# Efficacy and Safety of DNV3 (a Lymphocyte‐activation Gene 3–blocking Antibody) Combined With Toripalimab and Chemotherapy in Advanced Melanoma: An Open‐label, Single‐arm Clinical Trial

## TL;DR

A new treatment combining DNV3, toripalimab, and chemotherapy showed promising results in advanced melanoma, especially in patients who previously resisted other therapies.

## Contribution

The study introduces a novel combination therapy showing efficacy in anti-PD-(L)1-resistant melanoma and treatment-naïve mucosal melanoma.

## Key findings

- The regimen achieved a 44.4% overall response rate in advanced melanoma patients.
- It showed a 42.9% response rate in anti-PD-(L)1-resistant cases with 7.36-month median progression-free survival.
- Dose modification reduced severe adverse events from 55.6% to 22.2%, improving treatment tolerability.

## Abstract

Despite the remarkable therapeutic advances achieved with immune checkpoint inhibitors in advanced melanoma, treatment options remain limited for patients with refractory subtypes. This study evaluated a novel combination of DNV3 (anti‐LAG‐3), toripalimab (anti‐PD‐1), and chemotherapy (nab‐paclitaxel/cisplatin) in 27 Asian patients with unresectable or metastatic melanoma (77.8% [21/27] previously treated with anti‐PD‐[L]1 and 22.2% [6/27] treatment‐naïve mucosal melanoma; subtypes: 13 mucosal, 6 acral, 5 cutaneous, and 3 of unknown primary origin). The regimen achieved an overall response rate (ORR) of 44.4%, which was further elevated to 54.5% in the subgroup of 11 patients with hepatic metastases. Notably, it also demonstrated substantial efficacy in anti‐PD‐(L)1‐resistant cases, with a 42.9% ORR and a median progression‐free survival (PFS) of 7.36 months. Among treatment‐naïve mucosal melanoma, the ORR reached 50%. At data cutoff, median overall survival remained unreached in all cohorts. Grade ≥3 treatment‐related adverse events initially occurred in 55.6% of participants; subsequent dose modification of nab‐paclitaxel (from 260 mg/m2 to 200 mg/m2) improved tolerability, reducing the incidence of grade ≥3 events to 22.2%. Immune‐related toxicities (grade 3–4, 22.2%) were clinically manageable. Therefore, the combination of LAG‐3/PD‐1 blockade and chemotherapy demonstrated promising efficacy, notably in treatment‐naïve mucosal melanoma with liver metastases. (Chinese Clinical Trial Registry number, ChiCTR2400079543)

This investigator‐initiated trial demonstrates that LAG‐3/PD‐1 dual blockade (DNV3 + toripalimab) combined with chemotherapy achieves a 44.4% overall response rate (ORR) in advanced melanoma, showing particular efficacy in anti‐PD‐(L)1‐resistant patients (42.9% ORR, 7.36‐month median PFS), treatment‐naïve mucosal melanoma (50.0% ORR), and those with liver metastases (54.5% ORR). Following dose optimization, the regimen exhibited improved tolerability, supporting this quadruplet approach as a promising therapeutic strategy for refractory melanoma populations with urgent unmet needs, warranting further validation in larger cohorts.