RELATIVITY-047; evaluating the anti-LAG-3 antibody relatlimab plus nivolumab in patients with previously untreated advanced melanoma
The RELATIVITY-047 trial is the first phase III study to validate dual LAG-3 and PD-1 inhibition. In this trial, the fixed-dose combination of relatlimab, an anti-LAG-3 antibody, and nivolumab versus nivolumab alone in patients with previously untreated metastatic or unresectable melanoma was evaluated. Primary results demonstrate that the trial met its primary endpoint of improved progression-free survival without any unexpected toxicities.
Immune checkpoint inhibitor therapy has revolutionised the treatment of patients with advanced melanoma. However, novel combinations are needed to optimise the benefit-risk profile. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint that inhibits T-cell activity and is upregulated in many tumour types, including melanoma. Relatlimab (RELA) is a human LAG-3-blocking antibody that restores effector function of exhausted T-cells. RELA in combination with nivolumab (NIVO) modulates potentially synergistic immune checkpoint pathways and can enhance antitumour immune responses. RELATIVITY-047 is a global, randomised, double-blind, phase II/III study evaluating a novel immune checkpoint inhibitor combination of RELA+NIVO as a fixed-dose combination (FDC) treatment in first-line advanced melanoma.
RELATIVITY-047 study design
In total, 714 patients with previously untreated unresectable or metastatic melanoma and an ECOG performance status of 0 or 1 were randomised (1:1) to receive RELA 160 mg + NIVO 480 mg FDC intravenously (IV) every 4 weeks (Q4W) or NIVO monotherapy 480 mg IV Q4W, stratified by LAG-3 expression, programmed death ligand 1 expression, BRAF mutation status, and AJCC (v8) metastatic stage. In this, ‘fixed dose combination’ refers to the preparation of RELA and NIVO in the same medication vial and administered as a single IV infusion to reduce preparation and infusion times and minimise the risk of administration errors. Patient characteristics were well balanced between treatment groups. After 425 patients were treated, enrolment was paused in order for an independent data monitoring committee (IDMC) to perform a prespecified interim progression free survival (PFS) analysis. Thereafter, the IDMC recommended continuation into phase III and recruitment continued until a total of 714 patients were enrolled. The primary endpoint of the study was progression-free survival (PFS) per RECIST v1.1, as assessed by blinded independent central review (BICR). Secondary endpoints were overall survival (OS) and objective response rate (ORR)
Relatlimab superior progression-free survival
After a median follow-up of 13.2 months, median PFS in the RELA+NIVO FDC group was 10.12 months and thereby significantly longer than the median PFS of 4.63 months reported in the NIVO group (HR [95%CI]: 0.75 [0.62–0.92], p=0.0055). Separation of the Kaplan-Meier curves already started after twelve weeks, when the first on-treatment imaging was performed, and was sustained through the median follow-up time of 13 months. PFS rates at 12 months were 47.7% and 36.0% for RELA+NIVO FDC and NIVO, respectively. PFS favoured RELA+NIVO FDC across key prespecified subgroups, including age, sex, baseline lactate dehydrogenase levels, ECOG performance status and tumour burden. In addition, PFS benefit favoured RELA+NIVO FDC regardless of LAG-3 expression status (HR: 0.75 for LAG-3 expression ≥1% and HR: 0.78 for LAG-3 expression < 1%).
The incidence of grade 3/4 treatment-related adverse events (TRAEs) was higher in the RELA+NIVO FDC group (18.9%) versus NIVO (9.7%). However, the toxicity profile was manageable and without unexpected safety signals. TRAEs of any grade led to treatment discontinuation in 14.6% and 6.7% of patients in the RELA+NIVO FDC and NIVO groups, respectively. There were three treatment-related deaths with RELA+NIVO FDC (haemophagocytic lymphohistiocytosis, acute oedema of the lung and pneumonitis) and two with NIVO (sepsis and myocarditis, and worsening pneumonia). Similarly, immune-mediated adverse events seen in the study were typical and manageable, generally supporting a favourable risk-benefit profile of RELA+NIVO. Any grade myocarditis occurred in 1.7% of patients with RELA+NIVO and 0.6% with NIVO. Of note, troponin monitoring was performed for the first two months of treatment protocol.
In RELATIVITY-047, relatlimab plus nivolumab as a fixed-dose combination demonstrated superior PFS by BICR, with more than a doubling of improvement in median PFS compared with nivolumab alone. Relatlimab plus nivolumab FDC demonstrated a manageable safety profile without unexpected safety signals. As such, RELATIVITY is the first phase III study to validate dual LAG-3 and PD-1 inhibition.
Lipson EJ, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047). Presented at ASCO 2021; Abstract 9503.