RP1 Combined With Nivolumab in Advanced Anti-PD-1-Failed Melanoma (IGNYTE).

PURPOSE: Effective treatment options for melanoma after immune checkpoint blockade failure are limited. RP1 (vusolimogene oderparepvec) is an HSV-1-based oncolytic immunotherapy, here evaluated in combination with nivolumab in anti-PD-1-failed melanoma. PATIENTS AND METHODS: Patients had advanced melanoma that had confirmed progression on anti-PD-1 (≥8 weeks, last prior treatment). RP1 was administered intratumorally (≤8 doses, ≤10 mL/dose; additional doses allowed) with nivolumab (≤2 years). The objective response rate (ORR) was assessed by independent central review using Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Of 140 patients enrolled, 48.6% had stage IVM1b/c/d disease, 65.7% had primary anti-PD-1 resistance, 56.4% were PD-L1 negative, and 46.4% received prior anti-PD-1 and anti-CTLA-4 therapy (43.6% in combination and 2.9% sequentially). Confirmed ORR (95% CI) was 32.9% (25.2%-41.3%; 15.0% complete response). Responses occurred with similar frequency, depth, duration, and kinetics for injected and non-injected, including visceral, lesions. Median (95% CI) duration of response was 33.7 (14.1-not reached) months. Overall survival rates (95% CI) at 1 and 2 years were 75.3% (66.9%-81.9%) and 63.3% (53.6%-71.5%), respectively. Biomarker analysis demonstrated broad immune activation associated with response, including increased CD8+ T-cell infiltration and PD-L1 expression. Treatment-related adverse event rates were 77.1% grade 1/2, 9.3% grade 3, 3.6% grade 4, and no grade 5 events. CONCLUSIONS: RP1 combined with nivolumab provided deep and durable systemic responses in patients with anti-PD-1-failed melanoma, including those with poor prognostic factors. The safety profile was favorable, with mostly grade 1/2 adverse events. (Funded by Replimune, Inc.; IGNYTE ClinicalTrials.gov, NCT03767348; EudraCT number, 2016-004548-12).