LBA5 - Primary results of the phase III KEYNOTE-412 study: Pembrolizumab (pembro) with chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC)

Background

Pembro is approved as monotherapy or in combination with chemotherapy for recurrent/metastatic HNSCC. The randomized, double-blind, phase 3 KEYNOTE-412 (NCT03040999) study investigated the efficacy and safety of pembro + CRT vs placebo + CRT in patients (pts) with LA-HNSCC.

Methods

Pts with newly diagnosed, pathologically proven, treatment-naive LA-HNSCC (T3–T4 [N0–N3] or any N2a–3 [T1–T4] larynx/hypopharynx/oral cavity/p16-negative oropharynx cancers and T4 or N3 p16-positive oropharynx cancer) who were eligible for definitive CRT were randomized (1:1) to pembro 200 mg Q3W + CRT (70Gy/35F + cisplatin 100 mg/m² Q3W) followed by pembro or placebo Q3W + CRT followed by placebo. A pembro/placebo priming dose was given 1 wk before CRT, followed by 2 doses during CRT and 14 doses of maintenance therapy after CRT, for a total of 17 doses. Primary endpoint was EFS (Efficacy boundary, one-sided P=0.0242). OS and safety/tolerability were secondary endpoints.

Results

804 pts were randomized (402 pts in each arm). Overall, baseline characteristics were well balanced between arms. At data cutoff (May 31, 2022) for the final analysis, median time from randomization to data cutoff was 47.7 (range, 37.0-61.4) mo. There was a favorable trend toward improved EFS with adding pembro vs placebo to CRT (HR 0.83, P=0.0429; Table), but the difference did not achieve statistical significance. AEs were grade ≥3 in 92.2% of pts in the pembro arm vs 88.4% in the placebo arm and led to discontinuation of cisplatin, RT, and/or pembro/placebo in 41.2% vs 33.2%; treatment-related AEs led to death in 1.0% vs 1.5%. Table: 000LBA5

*Per the statistical analysis plan, the OS difference would be tested only if there was a significant difference in EFS.

Conclusions

Pembro + CRT was associated with a favorable trend toward improved EFS vs placebo + CRT in patients with LA-HNSCC, but the difference did not reach statistical significance. No new safety signals were seen.

Clinical trial identification

NCT03040999.

Editorial acknowledgement

Medical writing assistance was provided by Yue Liu of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

J. Machiels: Financial Interests, Institutional, Advisory Board: Novartis, Pfizer, Roche, Debio, AstraZeneca, Innate, Nanobiotix, Bayer, Merck-Serono, Boerhinger-Ingelheim, BMS, Pfizer, Cue Pharma, Incyte, Janssen, Johnson & Johnson, ALX Oncology; Financial Interests, Institutional, Advisory Board, uncompensated: MSD; Financial Interests, Institutional, Invited Speaker: AstraZeneca, MSD, MSD, iTeos, eTheRNA, Pfizer, Ceylad, MSD, Novartis, KURA, Roche, Lilly, Boehringer, Sanofi-Aventis, Incyte, Bayer, Merck - Serono, Janssen, Johnson & Johnson, Amgen, AbbVie, GalxoSmithKline; Non-Financial Interests, Leadership Role, Chair: EORTC Head and Neck Group. Y. Tao: Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Sponsor/Funding: Travel with MSD and Merck Serono. B. Burtness: Financial Interests, Personal, Invited Speaker: Fred Hutchinson Cancer Center, Massachusetts General Hospital, Stand Up to Cancer; Non-Financial Interests, Personal, Invited Speaker: National Cancer Institute, American Society of Clinical Oncology, Gordon Research Conference; Financial Interests, Personal, Speaker’s Bureau: I3 Health Clinical Education Alliance; Financial Interests, Personal, Advisory Board: Merck, Merck KgA, Debio, Kura, AstraZeneca, Genentech, Nektar, ALX Oncology, Actinium, Cue BioPharma, Janssen, Vaccinex; Financial Interests, Personal, Full or part-time Employment: Yale University; Financial Interests, Institutional, Research Grant: Merck, Cue, Vaccinex; Financial Interests, Personal and Institutional, Principal Investigator: National Institutes of Health Department of Defense Stand Up to Cancer Fanconi Anemia Research Foundation; Non-Financial Interests, Personal, Member: ECOG-ACRIN Oncology Research Group ASCO AACR ESMO; Financial Interests, Personal, Advisory Role: Mirati. M. Tahara: Financial Interests, Personal, Advisory Board: Merck Biopharma, Ono Pharma, Bristol Myers Squibb, MSD, Pfizer, Bayer, Lilly, Rakuten Medical, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Institutional, Invited Speaker: MSD, AstraZeneca, Ono Pharma, Novartis, Pfizer, Bristol-Myers Squibb, Loxo, GlaxoSmithKline, Lilly, Rakuten Medical; Financial Interests, Institutional, Research Grant: Bayer. D. Rischin: Non-Financial Interests, Institutional, Invited Speaker: Sanofi, MSD; Non-Financial Interests, Institutional, Advisory Board: MSD, Regeneron, BMS, GSK, Sanofi; Non-Financial Interests, Personal and Institutional, Principal Investigator: MSD, Merck KGgA, Regeneron, Sanofi, Roche, BMS, GSK, Kura, ALX Oncology; Financial Interests, Institutional, Sponsor/Funding: MSD, Merck KGgA, Regeneron, Sanofi, Roche, BMS, GSK, ALX Oncology. G.V. Alves: Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK; Financial Interests, Personal, Advisory Board: Merck Seromo, MSD; Financial Interests, Personal and Institutional, Principal Investigator: Roche, AstraZeneca, MSD, Bristol, Janssen, Merck Seromo, Beigene, GSK. Y. Pointreau: Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Advisory Board: MSD BMS. S. Laban: Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Speaker’s Bureau: Merck Sharp & Dohme, Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board: Merck Sharp & Dohme, Bristol Myers Squibb, Sanofi Genzyme; Financial Interests, Institutional, Principal Investigator: ISA Pharmaceuticals. R. Greil: Financial Interests, Personal, Funding: Celgene, Roche, Merck, Takeda, AstraZeneca Novartis, Amgen, BMS, MSD, Sandoz, AbbVie Gilead, Daiichi Sankyo, Sanofi; Financial Interests, Personal, Advisory Board: Celgene, Novartis, Roche, BMS, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Merck, Gilead, Daiichi Sankyo, Sanofi; Financial Interests, Institutional, Research Grant: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie Gilead, Daiichi Sankyo; Financial Interests, Personal, Sponsor/Funding: Roche, Amgen, Janssen, AstraZeneca, Novartis, MSD, Celgene, Gilead, BMS, AbbVie, Daiichi Sankyo. M. Burian: Financial Interests, Personal, Advisory Board: MSD Austria, BMS Austria. M. Hetnal: Financial Interests, Personal and Institutional, Principal Investigator: Rydygier Memorial Hospital in Krakow. L.F. Licitra: Financial Interests, Personal, Advisory Board, for expert opinion in advisory boards: AstraZeneca, Bayer, BMS, Eisai, MSD, Merck Serono, Boehringer Ingelheim, Hoffmann-La Roche Ltd, Novartis, Roche, Debiopharm International SA, Sobi, Incyte Biosciences Italy srl, Doxa Pharma srl, Amgen, Nanobiotics e GSK.; Financial Interests, Institutional, Research Grant, Funds received by my institution for clinical studies and research activities in which I am involved: AstraZeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis, Debiopharm International SA, Hoffmann-La roche ltd, IRX Therapeutics, Medpace, Merck–Serono, Merck Healthcare KGaA, MSD, Novartis, Pfizer, Roche, Buran. R. Swaby: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. Y. Zhang: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. B. Gumuscu: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. B. Bidadi: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche, Oncorus, Seattle Genetics, Voronoi, Arvinas, Tessa, Navire, Relay Therapeutics, Janpix, Amgen, Marengo, InterRNA, Medicenna, Hoopika, Coherus; Financial Interests, Personal, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, Spouse has stock ownership: Agios; Financial Interests, Institutional, Invited Speaker: Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Astellas, Bayer, Amgen, Symphogen, Intensity Therapeutics, Shattucks, EMD Serono; Non-Financial Interests, Advisory Role: ICR. All other authors have declared no conflicts of interest.