Background: T-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to preferentially replicate in tumors, produce GM-CSF and stimulate an anti-tumor immune response. OPTiM, a phase III trial of T-VEC vs GM-CSF in unresected stage IIIB-IV melanoma (n = 436), met the primary endpoint of improved durable response rate (DRR) in the T-VEC arm (16 vs 2%; Andtbacka et al ASCO 2013). Pembrolizumab is a human programmed death receptor-1 (PD-1)-blocking antibody indicated in the U.S. for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Combining T-VEC with pembrolizumab may enhance the anti-tumor immune response vs either therapy alone. Here, we describe a study (NCT02263508) assessing safety and efficacy of T-VEC + pembrolizumab in previously untreated, unresected stage IIIB-IV melanoma. Phase 1b enrolment began 12/2014. Methods: 1^o objectives: Phase 1b: assess dose-limiting toxicities of T-VEC + pembrolizumab. Phase 2: compare confirmed ORR by immune-related response criteria (irRC) at Wk 24 for T-VEC + pembrolizumab vs pembrolizumab alone 2^o objectives: Best OR, DRR, duration of response (DOR), PFS, OS, treatment-emergent/related AEs Treatment: T-VEC is injected into cutaneous, subcutaneous or nodal lesions at up to 4 mL of 10⁶ plaque forming units (PFU)/mL Day 1, then at up to 4 mL of 10⁸ PFU/mL Day 22 and Q2W (phases 1b and 2). Pembrolizumab is given at 200 mg IV Q2W from Day 36 in phase 1b (n = 20) and Day 1 in phase 2 (n = 90). Treatment with both therapies will continue until (whichever comes first): CR or PD per irRC, intolerance, for up to 2 yrs or, for T-VEC only, when there are no longer injectable lesions. Pts in phase 2 will be randomized 1:1 to T-VEC + pembrolizumab vs pembrolizumab alone. Key eligibility: Stage IIIB-IV melanoma naïve to systemic treatment (except adjuvant), injectable lesions, ECOG PS 0-1, no active cerebral metastases, no autoimmunity/immunosuppression, no active herpetic infection. Clinical trial information: NCT02263508