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Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047).
Abstract
9503 Background: Immune checkpoint inhibitor therapy has revolutionized the treatment of patients with advanced melanoma. However, novel combinations are needed to optimize the benefit-risk profile. Lymphocyte-activation gene 3 (LAG-3) regulates an immune checkpoint pathway, which inhibits T-cell activity, and is upregulated in many tumor types including melanoma. Relatlimab (RELA), a human IgG4 LAG-3-blocking antibody, restores effector function of exhausted T cells. RELA in combination with nivolumab (NIVO; anti-programmed death [PD]-1) modulates potentially synergistic immune checkpoint pathways and can enhance antitumor immune responses. RELATIVITY-047 is a global, randomized, 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. Methods: Patients with previously untreated advanced melanoma were randomized 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) M stage. The primary endpoint was progression-free survival (PFS) per RECIST v1.1 as assessed by blinded independent central review. Secondary endpoints were overall survival and objective response rate. PFS in prespecified subgroups and safety were additional objectives. Results: 714 patients were randomized to RELA+NIVO FDC (n = 355) or NIVO (n = 359). Patient characteristics were well balanced between treatment groups. Median follow-up was 13.2 months. Median PFS in the RELA+NIVO FDC group (10.1 months [95% CI, 6.4–15.7]) was significantly longer than in the NIVO group (4.6 months [95% CI, 3.4–5.6]; hazard ratio, 0.75 [95% CI, 0.6–0.9]; P = 0.0055). PFS rates at 12 months were 47.7% (95% CI, 41.8–53.2) and 36.0% (95% CI, 30.5–41.6) for RELA+NIVO FDC and NIVO, respectively. PFS favored RELA+NIVO FDC across key prespecified subgroups. 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%). There were 3 treatment-related deaths with RELA+NIVO FDC and 2 with NIVO. TRAEs (any grade) led to treatment discontinuation in 14.6% and 6.7% of patients in the RELA+NIVO FDC and NIVO groups, respectively. Conclusions: First-line treatment with RELA+NIVO FDC demonstrated a statistically significant PFS benefit compared to NIVO monotherapy in patients with advanced melanoma. RELA+NIVO FDC was well tolerated with a manageable safety profile and without unexpected safety signals. This is the first phase III study of a novel FDC to demonstrate a clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways. Clinical trial information: NCT03470922.
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“In the phase 2/3 study RELATIVITY-047, relatlimab (α-LAG-3) plus nivolumab therapy demonstrated a significant PFS benefit (10.1 vs. 4.6 months, HR: 0.75) in advanced melanoma, relatively to nivolumab monotherapy [165].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [165]
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Metadata
- Authors
- Lipson, E. J., Tawbi, H. A.-H., Schadendorf, D., Ascierto, P. A., Matamala, L., Gutiérrez, E. C., Rutkowski, P., Gogas, H., Lao, C. D., Janoski de Menezes, J., Dalle, S., Arance, A. M., Grob, J.-J., Srivastava, S., Abaskharoun, M., Simonsen, K. L., Li, B., Long, G. V., & Hodi, F. S.
- Affiliations
- Johns Hopkins University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
- Fundación Arturo López Pérez (CL)
- FAICIC Clinical Research, Veracruz, Mexico;
- The Maria Sklodowska-Curie National Research Institute of Oncology (PL)
- National and Kapodistrian University of Athens (GR)
- University of Michigan (US)
- Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil;
- Hospices Civils de Lyon (FR)
- Hospital Clínic de Barcelona (ES)
- Aix-Marseille Université (FR)
- Bristol-Myers Squibb (United States) (US)
- The University of Sydney (AU)
- Dana-Farber Cancer Institute (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2021-05-20
- Volume
- 39
- Issue
- 15_suppl
- Pages
- 9503-9503
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W3169720255
- Cited by
- 150
- References
- 0
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 12 · 2023: 24 · 2022: 68 · 2021: 34
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Funders
- Bristol-Myers Squibb
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- relatlimab, nivolumab, LAG-3 blockade, anti-PD-1 therapy, advanced melanoma, first-line therapy, immune checkpoint inhibitors, fixed-dose combination, progression-free survival, objective response rate, overall survival, PD-L1 expression, BRAF mutation, treatment safety, T cell exhaustion, antitumor immunity, combination immunotherapy
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