Avelumab in Combination with Standard of Care Chemoradiotherapy Versus Chemoradiotherapy Alone in Patients with Locally Advanced Scchn: A Randomised, Double-Blind, Phase 3 Trial

Abstract

Background: Chemoradiotherapy (CRT) is the current standard of care for unresected locally advanced squamous cell carcinoma of the head of neck (LA SCCHN). We report the results of avelumab (anti–PD-L1) combined with CRT in LA SCCHN (JAVELIN Head and Neck 100). Methods: In this randomised, double-blind, placebo-controlled, multi-centre phase 3 study, patients with histologically confirmed, previously untreated LA SCCHN of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status) and eligible for CRT were randomised 1:1 (stratified by human papillomavirus status, tumour stage, and nodal stage) to receive either avelumab 10 mg/kg intravenously every 2 weeks plus CRT (cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiation therapy with standard fractionation of 70 Gy [35 fractions/7 weeks]), or placebo plus CRT. This was preceded by an avelumab/placebo lead-in dose and followed by avelumab/placebo bi-weekly maintenance therapy for up to 1 year. The primary endpoint was progression-free survival (PFS) by investigator assessment per modified Response Evaluation Criteria in Solid Tumours version 1·1. Findings: Between December 12, 2016 and January 29, 2019, 697 patients were enrolled and randomised to the avelumab plus CRT (n=350) or placebo plus CRT (n=347) arms. The stratified hazard ratio for PFS based on 224 events was 1·21 (95% CI, 0·93-1·57) favouring the placebo arm; one-sided p=0·92. Median PFS was not reached in either arm. Grade ≥3 adverse events were more frequent with avelumab + CRT vs placebo + CRT (305 [88%] vs 281 [82%]). There were 73 deaths (21%) in the avelumab arm and 58 deaths (17%) in the placebo arm. Interpretation: The primary endpoint of prolonging PFS with avelumab plus CRT followed by avelumab maintenance vs placebo plus CRT in patients with LA SCCHN was not met. Trial Registration: This study is registered with ClinicalTrials.gov NCT02952586. Funding Statement: Pfizer and Merck KGaA, Darmstadt, Germany. Declaration of Interests: N Y Lee reports providing a consulting or advisory role for Eli Lilly, EMD Serono (a business of Merck KGaA, Darmstadt, Germany), Merck KGaA, Pfizer, Sanofi-Aventis, and UpToDate and has received research funding from AstraZeneca, EMD Serono, and Pfizer. R L Ferris reports providing a consulting or advisory role for Aduro Biotech, AstraZeneca/MedImmune, Bristol Myers Squibb, EMD Serono, GlaxoSmithKline, Iovance Biotherapeutics, MacroGenics, Merck KGaA, Nanobiotix, Novasenta, Numab Therapeutics, Oncorus, Ono Pharmaceutical, Pfizer, PPD (Benetec Immunicum), Regeneron Pharmaceuticals, and Torque Therapeutics; has received research funding from AstraZeneca/MedImmune, Bristol Myers Squibb, Merck KGaA, Novasenta, and Tesaro; has received reimbursement for travel expenses from Ono Pharmaceutical; and owns stock in Novasenta. A Psyrri has received honoraria from Bristol Myers Squibb, EMD Serono, Merck & Co, and Pfizer; has provided a consulting or advisory role for AstraZeneca; has received research funding from AstraZeneca, Bristol Myers Squibb, Kura Oncology, and Roche; and has received reimbursement for travel expenses from Ipsen. R I Haddad has received research funding from Pfizer; and has provided a consulting or advisory role for AstraZeneca, BioNTech, Bristol Myers Squibb, Eisai, Genentech, GlaxoSmithKline, IO Biotech, Kura Oncology, Merck KGaA, Pfizer, and Roche. M Tahara has received honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eisai, EMD Serono, Loxo Oncology, Merck & Co, Novartis, Ono Pharmaceutical, Pfizer, and Rakuten Medical; and has received research funding from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Merck & Co, Novartis, Ono Pharmaceutical, Pfizer, and Rakuten Medical. K Harrington has received honoraria from AstraZeneca, Boehringer Ingelheim, Merck & Co, and Replimune; and has received research funding from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Merck & Co, Pfizer, and Replimune. M A Razaq reports providing speakers services for Merck & Co. J Lovey reports providing speakers services for Danone and Merck & Co. A Rueda reports providing speakers services and a consulting or advisory role for Bristol Myers Squibb, Merck KGaA, Roche, and Takeda. S De Beukelaer reports employment at Pfizer AG, Zurich, Switzerland. D Pavlov reports employment at Pfizer, Inc, La Jolla, CA, USA. H Thurm reports employment at and owns stock in Pfizer, Inc, La Jolla, CA, USA. E Cohen reports providing a consulting or advisory role for ALX Oncology, Ascendis Pharma, Bayer, BioLineRx, Bristol Myers Squibb, Debiopharm, Dynavax Technologies, Merck KGaA, Merck & Co, Regeneron Pharmaceuticals, and Sanofi. All other authors declare no competing interests. Ethics Approval Statement: The trial was conducted in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, the International Conference on Harmonization Guidelines for Good Clinical Practice, and the Declaration of Helsinki. All patients provided written, informed consent prior to enrolment. The protocol was approved by the institutional review board or independent ethics committee at each participating centre.