Medical Technology

Relatlimab Plus Nivolumab is a ‘Game Changer in Advanced Melanoma

For patients who have not been treated for advanced malignant melanoma The fixed dose combination of relatlimab and nivolumab is a “game changer that we have been waiting for for the last 10 years,” Hussein Tawbi, MD PhD, University of Texas MD Anderson Cancer Center, Houston told Medscape Medical Newsabout the publication today of the phase 2/3 RELATIVITY-047 study.

Tawbi said that the progression-free survival (PFS), was “essentially double” when the relatlimab/nivolumab combo was compared with nivolumab on its own. “We were always excited about the relatlimab-nivolumab combination…but I didn’t anticipate it to be this efficient.”

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 in priority review at the US Food and Drug Administration (FDA) with a target date of March 19.

RELATIVITY-047 — an international phase 2/3 double-blind, randomized study which examined 714 patients suffering from previously untreated unresectable or metastatic Melanoma. Randomly, patients were assigned to receive either the fixed dose combination relatlimab/nivolumab (n = 355) or nivolumab intravenously every four weeks (n 359).

The results of the RELATIVITY-047 trial were presented at the American Society of Clinical Oncology 2021 annual conference and was reported at the time by Medscape Medical News.

The New England Journal of Medicine published the complete analysis. Tawbi and coworkers reported a median PFS of 10.2 months with relatlimab/nivolumab compared to 4.6 with nivolumab. The rate of progression or death was 0.75 ( P= .0006). PFS at 12 months was 47.7% for the relatlimab–nivolumab cohort, in contrast to 36% in the Nivolumab.

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

Grade 3 and 4 adverse reactions related to treatment were more prevalent in the group that was a combination. They were seen in 18.9 percent of patients who received relatlimab/nivolumab, compared to 9.7 percent of patients who received just nivolumab.

“Seeing that the toxicity was only 18.9% for relatlimab/nivolumab combination is still exciting,” Tawbi said. This is despite the fact that more than half of patients who receive an anti–CTLA-4 inhibitor, such as ipilimumab, (Yervoy) in combination with an Anti-PD-1 drug suffer from adverse reactions.

UK researchers Adam Frampton (Doctor of Philosophy, University of Surrey) and Shivan Sivakumar (Doctor of Philosophy, University of Oxford) observe that there are questions regarding the long-term impact. Further analyses will be conducted to include data on overall survival.

And as the data mature, time will tell whether the survival benefits of the relatlimab-nivolumab combo will be similar or greater 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.

Patients with high HTML3 expression could have a shorter survival rate than those with lower HTML3 expression.

They suggest that patients with low HTML3 expression could be benefitted by receiving anti-PD-1, anti-CTLA-4, and then anti-HT1_ LAG-3 second-line treatment.

The editorial writers state that it is also crucial to determine if relatlimab is beneficial in the salvage setting in the event that primary immune checkpoint therapy fails and whether it is useful in conjunction with or following targeted therapy aimed at BRAF and MEKgenes.

Overall the results of the RELATIVITY-047 trial provide evidence to “support the addition of relatlimab into the arsenal of immunotherapeutics, which will open up more options in the treatment landscape for advanced melanoma,” the editorialists conclude.

Bristol Myers Squibb funded the study with Bristol Myers Squibb. The full article’s text can be found at with disclosures for authors and editors.

N Engl J Med. Online publication on January 5, 2022. Abstract

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