Novel dual checkpoint blockade improves progression-free survival in melanoma

First results of the phase 3 RELATIVITY-047 trial validated the efficacy of dual checkpoint blockade demonstrated with the LAG-3 inhibitor relatlimab and nivolumab in patients with advanced melanoma.

Lymphocyte-activation gene 3 (LAG-3) regulates an immune checkpoint pathway that inhibits T-cell activity and is upregulated in many tumour types including melanoma [1]. Relatlimab, a human IgG4 LAG-3-blocking antibody, restores effector function of exhausted T cells [2]. Relatlimab in combination with nivolumab modulates potentially synergistic immune checkpoint pathways and can enhance anti-tumour immune responses [3].

RELATIVITY-047 (NCT03470922) is a global, randomised, double-blind, phase 2/3 study evaluating the combination of relatlimab plus nivolumab treatment in first-line advanced melanoma. In this trial, 714 patients with previously untreated advanced melanoma were randomised 1:1 to receive relatlimab (160 mg) plus nivolumab (480 mg) every 4 weeks or nivolumab alone. Patients were stratified by LAG-3 expression, PD-L1 expression, and BRAF mutation status. The primary endpoint was progression-free survival. Secondary endpoints were overall survival and objective response rate. Dr Evan Lipson (Johns Hopkins University, MD, USA) presented the first results of RELATIVITY-047 [4].

At a median follow-up of 13.2 months, progression-free survival in the relatlimab plus nivolumab arm was significantly improved compared with the nivolumab monotherapy arm (10.1 months vs 4.6 months, respectively). Progression-free rate at 12 months was 47.7% in the relatlimab/nivolumab arm versus 36.0% in the nivolumab arm. Progression-free survival favoured relatlimab/nivolumab regardless of age, LDH, tumour burden, BRAF-mutation status, PD-L1 expression, and LAG-3 expression.

The incidence of grade 3/4 treatment-related adverse events was higher in the relatlimab/nivolumab arm versus the nivolumab arm (18.9% vs 9.7%). Treatment-related adverse events of any grade led to treatment discontinuation in 14.6% and 6.7% of patients in the relatlimab/nivolumab arm and nivolumab arm, respectively.

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   1. Durham NM, et al. PLOS One. 2014;9(11):e109080.
   2. Yu X, et al. MAbs. 2019;11(6):1139-1148.
   3. Ascierto PA, et al. Abstract 4998, ESMO 2017, 8–12 Sept, Madrid, Spain.
   4. Lipson E, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047). Abstract 9503, ASCO 2021 Virtual Meeting, 4–8 June.

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Posted on 12 August 202129 February 2024