The US Food and Drug Administration’s (FDA) approval of Bristol-Myers Squibb’s (BMS) Opdualag, a fixed-dose combination of Opdivo (nivolumab) and relatlimab for the treatment of metastatic melanoma, marks the market entry of a new class of immune checkpoint inhibitors.

Relatlimab is a monoclonal antibody (mAb) targeting the lymphocyte activation gene-3 (LAG-3) cell surface molecule. The LAG-3 pathway has now been established as the third immune checkpoint pathway that can be inhibited to stimulate an anti-tumour immune response. LAG-3 has been linked to tumour-infiltrating T-cell exhaustion and identified as a mechanism of resistance to some immunotherapies, including anti-programmed cell death protein-1 (PD-1) therapeutics. Opdualag’s approval comes eight years after the approval of the first anti-PD-1 agent, Merck’s Keytruda (pembrolizumab), and 11 years after the approval of BMS’s Yervoy (ipilimumab), the only FDA-approved anti-CTLA-4 mAb.

The approval of Opdualag is based on data from the Phase III RELATIVITY-047 trial, which compared Opdualag with Opdivo monotherapy in 714 patients with previously untreated, unresectable Stage III or IV melanoma. The trial reported a median progression-free survival (PFS) of 10.1 months in patients treated with Opdualag versus 4.6 months for patients treated with Opdivo monotherapy, with the combination checkpoint inhibition more than doubling the median time to disease progression. The median overall survival (OS) was not reached in the doublet arm and was 34.1 months in the Opdivo monotherapy arm.

In terms of safety, Opdualag-treated patients had a grade 3/4 treatment-related adverse event (TRAE) rate of 21.1%, higher than the 11.1% reported for the Opdivo monotherapy arm. Despite Opdualag demonstrating greater toxicity than Opdivo monotherapy, the new doublet appears to have a favourable toxicity profile in comparison with BMS’ Opdivo + Yervoy combination, which reported a grade 3/4 TRAE rate of 59% in the Phase III CheckMate-067 trial. Although cross-trial comparisons must be made with extreme caution, the stark contrast between the toxicity profiles of the two-immune-checkpoint-inhibitor combinations is likely to be of clinical significance. In the metastatic melanoma setting, Opdualag provides a treatment option with higher efficacy than Opdivo monotherapy, as well as likely superior tolerability to the Opdivo-Yervoy combination.

There are multiple late-phase trials in progress for relatlimab, both as a monotherapy and in combination with Opdivo, across a broad range of oncology indications, with this first-in-class agent predicted to achieve blockbuster status. GlobalData forecasts sales of relatlimab to reach $1.16bn by 2028. Despite this, relatlimab is expected to face fierce competition across oncology indications from other anti-LAG-3 agents currently in late-stage development, including Merck’s favezelimab, Regeneron’s fianlimab, MacroGenic’s bispecific tebotelimab, Novastis’ ieramilimab and Incyte’s INCAGN-2385. The FDA’s approval of a therapeutic targeting a novel checkpoint blockade is expected to be the start of significant change in the immuno-oncology landscape.