The efficacy and safety of neoadjuvant toripalimab combined with temozolomide in resectable stage III melanoma: A prospective, single-center, phase 2 trial.

Abstract

9562 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have demonstrated efficacy in resectable cutaneous melanoma and are recommended by current guidelines. Nevertheless, the clinical benefit of combining ICIs with chemotherapy as neoadjuvant setting in Chinese patients remains to be established. This study is being conducted to explore the efficacy and safety of neoadjuvant toripalimab combined with temozolomide in resectable stage III melanoma. Methods: This is a prospective, single-center, single-arm clinical trial (ClinicalTrials.gov identifier: NCT05827770). Patients with resectable stage IIIB-IIID acral or cutaneous melanoma and an ECOG performance status of 0-1 were enrolled and received two cycles of neoadjuvant temozolomide 200 mg/m² plus toripalimab 240 mg every 3 weeks, followed by radical surgery. The primary endpoint was the pathologic response rate (pRR). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), recurrence-free survival (RFS), overall survival (OS) and safety. Results: As of December 2025, 20 eligible patients with resectable stage IIIB-IIID melanoma were enrolled, with 14 (70%) acral, 5 (25%) cutaneous and 1 (5%) of unknown primary. Of 20 patients underwent surgery, nine achieved pRR (45%), including 3 with near pathologic complete response (near pCR) and 6 with partial pathologic response (pPR). Radiological assessment showed partial response in 5 patients, stable disease in 12 patients, and progressive disease in 3 patients, yielding an objective response rate of 25% (5/20) and a disease control rate of 85% (17/20) according to RECIST criteria. With a median follow-up of 12 months, 8 recurrence-free survival events had been observed; the median RFS and OS had not yet been reached. Notably, one patient who attained near pCR remained relapse free for 27 months. No new safety signals were observed with the combination therapy. We further performed single-cell-resolution spatial transcriptomics and single-cell RNA sequencing in the current cohort. Integrative multi-omics analyses identified a T cell-excluded tumor microenvironment preferentially associated with non-response. Leveraging these features, we robustly distinguished immunotherapy responders from non-responders. Conclusions: This study demonstrates the preliminary efficacy and tolerability of toripalimab combined with temozolomide in the neoadjuvant treatment of patients with resectable stage IIIB-IIID acral and cutaneous melanoma. Given the fact that ICIs alone has limited response rate in acral melanoma, further studies are warranted. Clinical trial information: NCT05827770 . Treatment outcomes. Pathologic Response Eligible patients (%)N=20 Radiological Response Eligible patients (%)N=20 Near pCR 3 (15) PR 5 (25) pPR 6 (30) SD 12 (60) pNR 11 (55) PD 3 (15) pRR (pCR+Near pCR+pPR) 9 (45) ORR (CR+PR) 5 (25) DCR (CR+PR+SD) 17 (85)