Relatlimab Plus Nivolumab a ‘Game Changer’ in Advanced Melanoma Relatlimab Plus Nivolumab a ‘Game Changer’ in Advanced Melanoma

For untreated advanced melanoma, the fixed-dose combination of relatlimab and nivolumab is a “game changer that we have been waiting 10 years for,” Hussein Tawbi, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News about today’s publication of the phase 2/3 RELATIVITY-047 trial.

Progression-free survival (PFS) was “essentially double” with the relatlimab-nivolumab combination vs nivolumab alone, Tawbi said. “We were always excited about the relatlimab-nivolumab combination…but I didn’t expect it to be this effective.”

Relatlimab is a lymphocyte-activation gene 3 (LAG-3) blocking antibody and nivolumab is a programmed cell death protein-1 (PD-1) blocker — both from Bristol Myers Squibb.

The fixed-dose combination immunotherapy is currently under priority review at the US Food and Drug Administration (FDA) with a target action date of March 19. 

RELATIVITY-047 — a global phase 2/3 double-blind, randomized trial — evaluated 714 patients with previously untreated unresectable or metastatic melanoma. Participants were randomly assigned to receive either the relatlimab-nivolumab fixed-dose combination (n = 355) or nivolumab alone (n = 359) administered intravenously every 4 weeks.

Results of the RELATIVITY-047 trial were presented, in part, at the American Society of Clinical Oncology 2021 Annual Meeting and reported by Medscape Medical News at the time.

The full analysis appeared today in The New England Journal of Medicine. Tawbi and colleagues reported median PFS of 10.1 months with relatlimab-nivolumab compared to 4.6 months with nivolumab alone. The hazard ratio for progression or death was 0.75 (P = .0006). Overall, PFS at 12 months was 47.7% in the relatlimab-nivolumab cohort vs 36% in the nivolumab group.

“This study proves that relatlimab-nivolumab combination is more effective than single-agent PD-1 and is actually quite comparable to CTLA-4 and PD-1 [inhibitors] together. That’s really exciting,” Tawbi told Medscape Medical News.

Grade 3 or 4 treatment-related adverse events were more common in the combination group, occurring in 18.9% of patients on relatlimab-nivolumab vs 9.7% of those on nivolumab alone.

Still, “to see that the toxicity was only 18.9% with relatlimab-nivolumab combination is also exciting,” said Tawbi, given that more than half of patients who receive an anti-CTLA-4 inhibitor, such as ipilimumab (Yervoy), in combination with an anti-PD-1 agent suffer grade 3 or 4 adverse events.

In an editorial in the journal, UK researchers Adam Frampton, PhD, with University of Surrey and Shivan Sivakumar, PhD, with University of Oxford, note that lingering questions about long-term outcomes remain. For instance, data on overall survival will come with additional analyses.

And as the data mature, time will tell whether the survival benefit of the relatlimab-nivolumab combination will be similar to or better than the combination of nivolumab plus the CTLA-4 agent ipilimumab.

If so, this would reinforce the relatlimab-nivolumab combination as the “new standard of care” for previously untreated patients with advanced melanoma, they write.

With longer follow-up, overall differences in survival may emerge between patients with high LAG-3 expression and those with low LAG-3 expression.

“Perhaps patients with low LAG-3 expression would derive more benefit from receiving anti-PD-1 and anti-CTLA-4 as first-line therapy, followed by anti–LAG-3 as second-line therapy,” they suggest.

The editorial writers say it will also be important to determine 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 genes.

Overall, the RELATIVITY-047 trial results provide evidence to “support adding relatlimab to the immunotherapeutic arsenal, which will create more options in the treatment landscape for advanced melanoma,” the editorialists conclude.

The study was funded by Bristol Myers Squibb. Disclosures for authors and editorial writers are available with the full text of this article at NEJM.org.

N Engl J Med. Published online January 5, 2022. Abstract

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