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Background: Treatment options for immunotherapy-refractory melanoma are an unmet need. The MASTERKEY-115 phase II, open-label, multicenter trial evaluated talimogene laherparepvec (T-VEC) plus pembrolizumab in advanced melanoma that progressed on prior programmed cell death protein-1 (PD-1) inhibitors., Methods: Cohorts 1 and 2 comprised patients (unresectable/metastatic melanoma) who had primary or acquired resistance, respectively, and disease progression within 12 weeks of their last anti-PD-1 dose. Cohorts 3 and 4 comprised patients (resectable disease) who underwent complete surgery, received adjuvant anti-PD-1, and experienced recurrence. Cohort 3 were disease-free for < 6 months and cohort 4 for ≥ 6 months after starting the adjuvant anti-PD-1 therapy and before confirmed recurrence. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included complete response rate (CRR), disease control rate (DCR) and progression-free survival (PFS) per RECIST v1.1 and irRC-RECIST, and safety., Results: Of the 72 enrolled patients, 71 were treated. The ORR (95% CI) was 0%, 6.7% (0.2-32.0), 40.0% (16.3-67.7), and 46.7% (21.3-73.4) in cohorts 1-4, respectively; iORR was 3.8% (0.1-19.6), 6.7% (0.2-32.0), 53.3% (26.6-78.7), and 46.7% (21.3-73.4). iCRR was 0%, 0%, 13.3%, and 13.3%. Median iPFS (months) was 5.5, 8.2, not estimable [NE], and NE for cohorts 1-4, respectively; iDCR was 50.0%, 40.0%, 73.3%, and 86.7%. Treatment-related adverse events (TRAEs), grade ≥ 3 TRAEs, serious AEs, and fatal AEs occurred in 54 (76.1%), 9 (12.7%), 24 (33.8%), and 10 (14.1%) patients, respectively., Conclusion: T-VEC-pembrolizumab demonstrated antitumor activity and tolerability in PD-1-refractory melanoma, specifically in patients with disease recurrence on or after adjuvant anti-PD-1., Trial Registration: ClinicalTrials.gov identifier - NCT04068181., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Caroline Robert: Consulting or advisory role: Bristol-Myers Squibb (BMS), Roche, Novartis, Pierre Fabre, MSD, Sanofi, AstraZeneca, Pfizer, Sunpharma; Scientific co-founder of Ribonexus. Brian Gastman: Consulting or advisory role: Quest Imaging, Castle Biosciences; Speakers' Bureau: Castle Biosciences; Stock and other ownership interests: Castle Biosciences; Research funding: Alkermes, NeoImmuneTech, Merck, Instil Bio. Helen Gogas: Advisory board: BMS, MSD, Pierre Fabre, Sanofi; Invited Speaker: BMS, MSD, Novartis, Pierre Fabre, Sanofi; Local PI: Amgen, Bayer, BMS, Iovance, MSD, Replimune; Research Grant: BMS, Lilly, Pfizer, Pierre Fabre; Steering Committee Member: Amgen, Replimune. Piotr Rutkowski: Consulting or advisory role: BMS, MSD, Novartis, Pierre Fabre, Sanofi, Merck, Philogen, Blueprint Medicine; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Sanofi, Merck, Astra Zeneca, Philogen, Blueprint Medicine. Georgina V. Long: Consulting fees and advisory boards: Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, BMS, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IOBiotech, Immunocore, Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR Ltd, Pierre Fabre, Regeneron, Scancell; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, Pierre Fabre. Marya F. Chaney: Employee: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Stock Ownership: Merck & Co., Inc., Rahway, NJ, USA. Harshada Joshi: Employee: Parexel. Yu-Lin Lin: Employee/stock ownership: Amgen. Wendy Snyder: Employee/stock ownership: Amgen. Jason A. Chesney: Research funding: Amgen., (Copyright © 2024. Published by Elsevier Ltd.)