Background: Patients (pts) with R/M SCCHN have a poor prognosis, with current systemic therapy options after failure of first-line platinum-based chemotherapy yielding objective response rates (ORRs) of approximately 10% and an overall survival (OS) of 6 months. In SCCHN, tumors create a highly immunosuppressive environment and evade immune detection by exploiting inhibitory immune checkpoints such as the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis. Upregulation of PD-L1 by SCCHN tumor cells is associated with inhibition of antitumor T-cell responses. Thus, therapeutic intervention with immune-modulating agents targeting this pathway holds promise. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 with high affinity and selectivity. Evidence of clinical activity for MEDI4736 in R/M SCCHN has been seen in a Phase 1 study (NCT01693562), with initial data indicating that PD-L1 expression is associated with a higher ORR. A comprehensive clinical development program of MEDI4736 in SCCHN is underway. Here we describe the HAWK study (NCT02207530), a trial with registrational potential, assessing MEDI4736 monotherapy in pts with PD-L1⁺ R/M SCCHN. Methods: In this Phase 2, open-label, single-arm, multicenter study, 112 PD-L1⁺ pts will be enrolled from North American and European sites to investigate the efficacy and safety of MEDI4736 (10 mg/kg IV every 2 weeks for up to 12 months). Eligible pts, who are immunotherapy naïve and have tumor progression or recurrence during or after treatment with 1 platinum-containing regimen for R/M disease, will receive MEDI4736 monotherapy. The primary outcome measure is ORR (RECIST v1.1), based on independent central review. Secondary outcome measures will further assess disease control rate, duration of response, progression-free survival, and OS (using RECIST v1.1 and immune-related RECIST criteria); safety (CTCAE v4.03) and tolerability; and health-related quality of life. Exploratory outcomes include PK, immunogenicity, and potential biomarkers of response to MEDI4736. Recruitment is ongoing. Clinical trial information: NCT02207530