Originally published by 2 Minute Medicine^® (view original article). Reused on AccessMedicine with permission.

1. In patients with untreated metastatic or unresectable melanoma, the combination of Relatlimab and Nivolumab was associated with greater progression-free survival than Nivolumab alone.

2. In patients with advanced melanoma, treatment with Relatlimab and Nivolumab demonstrated no new safety signals than Nivolumab alone.

Evidence Rating Level: 1 (Excellent)

Study Rundown:

Immunotherapy with PD-1 inhibitors (Nivolumab) and LAG-3 inhibitors (Relatlimab) have been shown to improve outcomes in patients with untreated or advanced melanoma. Relatlimab and Nivolumab have been proposed to have synergistic antitumor activity, and thus the combination of these medications has been proposed for untreated metastatic or unresectable melanoma. There is a gap in knowledge as to understanding the progression-free survival benefit of Relatlimab and Nivolumab used together. This study found that treatment with Relatlimab and Nivolumab provided a greater progression-free survival than Nivolumab alone in patients with advanced melanoma. This study was limited by the exclusion of patients with rare melanoma subtypes and patients that are typically excluded from melanoma clinical trials such as those with brain metastases. Nevertheless, these study’s findings are significant, as they demonstrate that combination therapy of Relatlimab with Nivolumab is more effective than Nivolumab alone for patients with melanoma, suggesting a new therapeutic strategy for previously untreated metastatic or unresectable melanoma.

Click to read the study in NEJM

Relevant Reading: A New Combination Immunotherapy in Advanced Melanoma

In-Depth [randomized control trial]:

This randomized control trial included 714 patients; 355 in the Relatlimab-Nivolumab group and 359 in the Nivolumab only group at 111 sites in North America, Central America, South America, Europe, Australia, and New Zealand. Patients were eligible if they were older than 12 years and had confirmed unresectable stage III or IV melanoma, and were eligible even if they had previously received immunotherapies. Patients who had uveal melanoma or untreated brain or leptomeningeal metastases were excluded from the study. The primary outcome measure was progression-free survival, defined as the time between the date of randomization and the earliest date of documented disease progression or the date of death from any cause, whichever occurred first. Outcomes in the primary analysis were assessed via a two-sided log-rank test and a Cox proportional-hazards model, as well as Kaplan-Meier methods. Between the two treatment groups, Relatlimab-Nivolumab had a longer median progression-free survival of 10.1 months (95% confidence interval [CI], 6.4 to 15.7) as compared to 4.6 months with Nivolumab (95% CI, 3.4 to 5.6). Furthermore, progression-free survival at one year from treatment was higher in the Relatlimab-Nivolumab group (47.7%, 95% CI 41.8 to 53.2) as compared to Nivolumab (36.0%, 95% CI 30.5 to 41.6). The study also demonstrated that Relatlimab-Nivolumab demonstrated no new safety signals, as there were no significant differences in health-related quality of life between the treatment groups. Overall, this study determined that there was a significantly greater benefit regarding progression-free survival when using Relatlimab-Nivolumab as compared to Nivolumab alone.

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