Clinical Research, START, San Antonio, Texas.
Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2021 Apr 1;27(7):1904-1911. doi: 10.1158/1078-0432.CCR-20-2886. Epub 2020 Dec 21.
In this first-in-human phase I study (NCT02132754), we explored MK-4166 [humanized IgG1 agonist mAb targeting glucocorticoid-induced TNF receptor (GITR)] with and without pembrolizumab in advanced solid tumors.
MK-4166 was tested alone (0.0015-900 mg i.v. every 3 weeks for four doses) or with pembrolizumab (200 mg i.v. every 3 weeks for ≤35 doses) in patients with metastatic solid tumors (dose escalation/confirmation) and advanced melanoma (expansion). Primary objectives were to evaluate the safety and tolerability and establish the MTD of MK-4166. Exploratory endpoints were objective response rate (ORR) and T cell-inflamed gene expression profile (GEP) analysis using RNA from baseline tumor samples.
A total of 113 patients were enrolled [monotherapy, = 48; combination therapy, = 65 (20 in the expansion)]. Forty-six patients (40.7%) had grade ≥3 adverse events, 9 (8.0%) of which were treatment related. No treatment-related deaths were observed. One dose-limiting toxicity event with monotherapy (bladder perforation in patient with neobladder) was considered related to study drug. MTD was not reached. MK-4166 pharmacodynamics showed decreased GITR availability on circulating T cells with increasing doses. One objective response (ORR, 2.2%) was achieved with combination therapy in the dose escalation/confirmation ( = 45). In the expansion, 8 of 13 patients with immune checkpoint inhibitor (ICI)-naïve melanoma achieved a response (ORR, 62%; 95% confidence interval, 32-86; 5 complete responses and 3 partial responses). None of the ICI-pretreated patients ( = 7) responded. High response rates were observed in ICI-naïve patients irrespective of GEP status.
MK-4166 900 mg i.v. every 3 weeks as monotherapy and with pembrolizumab was tolerable. Responses were observed with combination therapy, mostly in patients with ICI-naïve melanoma.
在这项首次人体 I 期研究（NCT02132754）中，我们研究了 MK-4166[靶向糖皮质激素诱导的 TNF 受体（GITR）的人源化 IgG1 激动型单克隆抗体]单药治疗和联合 pembrolizumab 治疗晚期实体瘤的情况。
MK-4166 单独（静脉注射 0.0015-900mg，每 3 周 1 次，共 4 个剂量）或联合 pembrolizumab（静脉注射 200mg，每 3 周 1 次，最多 35 个剂量）治疗转移性实体瘤（剂量递增/确认）和晚期黑色素瘤（扩展）患者。主要目的是评估安全性和耐受性，并确定 MK-4166 的最大耐受剂量。探索性终点是使用基线肿瘤样本的 RNA 分析客观缓解率（ORR）和 T 细胞炎症基因表达谱（GEP）。
共纳入 113 例患者[单药治疗， = 48；联合治疗， = 65（扩展组 20 例）]。46 例（40.7%）患者发生≥3 级不良事件，其中 9 例（8.0%）与治疗相关。未观察到治疗相关死亡。单药治疗时出现 1 例剂量限制性毒性事件（新膀胱患者膀胱穿孔），认为与研究药物相关。未达到最大耐受剂量。MK-4166 药代动力学显示，随着剂量的增加，循环 T 细胞上 GITR 的可用性降低。联合治疗在剂量递增/确认组（ = 45）中观察到 1 例客观缓解（ORR，2.2%）。在扩展组中，13 例免疫检查点抑制剂（ICI）初治黑色素瘤患者中有 8 例（ORR，62%；95%置信区间，32-86；5 例完全缓解和 3 例部分缓解）获得缓解。7 例 ICI 预处理患者均无缓解。ICI 初治患者的缓解率较高，无论 GEP 状态如何。
MK-4166 静脉注射 900mg，每 3 周 1 次，单药治疗和联合 pembrolizumab 治疗均耐受良好。联合治疗观察到应答，主要见于 ICI 初治黑色素瘤患者。
