• Hussein A Tawbi, Dirk Schadendorf, Evan J Lipson, Paolo A Ascierto, Luis Matamala, Erika Castillo Gutiérrez, Piotr Rutkowski, Helen J Gogas, Christopher D Lao, Juliana Janoski De Menezes, Stéphane Dalle, Ana Arance, Jean-Jacques Grob, Shivani Srivastava, Mena Abaskharoun, Melissa Hamilton, Sarah Keidel, Katy L Simonsen, Anne Marie Sobiesk, Bin Li, F Stephen Hodi, Georgina V Long, and RELATIVITY-047 Investigators.
• From the Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (H.A.T.); the Department of Dermatology, University Hospital Essen, and the German Cancer Consortium, Essen, Germany (D.S.); the Sidney Kimmel Comprehensive Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore (E.J.L.); Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale," Naples, Italy (P.A.A.); the Department of Oncology, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago, Chile (L.M.); FAICIC Clinical Research, Veracruz, Mexico (E.C.G.); Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); the Department of Medicine, National and Kapodistrian University of Athens, Athens (H.J.G.); Michigan Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor (C.D.L.); Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil (J.J.D.M.); the Unit of Dermatology, Hospices Civils de Lyon, Cancer Research Center of Lyon, Pierre-Bénite (S.D.), and Aix-Marseille University, CHU Timone, Marseille (J.-J.G.) - both in France; the Department of Medical Oncology, Hospital Clinic Barcelona and IDIBAPS, Barcelona (A.A.); Bristol Myers Squibb, Princeton, NJ (S.S., M.A., M.H., S.K., K.L.S., A.M.S., B.L.); the Dana-Farber Cancer Institute, Boston (F.S.H.); and Melanoma Institute Australia, University of Sydney, Royal North Shore and Mater Hospitals, Sydney (G.V.L.).
• N. Engl. J. Med. 2022 Jan 6; 386 (1): 243424-34.

BackgroundLymphocyte-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.MethodsIn 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.ResultsThe 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.ConclusionsThe 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.).Copyright © 2022 Massachusetts Medical Society.

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