Phase II trial of First-Line Axitinib Plus Nivolumab in Patients with Advanced Mucosal Melanoma.

PURPOSE: Mucosal melanoma (MM) is a rare subtype of melanoma with inferior response rates and outcomes to immunotherapy. Vascular endothelial growth factor (VEGF) signaling may contribute to immune resistance and represents a potential therapeutic target. We evaluated nivolumab plus axitinib in untreated, advanced MM in a Western population, and explored escalation to triplet strategies for PD-1-refractory disease. PATIENTS AND METHODS: In this single center, investigator-initiated phase II study, patients with previously untreated unresectable or metastatic MM received nivolumab every 4 weeks and axitinib twice daily. The primary endpoint was objective response rate (ORR) per RECIST v1.1. A sequential phase Ib exploratory cohort evaluated treatment intensification with addition of ipilimumab or stereotactic body radiotherapy (SBRT) at progression, with safety as the primary endpoint. RESULTS: Among 20 evaluable patients, the ORR was 45% (95% CI, 23-68), including 4 complete responses (20%) and 5 partial responses (25%). Median duration of response was 21 months (95% CI 8.6-NR). Median progression-free survival was 6.4 months (95% CI 3.5-NR); median overall survival was not reached. Grade 3-5 treatment-related adverse events occurred in 67%, including two treatment-related deaths. Seven patients received triplet therapy (n=5 ipilimumab, n=2 SBRT), with no unexpected toxicities observed. CONCLUSIONS: Nivolumab plus axitinib demonstrated meaningful activity in advanced mucosal melanoma and warrants further evaluation in randomized studies. The addition of ipilimumab or SBRT after progression was feasible and may inform future studies, including biomarker‑directed intensification to triplet strategies.