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):24-34. doi: 10.1056/NEJMoa2109970.
BACKGROUND: Lymphocyte-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. METHODS: In 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. RESULTS: The 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. CONCLUSIONS: The 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.).
背景：淋巴细胞激活基因 3（LAG-3）和程序性死亡受体 1（PD-1）是两种不同的抑制性免疫检查点，它们导致 T 细胞耗竭。LAG-3 阻断抗体 relatlimab 与 PD-1 阻断抗体 nivolumab 的联合应用已被证实对先前接受过治疗的黑色素瘤患者是安全且具有抗肿瘤活性的，但在先前未经治疗的黑色素瘤患者中的安全性和活性仍需研究。
方法：在这项全球性、双盲、随机 2-3 期临床试验中，我们评估了 relatlimab 和 nivolumab 作为固定剂量联合用药，与 nivolumab 单药治疗相比，在静脉输注每 4 周时用于治疗先前未经治疗的转移性或不可切除的黑色素瘤患者。主要终点是盲法独立中心评估的无进展生存期。
结果：与 nivolumab 相比，relatlimab-nivolumab 组的中位无进展生存期为 10.1 个月（95%置信区间[CI]，6.4 至 15.7），而 nivolumab 组为 4.6 个月（95%CI，3.4 至 5.6）（进展或死亡的风险比，0.75[95%CI，0.62 至 0.92]；对数秩检验 P=0.006）。relatlimab-nivolumab 组 12 个月时无进展生存率为 47.7%（95%CI，41.8 至 53.2），而 nivolumab 组为 36.0%（95%CI，30.5 至 41.6）。在关键亚组中，无进展生存期均有利于 relatlimab-nivolumab 组。relatlimab-nivolumab 组有 18.9%的患者和 nivolumab 组有 9.7%的患者发生 3 级或 4 级与治疗相关的不良事件。
结论：与单独抑制 PD-1 相比，抑制两种免疫检查点（LAG-3 和 PD-1）在先前未经治疗的转移性或不可切除的黑色素瘤患者中能更显著地改善无进展生存期。relatlimab 和 nivolumab 联合应用未显示出新的安全性信号。（由 Bristol Myers Squibb 资助；RELATIVITY-047 ClinicalTrials.gov 编号，NCT03470922）。
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