Many tumor types, including melanoma, have an upregulated immune checkpoint pathway involving lymphocyte-activation gene-3 (LAG-3) that inhibits T-cell activity. Relatlimab (RELA) is a human IgG4 anti–LAG-3 antibody that can restore the effector function of T-cells. RELA plus nivolumab (NIVO), an anti–PD-1 drug, may be able to augment antitumor immune responses by modulating synergistic immune checkpoint pathways. RELATIVITY-047 was a global, randomized, double-blind, phase 2/3 study evaluating a novel immune checkpoint inhibitor combination of RELA plus NIVO as a fixed-dose combination first-line treatment in advanced melanoma.1
Patients with advanced melanoma (N = 714) who had not been previously treated were randomized to RELA 160 mg plus NIVO 480 mg intravenously (IV) every 4 weeks (n = 355) or NIVO alone 480 mg IV every 4 weeks (n = 359). The patients were divided into cohorts by LAG-3 expression, PD-1 expression, BRAF mutation status, and stage. The primary end point was progression-free survival (PFS). Secondary end points were overall survival and objective response rate. Additional objectives were PFS in subgroups: LAG-3 (≥1% compared with <1%), BRAF (mutation positive compared with mutation wild-type), and American Joint Committee on Cancer M stage.1
The median PFS in the group receiving RELA plus NIVO was 10.1 months (95% confidence interval [CI], 6.4-15.7) and 4.6 months (95% CI, 3.4-5.6) in the NIVO monotherapy group (hazard ratio, 0.75; 95% CI, 0.62-0.92; P = .0055).1,2 The PFS at 12 months was 47.7% (95% CI, 41.8-53.2) for the RELA plus NIVO cohort and 36.0% (95% CI, 30.5-41.6) for NIVO alone.1,2 This benefit was also shown in the PFS rates in the subgroups.1
In the combination RELA plus NIVO group, the incidence of grade 3/4 treatment-related adverse events (TRAEs) was 18.9% compared with 9.7% in the NIVO monotherapy group. TRAEs of any grade led to discontinuation of therapy in 14.6% of the patients in the RELA plus NIVO group and 6.7% of those in the NIVO group. In addition, there were 3 treatment-related deaths with RELA plus NIVO and 2 with NIVO alone.1
In conclusion, first-line therapy of advanced melanoma with combination RELA plus NIVO demonstrated a benefit in PFS that was statistically significant compared with that of NIVO alone. This combination therapy was well-tolerated with manageable adverse events. This was the first phase 3 study of a novel fixed-dose combination to demonstrate a clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways.1
- Lipson EJ, Tawbi AHH, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol. 2021;39(suppl_15):9503-9503.
- Hodi FS, Tawbi HA, Lipson EJ, et al. Relatlimab (RELA) + nivolumab (NIVO) vs. NIVO in previously untreated metastatic or unresectable melanoma: additional efficacy in RELATIVITY-047. Presented at: 2021 ESMO Congress; September 16-21, 2021. Abstract 10360.