KEYNOTE-412: Phase 3 trial of pembrolizumab plus chemoradiation (CRT) vs CRT alone for locally advanced head and neck squamous cell carcinoma (LA-HNSCC)

Abstract

Background: CRT with cisplatin is the standard of care for patients with LA‐HNSCC not treated by surgery. Preclinical data in murine cancer models show improved tumor growth control and survival when RT is combined with a PD‐1 inhibitor. Pembrolizumab has proven effective for the treatment of recurrent/metastatic HNSCC, and initial results from a phase 1b study suggest that pembrolizumab plus CRT is tolerable in patients with LA‐HNSCC. KEYNOTE‐412 is a phase 3, randomized, placebo‐controlled, double‐blind trial to determine the efficacy and safety of pembrolizumab given concomitantly with CRT and as maintenance therapy versus placebo plus CRT in LA‐HNSCC. Trial design: Eligibility includes age > 18 years; newly diagnosed, treatment‐naive, oropharyngeal p16 positive (any T4 or N3), oropharyngeal p16 negative (any T3‐T4 or N2a‐N3), or larynx/hypopharynx/oral cavity (any T3‐T4 or N2a‐N3) SCC; evaluable tumor burden (RECISTv1.1); andECOGPS 0‐1. Patients will be randomly assigned (1:1) to receive pembrolizumab 200 mg every 3 weeks plus cisplatin‐based CRT or placebo plus cisplatin‐based CRT. Treatment will be stratified by RT regimen (accelerated RT [56‐70 Gy, 6 fractions/week for 6 weeks] or standard RT [56‐70 Gy, 5 fractions/week for 7 weeks]), tumor site/p16 status (oropharynx p16 positive vsp16 negative or larynx/hypopharynx/oral cavity), and disease stage (III vs IV). A priming dose of pembrolizumab or placebo will be given 1 week before CRT, followed by 2 doses during CRT and an additional 14 doses after CRT, for a total of 17 pembrolizumab or placebo infusions. Treatment will be discontinued upon centrally confirmed disease progression, unacceptable toxicity, or patient/physician decision to withdrawal. Response will be assessed by computed topography or magnetic resonance imaging 12 weeks after CRT, every 3 months for 3 years, then every 6 months for years 4 and 5. Safety will be monitored throughout the study and for 30 days after treatment end. The primary end point is event‐free survival. Secondary end points include overall survival, safety, and patient‐reported outcomes. Recruitment will continue until 780 patients are enrolled.