Safety and efficacy analysis of DNV3 plus toripalimab and chemotherapy in advanced melanoma: An open-label investigator-initiated trial.

9529 Background: Previous studies have shown that combining LAG-3 and PD-1 inhibitors is effective in advanced melanoma. Here, we presented the safety and efficacy of DNV3, a LAG-3 inhibitor, in combination with a PD-1 inhibitor and chemotherapy for patients with advanced acral and mucosal melanoma. Methods: Eligible patients were adults with confirmed unresectable or metastatic melanoma and an ECOG performance status of 0 or 1. BRAF-mutant patients must had progressed after BRAF inhibitor treatment. The dosages for chemotherapy (albumin-bound paclitaxel at 260 mg/m² on Day 1 and cisplatin at 25 mg/m² on Days 1 to 3 for the first 6 cycles) and DNV3 (administered at 3 mg/kg) were based on body surface area and weight, while Toripalimab was given at a fixed dose of 240 mg. The combination therapy was administered every 3 weeks. DNV3 and Toripalimab were continued for up to 2 years or until withdrawal from the study. The primary endpoint is the objective response rate (ORR), with secondary endpoints including progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), and overall survival (OS). Results: Overall, 27 patients participated (13 mucosal melanoma; 6 acral melanoma; 5 cutaneous melanoma; 3 unknown primary melanoma). 77.8% patients had prior anti-PD-(L)1 therapy. At a Nab-Paclitaxel dose of 260mg/m², 94.4% had treatment-related adverse events (TRAEs), with 50% facing severe TRAEs like infection and bone marrow suppression, leading to one death and a dose reduction for 9 patients. At 200mg/m², 77.8% had TRAEs, and 22.2% had severe TRAEs, mainly decreased PLT/WBC counts and bacteremia, with no further deaths. Among the 15 patients (55.6%) who experienced immune-related adverse events (irAEs), 6 (22.2%) had grade 3 or 4 irAEs, with no reported grade 5 cases. The most common grade 3 irAE was infection. An ORR of 37.0% (95% CI: 19.4% to 57.6%) was observed in 10 patients , 6 of whom had liver metastases according to RECIST 1.1 criteria. The median DOR had not yet been reached (95% CI: 3.65 months to not evaluable). Among the 27 patients, the overall ORR was 37%, with subtypes showing 38.5% for mucosal, 80% for cutaneous, and 16.7% for acral melanomas. Expression levels of BRAF or PD-L1 did not predict ORR within these subgroups. As of the cutoff date, neither median PFS nor OS had been achieved. Conclusions: The study provided preliminary evidence of the tolerability and potential efficacy of the combination of DNV3 plus Toripalimab with chemotherapy in patients with advanced melanoma, particularly in those with mucosal melanoma and liver metastases. Clinical trial information: ChiCTR2400079387, ChiCTR2400079543 .