Background: Preclinical data in murine cancer models show 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 head and neck squamous cell carcinoma (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 given with CRT and as maintenance therapy vs placebo plus CRT in LA-HNSCC. Methods: 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 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. Eligibility criteria include 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. Treatment will be discontinued at the time of centrally confirmed disease progression, unacceptable toxicity, or patient/physician decision to withdraw. Patients will be evaluated to determine the necessity of neck dissection 12 weeks after completion of CRT. The primary end point is event-free survival. Secondary end points are overall survival, safety, and patient-reported outcomes. Relationship between biomarkers and clinical activity will be included as an exploratory end point. Recruitment is ongoing in 21 countries and will continue until ~780 patients are enrolled. Clinical trial information: NCT03040999