Background: Anti–PD-1 immunotherapy has significantly changed outcomes for patients (pts) with recurrent/metastatic (RM) head and neck squamous cell cancer (HNSCC). However, only ≈20% of pts respond, so more effective therapies are needed. MEDI0457 (INO-3112), a plasmid DNA vaccine, comprises 3 plasmids expressing HPV-16 and HPV-18 E6 and E7 proteins along with IL-12. A pilot study in pts with locally advanced HPV-associated HNSCC found MEDI0457 to be safe and well tolerated; it was associated with induction of HPV-16/18 E6/E7–specific humoral and cellular immune responses and showed synergistic activity with anti–PD-1 therapy in immune correlative studies.¹ Durvalumab (MEDI4736) is a human IgG1 mAb that blocks programmed death-ligand 1 (PD-L1) binding to PD-1, stimulating anti-tumor immune response. 60-70% of HPV+ HNSCC can be PD-L1 positive.^2,3 We hypothesize that MEDI0457 administered with durvalumab may enhance anti-tumor effects against HPV-associated HNSCC and improve outcomes for pts with RM disease. Methods: This phase 1b/2a, open-label, multi-center study is evaluating MEDI0457 plus durvalumab in pts with confirmed HPV-16 or HPV-18–associated RM HNSCC after treatment with ≥1 platinum-based chemotherapy or platinum-ineligible pts in whom an approved treatment failed. Key exclusion criteria are nasopharyngeal cancer and prior immunotherapy. As this is the first study of MEDI0457 combined with durvalumab, a safety analysis run-in phase will assess the first 3-12 pts with a limit of 4 vaccine doses; this will be followed by the planned recommended dosing schedule in ≈50 pts until disease progression or unacceptable toxicity. Primary objectives are safety and objective response rate. Secondary objectives are disease control rate at 16 weeks, overall survival, progression-free survival, and pharmacokinetics and immunogenicity of durvalumab. Recruitment is ongoing (NCT03162224). ¹ Aggarwal, et al. SITC 2017 [P125]. 2 Badoual, et al. Cancer Res 2013 [128]. 3 Lyford-Pike, et al. Cancer Res 2013 [1733]. Clinical trial information: NCT03162224