Background: T-VEC is a herpes simplex virus (HSV)-1 -based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF and stimulate antitumor immune responses in melanoma. T-VEC significantly improved durable response rate vs GM-CSF in stage IIIB-IV melanoma patients (pts) with injectable tumors. Pembro inhibits programmed cell death protein 1 and improves survival in advanced melanoma. The combination may further improve clinical benefit. Here we report phase 1b efficacy, safety and biomarker data from a phase 1b/3 study of T-VEC+pembro in unresectable stage IIIB-IV melanoma (NCT02263508) with all pts having started on T-VEC+pembro ≥ 6 mo prior. Methods: Key inclusion criteria: unresectable stage IIIB-IV melanoma, injectable lesions; no prior systemic tx; and ECOG PS 0-1. T-VEC: ≤ 4 mL in (sub)cutaneous/nodal lesions, 10⁶ PFU/mL d1, 10⁸PFU/mL d22 then Q2W; pembro: IV, 200 mg d36 then Q2W. Tx until first occurrence of: complete response (CR); no injectable tumors (for T-VEC); confirmed PD per modified immune-related response criteria (irRC); tx intolerance; 24 mo of pembro. T cell subsets were evaluated by flow cytometry at baseline, during T-VEC alone, and during combination. Results: Of the 21 pts enrolled from Dec 2014 – Mar 2015, 48% had IIIB-IVM1a, 52% IVM1b/c, 76% HSV-1+, and 19% BRAFmut+. Median follow-up at data cut was 33 w. All pts received at least one dose of T-VEC+pembro. Tx-related AEs occurred in all pts: 33% G3/4, and no G5. Most common AEs were fatigue (62%), pyrexia (52%), and chills (48%). Per irRC, in 21 pts, confirmed/not yet confirmed objective response rate (ORR) was 48%/57%; CR rate was 14%/24%. Median time to response was 17 wks. Circulating CD8+ T cells including those expressing defined immune modulatory receptors (eg Tim3, BTLA) became elevated during tx with T-VEC initially but decreased after pembro began on d 36. Conclusions: The combination of T-VEC+pembro was associated with clinical benefit in advanced melanoma, as assessed by ORR and CR rate. A randomized, double-blind phase 3 trial of T-VEC+pembro vs T-VEC placebo+pembro is under way. Updated clinical and biomarker data will be presented at the meeting. Clinical trial information: NCT02263508