Background: Current therapies for pts with R/M SCCHN achieve poor survival, so more effective and better tolerated treatments are needed. Tumors can evade immune detection by exploiting inhibitory immune checkpoints such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), commonly expressed in SCCHN. Durvalumab (D) is a selective, high affinity, engineered human IgG1 mAb that blocks binding of programmed cell death ligand-1 (PD-L1) to PD-1 and CD80. Tremelimumab (T) is a selective human IgG2 mAb inhibitor of CTLA-4. Targeting both PD-L1 and CTLA-4 pathways has potential for synergistic antitumor effects. In a Phase 1b study in pts with advanced NSCLC (NCT2000947), D+T combination regimens demonstrated clinical activity and manageable tolerability profiles. The Phase 3 KESTREL study (NCT02551159) compares D ± T with SoC EXTREME regimen for first-line treatment of R/M SCCHN. Methods: KESTREL is an open-label, multicenter, global study of pts with R/M SCCHN (oral cavity, oropharynx, hypopharynx or larynx) who have received no prior systemic chemotherapy (unless part of multimodality treatment for locally advanced disease). Pts (n = 628) will be stratified by PD-L1 status, smoking history, tumor location, and then HPV status (oropharyngeal cancer) and randomized (2:1:1) to receive flat-doses of T 75 mg q4w (max 4 doses) + D 1500 mg q4w; D 1500 mg q4w; or SoC EXTREME regimen (carboplatin or cisplatin + 5FU + cetuximab), all until PD. The D+T combination will be assessed vs SoC in terms of co-primary endpoints PFS and OS. D+T vs SoC will be further assessed in terms of ORR; DoR; proportion of pts alive and progression free at 12 months; OS at 24 months; secondary progression; safety and tolerability; pharmacokinetics; immunogenicity; and HRQoL. The efficacy of D monotherapy vs both D+T and SoC will also be tested. Exploratory endpoints include blinded independent central review of antitumor activity (immune-related RECIST v1.1) and potential biomarkers of progression/response. Pts are enrolled from USA, Canada, Taiwan, South Korea, Greece and Spain (total of: 23 countries, 191 sites planned). Clinical trial information: NCT02551159