Background: Talimogene laherparepvec, an oncolytic viral immunotherapy, was designed to selectively replicate in tumors resulting in lytic cell death, antigen release, and production of GM-CSF to enhance systemic antitumor immune responses. Talimogene laherparepvec improved durable response rate vs GM-CSF in unresectable stage IIIB-IV melanoma (Andtbacka et al, JCO 2015). Pembrolizumab, a human programmed death receptor-blocking antibody approved for the treatment of advanced melanoma, improved PFS and OS vs ipilimumab in patients (pts) with stage III-IV melanoma (Robert et al, NEJM 2015). Combining talimogene laherparepvec + pembrolizumab may further enhance antitumor immune responses. Here we describe the phase 3 design of a phase 1b/3 double-blind, placebo-controlled study assessing the safety and efficacy of talimogene laherparepvec + pembrolizumab in unresected stage IIIB-IV melanoma (NCT02263508). Phase 1b enrolled 21 pts treated with talimogene laherparepvec + pembrolizumab. No dose limiting toxicities were observed (primary endpoint), and preliminary responses were observed in 9 of 16 evaluable pts with median tumor follow-up of 17 weeks (Long et al, SMR 2016). Methods: Approximately 660 pts will receive pembrolizumab + placebo or pembrolizumab + talimogene laherparepvec (1:1 randomization). Co-primary endpoints: PFS and OS. Key secondary endpoints: adverse events and response-based endpoints. Key eligibility criteria: unresectable stage IIIB-IV melanoma naïve to systemic treatment except up to one prior line of BRAF inhibitor-based treatment, measurable and injectable lesions, ECOG PS 0-1, no active cerebral metastases, no autoimmunity/immunosuppression, no active herpetic infection. Talimogene laherparepvec (10⁶ PFU/mL first dose, 10⁸ PFU/mL subsequent doses) or placebo is injected into cutaneous or nodal lesions on day 1, weeks 0, 3, 5, 7 then q3w starting day 1 week 9. Pembrolizumab 200 mg IV is given q3w starting day 1 week 0. Treatment continues until confirmed complete response or progressive disease, intolerance, up to 2 years, or for talimogene laherparepvec or placebo, when there are no longer injectable lesions. Clinical trial information: NCT02263508