A phase II peri-operative study of pembrolizumab plus lenvatinib for mucosal melanoma

Abstract Mucosal melanoma is an aggressive malignancy with limited neoadjuvant options. We conducted a single arm, phase II study of neoadjuvant pembrolizumab plus lenvatinib followed by surgery and adjuvant pembrolizumab in resectable mucosal melanoma (NCT04622566) along with exploratory biomarker analysis. Primary objective was pathological complete response (pCR) rate; secondary endpoints included relapse-free survival (RFS), overall survival (OS), clinical response, surgical outcomes, and safety. Among 21 surgical patients, the pCR rate was 9.5%, major pathologic response (MPR) rate was 19.0%, and the pathologic response rate was 38.1%. Median RFS was 14.8 months (1-year rate: 61.9%); median OS was not reached. No grade 4–5 treatment-related toxicities or additional perioperative complications occcurred. Spatial profiling revealed a more immune-inflamed baseline microenvironment in responders, with activated CD4⁺/CD8⁺ T cell signatures associated with favorable outcomes. Treatment induced vascular normalization and increased T cell infiltration in non-responders, partially narrowing the immune gap. Responders exhibited higher prevalence of persistent TCR clonotypes and tighter spatial proximity between activated CD4⁺ and CD8⁺ T cells. Although the pre-specified primary endpoint was not met, our findings identify activated CD4 + /CD8 + T cell states and TCR persistence as key outcome-associated features, supporting immune-informed optimization of peri-operative therapy in mucosal melanoma.