Background: Nivolumab, which inhibits the programmed death-1 (PD-1) receptor, improved survival for patients (pts) with platinum-refractory recurrent/metastatic HNSCC compared with standard therapy. This trial evaluates the safety of adding nivo to 4 standard radiotherapy (RT) regimens for pts with newly diagnosed IR/HR HNSCC (Table). Safety data for cohort 3 (cetuximab) are reported. Efficacy data for cohorts 1, 2, and 3 will be reported at the presentation. Methods: Eligibility includes IR (p16+, oropharynx (OP) T1-2N2b-N3/T3-4N0-3, >10 pack-years (pys) or T4N0-N3, T1-3N3 ≤10 pys) and HR HNSCC (oral cavity, larynx, hypopharynx, or p16(-) OP, stage T1-2N2a-N3 or T3-4N0-3). 10 pts are enrolled to obtain 8 evaluable pts. Primary endpoint is dose-limiting toxicity (DLT), defined as nivo-related: ≥grade 3 adverse event (AE) unresolved to ≤grade 1 in ≤28 days; RT delay >2 wks; incomplete RT; or inability to receive ≥70% of cetuximab. DLT window was from first nivo dose (day -14) to 28 days post RT. >2 DLTs in 8 evaluable pts is unacceptable. Results: Of 10 enrolled pts for cohort 3: median age 61.5, 80% male, 70% Caucasian, 70% PS 0, 80% >10 pys, 60% p16(+) OP cancer, 60% T3-4 and 100% N2-3 disease. 1 pt was inevaluable for DLT due to withdrawal of consent and 1 pt has not yet completed the DLT observation period. 1 DLT (mucositis) was reported in 8 evaluable pts; 1 other grade 3 AE attributed to nivo was reported (lipase increase) but was not a DLT. 11 SAEs in 3 pts, but none nivo-related. 7/8 pts completed RT, 7/8 pts completed cetuximab; 5 pts completed 10 concurrent doses of nivo, 1 pt received 6 doses, 1 pt 7 doses, and 1 pt is ongoing after 8 doses. Conclusions: Nivo is safe and feasible to administer concomitant with a cetuximab-RT regimen for patients with newly diagnosed IR/HR HNSCC. Clinical trial information: NCT02764593