Background: Despite advances in the treatment of SCCHN, the outlook for patients (pts) with R/M disease remains poor. Development of immunotherapies to treat this disease may hold promise. High mutational burden due to tobacco and expression of human papilloma virus (HPV)-associated viral antigens is linked to immunogenicity in SCCHN tumors. Despite this immunogenicity, tumors can evade immune detection by exploiting inhibitory checkpoints. PD-L1 is up-regulated on SCCHN tumors and is associated with antitumor T-cell response inhibition. MEDI4736 (M), a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity, has shown a manageable safety profile and promising antitumor activity in R/M SCCHN (ORR 24% in PD-L1+ pts, phase I)(Fury M, et al. Poster presented at ESMO 2014, 988PD). Tremelimumab (T), a selective human IgG2 mAb inhibitor of CTLA-4, has also shown antitumor activity in several tumor types (Tarhini AA. Immunotherapy 2013;5:215–29). Preclinical data suggest that combining anti-PD-L1 and anti-CTLA-4 provides non-redundant immune checkpoint blockade and synergistic antitumor activity. Preliminary data for M + T in NSCLC show encouraging clinical activity in both PD-L1-positive and PD-L1-negative pts (Antonia S, et al. Poster presented at ESMO 2014, 1327P). Here we describe a study assessing the safety, efficacy, and potential biomarkers of response to M + T, in pts with R/M SCCHN. Methods: This is a phase I, multicenter, open-label study (NCT02262741) in pts (N~164) with R/M SCCHN deemed incurable by local therapy. The dose exploration phase will evaluate the combination of M + T, followed by dose expansion in treatment-naive or pretreated R/M pts. Pts will have PD-L1 status determined prior to dosing with M IV + T IV or T IV alone. The primary objective is to assess safety/tolerability of M + T and T alone. Secondary objectives are to assess antitumor activity via RECIST (including ORR, DCR, DoR, PFS, and OS), PK/PD, immunogenicity, and if clinical activity correlates with potential biomarkers, including PD-L1 expression, HPV status, and tobacco use. Recruitment is ongoing. Clinical trial information: NCT02262741