Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
Nucleus Network, Alfred Hospital, Monash University, Melbourne, Victoria, Australia.
Cancer. 2020 Nov 15;126(22):4926-4935. doi: 10.1002/cncr.33133. Epub 2020 Aug 18.
Ligation of glucocorticoid-induced tumor necrosis factor receptor (GITR) decreases regulatory T cell-mediated suppression and enhances T-cell proliferation, effector function, and survival. MK-1248 is a humanized immunoglobulin G4 anti-GITR monoclonal antibody agonist.
In patients with advanced solid tumors, MK-1248 (starting dose, 0.12 mg) was tested alone and with pembrolizumab (200 mg) according to a 3 + 3 dose escalation design (ClinicalTrials.gov identifier NCT02553499); both treatments were administered intravenously every 3 weeks for ≤4 and ≤35 cycles, respectively. The safety and tolerability, maximum tolerated dose, and pharmacokinetics/pharmacodynamics were explored.
Twenty patients received MK-1248 monotherapy; 17 received combination therapy. The most frequent tumor types were colorectal cancer (n = 8), melanoma (n = 6), and renal cell carcinoma (n = 4). MK-1248 was generally well tolerated at the maximum tested doses of 170 (monotherapy) and 60 mg (combination). No dose-limiting toxicities (DLTs) or treatment-related deaths occurred. Adverse events (AEs) occurred in 36 of the 37 patients (97%); the most common were vomiting (n = 13 [35%]), anemia (n = 10 [27%]), and decreased appetite (n = 10 [27%]). Grade 3 to 5 AEs occurred in 19 of the 37 patients (51%). Treatment-related AEs occurred in 18 of the 37 patients (49%): 9 of the 20 patients (45%) on monotherapy and 9 of the 17 patients (53%) on combination therapy. Among the 17 patients receiving combination therapy, 1 achieved a complete response and 2 achieved a partial response, for an objective response rate of 18%; no patients achieved an objective response with monotherapy. The disease control rate (stable disease or better) was 15% with monotherapy and 41% with combination therapy.
MK-1248 was generally well tolerated at doses up to 170 (monotherapy) and 60 mg (combination), with no DLTs or treatment-related deaths. Combination therapy provided limited antitumor responses.
糖皮质激素诱导的肿瘤坏死因子受体（GITR）的交联可降低调节性 T 细胞介导的抑制作用，并增强 T 细胞的增殖、效应功能和存活。MK-1248 是一种人源化 IgG4 抗 GITR 单克隆抗体激动剂。
在晚期实体瘤患者中，根据 3+3 剂量递增设计（ClinicalTrials.gov 标识符 NCT02553499），单独使用 MK-1248（起始剂量 0.12mg）和联合使用 pembrolizumab（200mg）进行测试；两种治疗均每 3 周静脉输注一次，分别不超过 4 次和 35 次。探索了安全性和耐受性、最大耐受剂量以及药代动力学/药效学。
20 例患者接受 MK-1248 单药治疗；17 例患者接受联合治疗。最常见的肿瘤类型是结直肠癌（n=8）、黑色素瘤（n=6）和肾细胞癌（n=4）。MK-1248 在最高测试剂量 170（单药）和 60mg（联合）时通常具有良好的耐受性。未发生剂量限制性毒性（DLT）或治疗相关死亡。37 例患者中有 36 例（97%）发生不良事件（AE）；最常见的是呕吐（n=13[35%]）、贫血（n=10[27%]）和食欲下降（n=10[27%]）。19 例患者（51%）出现 3 级至 5 级 AE。37 例患者中有 18 例（49%）发生治疗相关 AE：20 例患者中有 9 例（45%）接受单药治疗，17 例患者中有 9 例（53%）接受联合治疗。在接受联合治疗的 17 例患者中，1 例患者获得完全缓解，2 例患者获得部分缓解，客观缓解率为 18%；单药治疗无患者获得客观缓解。单药治疗的疾病控制率（稳定疾病或更好）为 15%，联合治疗为 41%。
MK-1248 的剂量高达 170mg（单药）和 60mg（联合）时，通常具有良好的耐受性，无 DLT 或治疗相关死亡。联合治疗提供了有限的抗肿瘤反应。
