Division of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL.
Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL.
J Clin Oncol. 2020 Apr 10;38(11):1138-1145. doi: 10.1200/JCO.19.02394. Epub 2020 Feb 25.
We hypothesized that bevacizumab will potentiate activity of pembrolizumab. We conducted a phase Ib/II, single-arm, multisite clinical trial of the combination in metastatic renal cell carcinoma (RCC).
Patients with metastatic clear cell RCC who experienced progression after at least one systemic therapy (phase Ib) or were treatment naïve (phase II) were enrolled. In phase Ib, pembrolizumab (200 mg) and bevacizumab (10 or 15 mg/kg) were given intravenously every 3 weeks. The primary end point for phase II was overall response rate (ORR). With an 80% statistical power and a type I error probability of 0.1, 48 patients were to be accrued to detect an ORR of 42%.
Thirteen patients (ages 33-68 years; median, 55 years) were enrolled in the phase Ib study. No dose-limiting toxicities were reported. Pembrolizumab 200 mg and bevacizumab 15 mg/kg were chosen for phase II. Forty-eight patients (ages 42-84 years; median age, 61 years; 33 males) were accrued for the phase II study. The primary end point was met, with the ORR reaching 60.9% (95% CI, 45.4% to 74.9%), consisting of 1 complete response (CR), 2 CRs in target lesions, 25 partial responses, 18 responses of stable disease, 2 unevaluable responses. Median progression-free survival was 20.7 months (95% CI, 11.3 to 27.4 months). Median overall survival was not reached at the median follow-up of 28.3 months. The most common treatment-related grade 3 toxicities were hypertension and proteinuria. There were two grade 4 toxicities: duodenal ulcer and hyponatremia. Presence of tumor-infiltrating T cells, but not programmed death-ligand 1 expression, in tumor tissue correlated with response.
The combination of 200 mg of pembrolizumab and a 15 mg/kg dose of bevacizumab given every 3 weeks is safe and active in metastatic RCC.
我们假设贝伐珠单抗将增强帕博利珠单抗的活性。我们进行了一项 Ib/II 期、单臂、多中心临床试验，评估了转移性肾细胞癌（RCC）中该联合用药的疗效。
入组标准为至少接受过一次全身治疗后进展的转移性透明细胞 RCC 患者（Ib 期）或初治患者（II 期）。Ib 期给予帕博利珠单抗（200mg）和贝伐珠单抗（10 或 15mg/kg），每 3 周静脉给药。II 期的主要终点为总缓解率（ORR）。假设 80%的统计效能和 0.1 的Ⅰ类错误概率，需入组 48 例患者以检测 42%的 ORR。
13 例患者（33-68 岁；中位年龄 55 岁）入组 Ib 期研究。未报告剂量限制毒性。选择帕博利珠单抗 200mg 和贝伐珠单抗 15mg/kg 用于 II 期研究。共入组 48 例患者（42-84 岁；中位年龄 61 岁；33 例男性）。主要终点达到，ORR 为 60.9%（95%CI，45.4%至 74.9%），包括 1 例完全缓解（CR），2 例靶病灶 CR，25 例部分缓解，18 例疾病稳定，2 例无法评估的缓解。中位无进展生存期为 20.7 个月（95%CI，11.3 至 27.4 个月）。中位随访 28.3 个月时，中位总生存期尚未达到。最常见的治疗相关 3 级毒性为高血压和蛋白尿。有 2 例 4 级毒性反应：十二指肠溃疡和低钠血症。肿瘤组织中存在肿瘤浸润性 T 细胞，但不存在程序性死亡配体 1 表达与缓解相关。
每 3 周给予 200mg 帕博利珠单抗和 15mg/kg 贝伐珠单抗的联合治疗在转移性 RCC 中安全且有效。
