Thomas Baily, Burns Madison, Pervanas Helen, Ciurescu Daniel, Dima Lorena
Sanofi Specialty Care, Cambridge, MA.
Massachusetts College of Pharmacy and Health Sciences University, Manchester, NH.
Am J Ther. 2023;30(6):e526-e534. doi: 10.1097/MJT.0000000000001680.
Immune checkpoint inhibitors control effector mechanisms and work to restore downregulated T-cells in patients with melanoma. Examples of such include programmed death-1 inhibitors and lymphocyte-activating gene 3 inhibitors. The combination of nivolumab, a programmed death-1 inhibitor, and relatlimab-rmbw, a lymphocyte-activating gene 3 inhibitor, has shown antitumor activity and improved progression-free survival in patients with unresectable or metastatic melanoma.
MECHANISM OF ACTION PHARMACOKINETICS/PHARMACODYNAMICS: The fixed-dose combination of nivolumab and relatlimab immunotherapy is approved for adults and pediatrics 12 years of age or older with metastatic or unresectable melanoma. Volume of distribution is 6.6 L for relatlimab and nivolumab, and half-life is 27 and 26 days, respectively. Clearance at steady state is 7.6 mL/h for nivolumab and 5.5 mL/h for relatlimab. Sex, age, race, and mild hepatic/renal impairment had no clinical effect on clearance. The exposure-response relationship and pharmacodynamic response for the safety and effectiveness of nivolumab/relatlimab-rmbw have not been fully characterized. Safety concerns include severe and fatal immune-mediated adverse reactions, infusion-related reactions, and complications of allogeneic hematopoietic stem cell transplantation, and fetal toxicity. Dosing is determined by patient's age and weight. Solution is infused over a 30-minute timeframe.
In the RELATIVITY-047 trial, patients received nivolumab or nivolumab/relatlimab-rmbw. Results showed superiority of dual therapy over monotherapy with a progression-free survival of 10.1 months (95% CI, 6.4-15.7) compared with 4.6 months (95% CI, 3.4-5.6) and hazard ratio of 0.75 (95% CI, 0.62-0.92); P = 0.006, respectively. No safety concerns were observed compared with monotherapy with treatment-related adverse events occurring in 18.9% of patients on combination therapy compared with 9.7% on nivolumab alone.
The novel mechanism and improvement in progression-free survival compared with standard of care highlight the therapeutic advancement of nivolumab/relatlimab-rmbw in the treatment of unresectable and metastatic melanoma.
免疫检查点抑制剂可控制效应机制，并致力于恢复黑色素瘤患者体内下调的T细胞。此类抑制剂包括程序性死亡-1抑制剂和淋巴细胞激活基因3抑制剂。程序性死亡-1抑制剂纳武单抗与淋巴细胞激活基因3抑制剂瑞派利单抗- rmbw联合使用，已显示出对不可切除或转移性黑色素瘤患者具有抗肿瘤活性，并改善了无进展生存期。
作用机制、药代动力学/药效学：纳武单抗和瑞派利单抗免疫疗法的固定剂量组合已获批用于治疗患有转移性或不可切除黑色素瘤的12岁及以上成人和儿科患者。瑞派利单抗和纳武单抗的分布容积均为6.6L，半衰期分别为27天和26天。纳武单抗稳态清除率为7.6mL/h，瑞派利单抗为5.5mL/h。性别、年龄、种族以及轻度肝/肾功能损害对清除率均无临床影响。纳武单抗/瑞派利单抗- rmbw安全性和有效性的暴露-反应关系及药效学反应尚未完全明确。安全问题包括严重和致命的免疫介导不良反应、输液相关反应、同种异体造血干细胞移植并发症以及胎儿毒性。给药剂量根据患者年龄和体重确定。溶液在30分钟内输注完毕。
在RELATIVITY - 047试验中，患者接受纳武单抗或纳武单抗/瑞派利单抗- rmbw治疗。结果显示，联合治疗优于单药治疗，联合治疗的无进展生存期为10.1个月（95%CI，6.4 - 15.7），而单药治疗为4.6个月（95%CI，3.4 - 5.6），风险比为0.75（95%CI，0.62 - 0.92）；P分别为0.006。与单药治疗相比，联合治疗未观察到安全问题，联合治疗组18.9%的患者发生治疗相关不良事件，而纳武单抗单药治疗组为9.7%。
与标准治疗相比，其新机制及无进展生存期的改善突出了纳武单抗/瑞派利单抗- rmbw在治疗不可切除和转移性黑色素瘤方面的治疗进展。
