Dual inhibition of LAG-3, PD-1: a new therapeutic target for advanced melanoma?

In the phase II/III RELATIVITY-047 trial evaluating dual checkpoint inhibition for advanced melanoma, a new fixed-dose combination comprising the LAG-3 inhibitor relatlimab and the PD-1 inhibitor nivolumab fared better than nivolumab monotherapy.

Immune checkpoint inhibition has transformed treatment outcomes in advanced melanoma. [N Engl J Med 2019;381:1535-1546; J Clin Oncol 2021;40:127-137] “However, other immune checkpoints inhibit T-cell activation and function. [Hence,] new combinations of checkpoint inhibitors need to be explored to improve outcomes and enhance the benefit-risk profiles of immunotherapy combinations,” said the researchers.

“[In our study,] the inhibition of two immune checkpoints – LAG-3 and PD-1 – provided a greater benefit with regard to progression-free survival (PFS) than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma,” they continued.

In this study, 714 patients (median age 62 years, 42 percent female) were randomized 1:1 to receive nivolumab 480 mg either alone (monotherapy arm) or combined with relatlimab 160 mg (combination arm). Both regimens were administered via a single 60-minute IV infusion Q4W. [N Engl J Med 2022;386:24-34]

After a median follow-up of 13.2 months, median PFS was longer in the combination vs the monotherapy arm (10.1 vs 4.6 months; hazard ratio [HR] for progression or death, 0.75; p=0.006). PFS across key* subgroups also favoured the combination regimen over monotherapy.

“The separation of the PFS curves occurred at the initial post-baseline assessment (at ~12 weeks) and was sustained thereafter, with a 12-percent difference in PFS between arms at 12 months (48 percent vs 36 percent),” said the researchers.

In a separate editorial, Dr Adam Frampton from the University of Surrey, Guildford, UK, and Dr Shivan Sivakumar from the University of Oxford, UK noted the PFS benefit with the combination regimen as “the most notable result”, which might have been driven by the median PFS of 12.58 months in a subgroup of patients with positive LAG-3 expression of ≥1 percent. [N Engl J Med 2022;386:24-34]

Median PFS was also longer in the combination vs the monotherapy arm in subgroups of patients with PD-L1 expression of <1 percent (6.4 vs 2.9 months; HR, 0.66) and those with mutant (10.1 vs 4.6 months; HR, 0.74) and wild-type BRAF mutations (10.1 vs 4.6 months; HR, 0.76).

However, the better PFS with the combination regimen vs monotherapy came with more grade 3/4 treatment-related adverse events (TRAEs; 19 percent vs 10 percent) and treatment discontinuations owing to any-grade TRAEs (15 percent vs 7 percent). Nonetheless, there were no new safety signals reported with the combination regimen, and the safety profile seemed favourable compared with CTLA-4 and PD-1 inhibition. [N Engl J Med 2015;373:23-34]

A new addition to the immunotherapeutic arsenal

The findings establish LAG-3 as the ‘third immune checkpoint pathway’ target and validate LAG-3 and PD-1 inhibition as a therapeutic strategy for this disease, the researchers noted. “These data further support the added benefit of dual checkpoint inhibition over monotherapy, add another immune checkpoint combination to the therapeutic armamentarium, and establish relatlimab-nivolumab as a potential new [first-line] treatment option for patients with previously untreated metastatic or unresectable melanoma.”

“The single infusion [also] has the potential to reduce preparation and infusion times and minimize risk of errors related to administration,” they added.

“[This] trial provides evidence to support adding relatlimab to the immunotherapeutic arsenal, which will create more options in the treatment landscape for advanced melanoma,” noted Frampton and Sivakumar.

Follow-up evaluation on survival and long-term benefit is underway. The researchers called for further exploration to assess the efficacy of relatlimab-nivolumab in other patient groups, such as those with rare melanoma subtypes or those with active or untreated brain metastases.

“It is also important to assess whether relatlimab is useful in the salvage setting if primary immune checkpoint therapy fails and whether it is useful in combination with or after targeted therapy aimed at BRAF and MEK,” said Frampton and Sivakumar.