The RELATIVITY-047 study highlighted a survival benefit with the combination of relatlimab plus nivolumab compared with nivolumab alone for patients with previously untreated advanced melanoma.
The combination of relatlimab, a LAG-3–blocking antibody, and nivolumab (Opdivo), a, anti–PD-1 agent, resulted in an improved survival benefit compared with nivolumab monotherapy for patients with previously untreated metastatic or unresectable melanoma, according to results from the phase 2/3 RELATIVITY-047 trial (NCT03470922) published in The New England Journal of Medicine.
Treatment with the combination regimen resulted in a median progression-free survival (PFS) of 10.1 months (95% CI, 6.4-15.7) compared with 4.6 months (95% CI, 3.4-5.6) with nivolumab alone (HR, 0.75; 95% CI, 0.62-0.92; P = .006).
“These results validate blocking LAG-3 in combination with PD-1 as a therapeutic strategy for patients with melanoma and establish LAG-3 as the third immune checkpoint pathway the inhibition of which shows clinical benefit,” the investigators wrote.
Eligible patients were 12 years or older in age with previously untreated, histologically confirmed, unresectable stage III or IV melanoma, as well as measurable disease per RECIST 1.1 criteria and evaluable expression of LAG-3 and PD-L1.
Treatment, which was administered intravenously every 4 weeks, included either a fixed-dose combination of relatlimab at 160 mg and nivolumab at 480 mg or nivolumab monotherapy at 480 mg. Therapy was administered until disease progression, unacceptable toxicities, or consent withdrawal.
The research’s primary end point was PFS assessed according to RECIST 1.1 criteria by blinded independent review. Key secondary end points included overall survival (OS) and objective response.
A total of 714 patients randomized 1:1 to either the relatlimab plus nivolumab group (n = 355) or the nivolumab alone group (n = 359). The median age for the total population was 63.0 years (range, 20-94). Moreover, 41.7% of patients were female and 66.9% had an ECOG performance status of 0. Investigators reported that characteristics were well balanced across both groups. The study had a median follow-up of 13.2 months.
The PFS rate at 12 months was 47.7% (95% CI, 41.8%-53.2%) for patients in the relatlimab plus nivolumab group and 36.0% (95% CI, 30.5%-41.6%) for the nivolumab alone group. Across both treatment groups, estimates for median PFS were longer for patients with LAG-3 expression of 1% or more. Notably, a benefit was observed in the relatlimab plus nivolumab group vs the nivolumab alone group regardless of LAG-3 expression.
The median PFS for patients with PD-L1 expression of 1% or more was 15.7 months (95% CI, 10.1-25.8) in the relatlimab plus nivolumab group and 14.7 months (95% CI, 5.1–not reached) in the nivolumab alone group (HR, 0.95; 95% CI, 0.68-1.33). For PD-L1 expression of less than 1%, median PFS was 6.4 months (95% CI, 4.6-11.8) and 2.9 months (95% CI, 2.8-4.5) in the relatlimab plus nivolumab and nivolumab alone groups, respectively (HR, 0.66; 95% CI, 0.51-0.84).
The median duration of treatment for the relatlimab plus nivolumab group was 5.6 months and 4.9 months in the nivolumab alone group. The median time to treatment discontinuation was 8.3 months (95% CI, 6.5-11.0) in the relatlimab plus nivolumab group and 6.5 months (95% CI, 5.5-9.2) in the nivolumab alone group.
Grade 3/4 treatment-related adverse effects (TRAEs) were observed in 18.9% of patients in the relatlimab plus nivolumab group and 9.7% in the nivolumab alone group. Common grade 3/4 TRAEs in the relatlimab plus nivolumab group included increased levels of lipase (1.7%), alanine aminotransferase (1.4%), aspartate aminotransferase (1.4%), and fatigue (1.1%). Any-grade TRAEs that led to discontinuations occurred in 14.6% of patients in the relatlimab plus nivolumab group and 6.7% of patients in the nivolumab alone group.
“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 treatment option for patients with previously untreated metastatic or unresectable melanoma,” the investigators concluded.
Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34. doi:10.1056/NEJMoa2109970