Phase 2 study of perioperative pembrolizumab plus lenvatinib for mucosal melanoma

Mucosal melanoma is an aggressive malignancy with limited neoadjuvant options. The phase 2 NEOplus trial at Peking University Cancer Hospital and Institute (Beijing, China) evaluated neoadjuvant pembrolizumab plus lenvatinib followed by surgery and adjuvant pembrolizumab for resectable mucosal melanoma. Primary objective was pathological complete response (pCR) rate. Among 21 surgical patients, the pCR rate was 9.5%, whereas major pathologic response rate was 19.0% and the pathologic response rate was 38.1%. Median relapse-free survival was 14.8 months (1-year rate 61.9%) and median overall survival was not reached. No grade 4-5 treatment-related toxicities or additional perioperative complications occurred. Spatial profiling revealed a more immune-inflamed baseline microenvironment in responders, with activated CD4⁺/CD8⁺ T cell signatures associated with favorable outcomes. Responders exhibited higher prevalence of persistent TCR clonotypes and tighter spatial proximity between activated CD4⁺ and CD8⁺ T cells. The authors conclude that, although the pre-specified primary endpoint was not met, these findings identified 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.