Phase II Trial of First-line Axitinib plus Nivolumab in Patients with Advanced Mucosal Melanoma

Purpose: Mucosal melanoma 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 mucosal melanoma 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 mucosal melanoma 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 the 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% confidence interval (CI), 23–68], including 4 complete responses (20%) and 5 partial responses (25%). The median duration of response was 21 months [95% CI, 8.6–Not Reached (NR)]. The median progression-free survival was 6.4 months (95% CI, 3.5–NR); the median overall survival was not reached. Grade 3 to 5 treatment-related adverse events occurred in 67%, including two treatment-related deaths. Seven patients received triplet therapy (ipilimumab, n = 5; SBRT, n = 2), 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.