Eisai Europe, Genmab US, AstraZeneca UK, and AbbVie. BBu additionally reports participating on an advisory board for and receiving travel support for attending advisory board meetings from MSD. MTah additionally reports honoraria for lectures from MSD and participation on an advisory board for MSD. DR additionally reports study funding to their institution from MSD, GSK, Regeneron, Roche, BMS, Kura, ALX Oncology, Decibel Therapeutics, Eisai, and AstraZeneca and participating on an advisory board (no payment accepted) from MSD, Regeneron, and Sanofi. GA additionally reports receiving grants from MSD, BMS, Merck-Serono, Roche, Pfizer, AstraZeneca, Beigene, Ipsen, and Janssen; serving as an adviser for Merck-Serono and Janssen; and receiving travel support from Janssen. BGMH additionally reports participating on advisory boards for MSD, BMS, Pfizer, AstraZeneca, Eisai, Sanofi, and Takeda. YP additionally reports receiving payment for presenting during a congress symposium from MSD and Merck. SL additionally reports receiving honoraria to the institution for participating on an advisory board from MSD, BMS, and Sanofi Genzyme; receiving travel support to the institution from MSD; and having a pending patent for use of peptides for the vaccination of oropharyngeal cancer (22187930.7-1111). RG additionally reports consulting fees from Celgene, Novartis, Roche, BMS, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Amgen, Merck, Gilead, Daiichi Sankyo, and Sanofi; payment or honoraria from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, and Sanofi; travel support from Roche, Amgen, Janssen, AstraZeneca, Novartis, MSD, Celgene, Gilead, BMS, AbbVie, and Daiichi Sankyo; participation on a data safety monitoring board or advisory board for Celgene, Novartis, Roche, BMS, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Amgen, Merck, Gilead, Daiichi Sankyo, and Sanofi; stock or stock options in Novo Nordisk and Lilly; and research funding to the institution from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, and Daiichi Sankyo. MH additionally reports receiving honoraria for lectures from AstraZeneca. JPD additionally reports funding to the institution from AstraZeneca, Amgen, BMS, Genentech, and Transgene; receiving fees to the institution for serving as an invited speaker from Merck Serono; and receiving consulting fees to the institution for serving as an advisory board member from BMS, MSD, Roche-Genentech, and Pierre Fabre. RM additionally reports receiving payment or honoraria from MSD and Merck; receiving travel support from MSD, Merck, Roche, and BMS; and participating on advisory boards for MSD, Merck, Roche, Seagen, Boehringer, Seattle Genetics, Nanobiotix, and Bayer. KJH additionally reports receiving payment in kind to the institution through provision of reagents for experiments on radiation–immunotherapy combinations from AstraZeneca, funding and honoraria to the institution in supports of research on radiation-immunotherapy combinations from Boehringer Ingelheim, consulting fees to the institution from Arch Oncology, AstraZeneca, Boehringer-Ingelheim, Codiak Biosciences, F-start Therapeutics, Inzen Therapeutics, Johnson & Johnson, Merck Serono, MSD, Oncolys Biopharma, Pfizer, Replimmune, and VacV Therapeutics; and payment or honoraria to the institution from Merck Serono, MSD, and Replimmune. RFS additionally reports receiving salary for full-time employment from MSD during part of the time the study was conducted. YZ additionally reports receiving salary for full-time employment from MSD at the time the study was conducted. BG reports holding stock in Merck & Co and receiving salary for full-time employment from MSD. BBi reports holding stock in Merck & Co and receiving salary for full-time employment from MSD. LLS additionally reports receiving funding to the institution to support clinical trials from Novartis, BMS, Pfizer, Boehringer-Ingelheim, GSK, Roche/Genentech, AstraZeneca, Merck, Celgene, Astellas, Bayer, AbbVie, Amgen, Symphogen, Shattucks, BioNTech, 23Me, and EMD Serono; receiving consulting or advisory fees from Merck, Pfizer, AstraZeneca, Roche, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Daiichi Sankyo, Coherus, Marengo, InteRNA, Tubulis, LTZ Therapeutics, and NGM Biotherapeutics; participating on a data safety monitoring board or advisory board without compensation for Mirati Therapeutics; and reports that their spouse owns stock in Agios; and is a cofounder of Treadwell Therapeutics.
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