KEYNOTE-412: Phase III study of pembrolizumab plus chemoradiation vs chemoradiation alone for locally advanced head and neck squamous cell carcinoma (HNSCC)

Abstract

Background: Preclinical data suggest improved tumor growth control and survival when radiation therapy (RT) is combined with a PD‐1 inhibitor. Pembrolizumab is effective for treatment of recurrent/metastatic HNSCC, and initial results from a phase 1b study suggest that pembrolizumab plus chemoradiation therapy (CRT) is tolerable in patients with locally advanced (LA) HNSCC. KEYNOTE‐412 (NCT03040999) is a phase 3, randomized, placebo‐controlled, double‐blind trial to determine efficacy and safety of pembrolizumab plus CRT and as maintenance therapy vs placebo plus CRT in LA‐HNSCC. Trial design: Eligibility criteria are 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 (RECIST v1.1); and ECOG performance status 0/1. Patients will be randomly assigned (1:1) to receive pembrolizumab 200 mg every 3 weeks plus cisplatinbased 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 vs p16 negative or larynx/hypopharynx/oral cavity), and disease stage (III vs IV). 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. Response will be assessed by MRI and CT 12 weeks after CRT, every 3months for 3 years, then every 6 months for years 4 and 5. Treatment will be discontinued at time of centrally confirmed disease progression, unacceptable toxicity, or patient/physician decision to withdraw. Patients will be evaluated to determine necessity of neck dissection 12 weeks after completion of CRT. Primary end point is event‐free survival and secondary end points are overall survival, safety, and patientreported outcomes. Biomarkers will be an exploratory end point. Recruitment is ongoing in 21 countries and will continue until∼780 patients are enrolled.