Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma

Abstract

Background: Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation.

Methods: In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review.

Results: The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group.

Conclusions: The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.).

Figure 1.. Progression-free Survival.

Data shown include all patients who underwent randomization. Hazard ratios were estimated with a stratified Cox proportional-hazards model. P values were calculated with the use of a log-rank test stratified according to expression of lymphocyte-activation gene 3 (LAG-3) (≥1% vs. <1%), BRAF mutation status (mutant vs. wild-type), and American Joint Committee on Cancer metastasis stage (M0 or M1 with normal LDH level vs. M1 with elevated LDH level). Programmed death ligand 1 was not used for stratification because it resulted in subgroups with fewer than 10 patients. Tick marks indicate censored data.

Figure 2.. Progression-free Survival, According to Subgroup.

The exploratory and descriptive analyses and proportional-hazards assumptions were not tested for the subgroup exploratory analyses, so hazard ratios should be interpreted with caution. The Eastern Cooperative Oncology Group (ECOG) performance status is assessed on a 5-point scale, with 0 indicating no performance restrictions and higher scores indicating greater disability. The tumor burden was measured by blinded independent central review. Q1 denotes the middle value between the smallest value and the median; 25% of data are below Q1. Q3 denotes the middle value between the median and the highest value; 75% of data are below Q3. LDH denotes lactate dehydrogenase, PD-L1 programmed death ligand 1, and ULN upper limit of the normal range.

Figure 3.. Progression-free Survival, According to LAG-3 Expression.

Hazard ratios were estimated with an unstratified Cox proportional-hazards model.