Background: Outcomes are poor for patients (pts) with recurrent/metastatic (R/M) SCCHN, and new treatments are needed. An ongoing phase I/II, multicenter, open-label study (NCT01693562) is evaluating the safety and efficacy of MEDI4736 (M), a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity, in multiple solid tumor types including SCCHN. PD-L1 is expressed in SCCHN tumors and may be associated with response to anti-PD-L1 treatment. Methods: Pts with R/M SCCHN, an ECOG of 0 or 1, without prior anti-PD-1/PD-L1 exposure are eligible. M is administered IV every 2 weeks at 10 mg/kg for 12 months. Retreatment is permitted upon progression after 12 months. PD-L1 expression is assessed by IHC using the Ventana SP263 clone. Prior documented HPV status is collected at study entry. Response is based on investigator assessment per RECIST v1.1. Data included represent a larger population with more mature follow up than previously reported (Fury M, et al. Poster presented at ESMO 2014, 988PD). Results: As of 31 Oct 2014, 62 pts (mean age 58 years [range 24–96]; 86% male; 64% current/prior smokers; ECOG 0/1: 38%/62%; HPV pos/neg/unk: 40%/39%/21%), with a median of 3 prior systemic treatments (1–10), received a median of 6 doses (1–26). Drug-related AEs were observed in 60% of pts; the most frequent were fatigue (11%), diarrhea, (8%), and nausea (7%). Grade ≥ 3 related AEs were reported in 7% of pts: rash (2 pts), and increased GGT, fatigue, and tumor inflammation (1 pt each). No drug-related AEs led to discontinuation or death. No colitis or grade ≥ 3 pneumonitis was observed. Overall, 51 pts were evaluable for response with ≥ 24 weeks of follow up; ORR was 12% (25% in PD-L1+ pts), and DCR at 24 weeks was 16% (25% in PD-L1+ pts). Responses are ongoing in 5/6 responding pts, with response durations ranging from 4+ to 43+ weeks. Median duration of response has not been reached. Conclusions: With more mature follow up, the safety profile of M in SCCHN is manageable and consistent with previous reports. Responses are durable; ORR and DCR are higher in PD-L1+ pts. A registration program is underway in pts with SCCHN for M alone and in combination with tremelimumab. Clinical trial information: NCT01693562