RELATIVITY-047 is a phase III trial that evaluated the dual inhibition of LAG-3 and PD-1 using a new combination of relatlimab, a human IgG4 LAG-3–blocking antibody, and nivolumab as compared to the current standard therapy of nivolumab monotherapy, in patients with melanoma. Primary results demonstrate that the trial met its primary endpoint of improved progression-free survival without any unexpected toxicities.
EXPERT OPINION OF PROF. DR. HANS PRENEN, ONCOLOGIST, UNIVERSITY HOSPITAL ANTWERP
“The inhibition of two immune checkpoints (LAG-3 and PD1) is superior to PD1 alone in metastatic melanoma.”
Immune checkpoint inhibitor therapy has transformed treatment outcomes of patients with advanced melanoma. However, new combinations of checkpoint inhibitors need to be explored to improve outcomes and enhance the benefit–risk profiles of immunotherapy combinations. 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 is a human LAG-3-blocking antibody that restores the effector function of exhausted T-cells. The combination of relatlimab and nivolumab (RELA+NIVO) demonstrated to be safe and to have antitumour activity in patients with previously treated melanoma. However, the safety and activity in patients with previously untreated melanoma needs investigation. RELATIVITY-047 is a global, randomised, double-blind, phase II/III study evaluating combined LAG-3 and PD-1 inhibition with RELA+NIVO as a new fixed-dose combination (FDC) as compared with NIVO alone in patients with previously untreated metastatic or unresectable melanoma.
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. Stratification was done 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. Key exclusion criteria of the trial were uveal melanoma and active, untreated brain or leptomeningeal metastases. The primary endpoint was progression-free survival (PFS) per RECIST v1.1, as assessed by blinded independent central review (BICR).
After a median follow-up of 13.2 months, median PFS in the RELA+NIVO group was 10.1 months and thereby significantly longer than the median PFS of 4.6 months reported in the NIVO group (HR[95%CI]: 0.75[0.62–0.92], p=0.006). PFS rates at 12 months were 47.7% and 36.0% for RELA+NIVO and NIVO, respectively. In prespecified exploratory analyses, PFS also favoured RELA+NIVO over NIVO across key subgroups. In both treatment groups, the median PFS estimates were longer for patients with LAG-3 expression of 1% or greater. However, a benefit was seen with RELA+NIVO over NIVO regardless of LAG-3 expression. Among patients with PD-L1 ≥ 1%, median PFS was similar in the two groups. Among patients with PD-L1 < 1%, the median PFS with RELA+NIVO was 6.4 months as compared with 2.9 months with nivolumab (HR[95%CI]: 0.66[0.51-0.84]). The benefit of treatment with RELA+NIVO was observed regardless of patients’ BRAF mutation status. Similarly, patients who received RELA+NIVO had longer PFS regardless of key prognostic indicators, such as the AJCC metastasis stage of the tumour, LDH level, and tumour burden.
The incidence of grade 3/4 treatment-related adverse events was higher in the RELA+NIVO group (18.9%) versus the NIVO group (9.7%). Treatment-related adverse events (of any grade) leading to discontinuation occurred in 14.6% of patients in the RELA+NIVO group as compared with 6.7% of those in the nivolumab group. There were three treatment-related deaths with RELA+NIVO (haemophagocytic lymphohistiocytosis, acute pulmonary oedema and pneumonitis) and two with NIVO (sepsis and myocarditis in one patient and pneumonia in one patient). The most common categories of immune-mediated adverse events that occurred in the RELA+NIVO group were hypothyroidism or thyroiditis (in 18.0% of the patients), rash (in 9.3%), and diarrhoea or colitis (in 6.8%). Myocarditis occurred in 1.7% of the patients in the RELA+NIVO group and in 0.6% of those in the INVO group. Of note, routine troponin monitoring was performed for the first two months of treatment protocol. Overall, no substantial differences in health-related quality of life were noted between the treatment groups.
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. In addition, relatlimab plus nivolumab FDC demonstrated a manageable safety profile without unexpected safety signals. These data thus 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.