Background: Overall responses (OR) are reported in 34% of patients (pts) with advanced MEL treated with Pembro. Landmark survival is 66%/49% at 1-/2- years respectively. Pre-existing CD8+ T-cell infiltrates and IFN gene signature at tumor sites correlate with response to PD-1 blockade. To evaluate synergy between PD-1 blockade and Peg-IFN, we implemented a phase Ib study of Pembro/Peg-IFN combination with dose-seeking and dose-expansion phases in stage IV MEL. Methods: Pts with IV MEL were enrolled. Peg-IFN was dose-escalated using modified toxicity probability interval (mTPI) design in 3 cohorts (4 pts each) at 1,2 and 3 mcg/kg SC while Pembrolizumab was dosed at 2mg/kg q3weeks in all pts. Primary endpoints were safety and incidence of dose-limiting toxicities (DLTs). Secondary endpoints were OR rate (ORR), progression free and overall survival. Response was assessed every 12 weeks (RECIST 1.1). Sequential blood draws and tumor biopsies were collected. Here, we report on response observed in 24 pts treated in phase Ib portion. Results: 24 pts with advanced MEL were enrolled (20 cutaneous, 2 mucosal, 2 with no primary) to 3 dose-levels. Disease sub-stage is as follows: 11/24 (45.8%) M1a, 5/24 (20.8%) M1b, 8/24 (33.3%) M1c including 4/24 pts (16.7%) with treated CNS metastases. 34.8% were BRAF mutant while 10.5% were NRAS mutant. 11/24 (45.8%) of pts had prior Ipilimumab; 6/24 (25.0%) ≥ 2 lines of systemic therapy. G1/2 toxicities included anemia, nausea, hyponatremia and transaminitis. G3 toxicities of note included rash (11%), hyponatremia (15%), neutropenia (15%) and fatigue (30%). No DLTs were observed. Pembro 2mg/kg + Peg-IFN 3mcg/kg identified as RP2D – to which 12 further pts enrolled. Responses were seen at all 3 dose levels among 21 evaluable pts including 2 CR (9.5%), 7 PR (33.3%) for ORR 42.9%. Autoimmune toxicities included adrenal insufficiency and Vogt-Koyonagi-Harada uveitis seen in 2 pts with ongoing PR off therapy. Conclusions: Pembro/Peg-IFN combination has an acceptable toxicity profile and shows evidence of clinical efficacy in stage IV MEL. Observed ORR has prompted further expansion at RP2D. Clinical trial information: NCT02112032