Axelopran and Nivolumab in PD-1-Refractory Metastatic Melanoma

Immune checkpoint inhibitors have substantially improved outcomes in melanoma; however, resistance to PD-1 blockade remains a major clinical limitation. Approximately 60% of patients with metastatic melanoma fail to achieve an objective response to anti-PD-1 therapy, and many initial responders ultimately develop acquired resistance. These limitations highlight the need to identify additional, biologically grounded mechanisms of immune escape that can be therapeutically targeted. Importantly, pharmacologic inhibition of MOR with axelopran, a peripherally acting MOR antagonist restores T-cell effector function and enhances antitumor responses to PD-1 inhibition in preclinical oral squamous cell carcinoma models exposed to exogenous opioids. Notably, endogenous μ-opioid signaling in melanoma suppresses antitumor immunity via MOR, providing a rationale for evaluating peripheral MOR antagonism to enhance checkpoint inhibitor efficacy in melanoma. These findings suggest that constitutive MOR signaling may represent a distinct and targetable pathway of immune resistance that has not been addressed in current immunotherapy strategies. To date, the role of MOR antagonism has not been evaluated clinically in melanoma, and the OPRM1-MOR axis has not been studied as a mechanism of immune escape in humans. This first-in-human study will evaluate the safety, clinical activity, and immunologic effects of combining axelopran with anti-PD-1 therapy in patients with unresectable or metastatic melanoma who have progressed on prior PD-1-based treatment. Post hoc analyses incorporating exogenous opioid exposure and OPRM1 genotype will explore biologically relevant heterogeneity in treatment response and inform future precision-based approaches. Given the strong mechanistic rationale, consistent preclinical evidence of synergy, and the lack of effective options for patients with PD-1-refractory melanoma, this study addresses a critical unmet need and may establish MOR antagonism as a novel therapeutic strategy to overcome immune resistance in melanoma.