First results of the phase 3 RELATIVITY-047 trial validate 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 which inhibits T-cell activity, and is upregulated in many tumor 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-tumor immune responses [3]. RELATIVITY-047 (NCT03470922) is a global, randomized, double-blind, phase 2/3 study evaluating the combination of relatlimab plus nivolumab in first-line advanced melanoma. In this trial, 714 patients with previously untreated advanced melanoma were randomized 1:1 to receive relatlimab (160 mg) plus nivolumab (480 mg Q4W) 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. At a median follow-up of 13.2 months, progression-free survival in the relatlimab plus nivolumab arm was significantly improved versus nivolumab monotherapy: median 10.1 months versus 4.6 months, respectively. Progression-free survival 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, tumor 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% versus 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. “First-line treatment with relatlimab/nivolumab demonstrates a statistically significant progression-free survival compared with nivolumab monotherapy in patients with advanced melanoma,” concluded Dr Lipson. “In addition, relatlimab/nivolumab is well tolerated with a manageable safety profile and without unexpected safety signals. Therefore, this dual checkpoint blockade is a potential new treatment option for patients with advanced melanoma.”

  1. Durham NM, et al. PLoS One 2014; 9(11): e109080.
  2. Yu X, et al. MAbs 2019; 11: 1139-1148.
  3. Ascierto PA, et al. ESMO 2017; abstract LBA18.
  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). ASCO 2021 Virtual Meeting, abstract 9503.

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