Department of Gynecologic Oncology, Clinical Sciences Center, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
JAMA Oncol. 2021 Jan 1;7(1):78-85. doi: 10.1001/jamaoncol.2020.5945.
IMPORTANCE: Treatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable effective therapies. OBJECTIVE: To assess the efficacy and safety of a combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer. DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-arm phase 2 cohort study enrolled patients from September 6, 2016, to June 27, 2018, at a single institution in the United States. Eligible patients had recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1. Data were analyzed from September 6, 2016, to February 20, 2020. INTERVENTIONS: Patients received intravenous pembrolizumab, 200 mg, and bevacizumab, 15 mg/kg, every 3 weeks and oral cyclophosphamide, 50 mg, once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent. MAIN OUTCOMES AND MEASURES: Primary outcomes were objective response rate (ORR) and progression-free survival (PFS). RESULTS: Of the 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer with a mean (SD) age of 62.2 (9.4) years. Three women (7.5%) had complete responses, 16 (40.0%) had partial responses, and 19 (47.5%) had stable disease in response to treatment based on irRECIST criteria, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 (90% CI, 6.5-17.4) months. The most common grade 3 to 4 treatment-related adverse events were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). The most frequently reported adverse events included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]). CONCLUSIONS AND RELEVANCE: In this phase 2 nonrandomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated and demonstrated clinical benefit in 95.0% and durable treatment responses (>12 months) in 25.0% of patients with recurrent ovarian cancer. This combination may represent a future treatment strategy for recurrent ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02853318.
重要性：复发性卵巢癌的治疗选择临床获益有限，并对患者的生活质量产生不利影响，这代表了对可耐受有效治疗的未满足需求。
目的：评估帕博利珠单抗联合贝伐珠单抗和口服低剂量环磷酰胺在铂敏感、铂耐药或难治性上皮性卵巢癌、输卵管癌或原发性腹膜癌患者中的疗效和安全性。
设计、地点和参与者：这是一项在美国一家机构进行的开放标签、单臂 2 期队列研究。研究于 2016 年 9 月 6 日至 2018 年 6 月 27 日入组患者。入组标准为复发性卵巢癌，根据免疫相关实体瘤反应评估标准（irRECIST）可测量疾病，东部肿瘤协作组体力状态评分为 0 至 1 分。数据于 2016 年 9 月 6 日至 2020 年 2 月 20 日进行分析。
干预措施：患者接受静脉注射帕博利珠单抗 200mg 和贝伐珠单抗 15mg/kg，每 3 周 1 次，以及在治疗周期内口服环磷酰胺 50mg，每日 1 次，直至疾病进展、无法耐受的毒性或患者撤回同意。
主要结局和测量：主要结局为客观缓解率（ORR）和无进展生存期（PFS）。
结果：40 名入组的女性中，30 名（75.0%）患有铂耐药卵巢癌，10 名（25.0%）患有铂敏感卵巢癌，平均年龄（标准差）为 62.2（9.4）岁。根据 irRECIST 标准，有 3 名女性（7.5%）达到完全缓解，16 名（40.0%）达到部分缓解，19 名（47.5%）达到稳定疾病，ORR 为 47.5%，临床获益率为 38.0%（95%CI，29.2%-47.0%），持久缓解率为 10.0%（95%CI，4.6%-17.4%）。中位 PFS 为 10.0 个月（90%CI，6.5-17.4）。最常见的 3 级至 4 级治疗相关不良事件为高血压（6 例[15.0%]）和淋巴细胞减少症（3 例[7.5%]）。最常报告的不良事件包括疲劳（18 例[45.0%]）、腹泻（13 例[32.5%]）和高血压（11 例[27.5%]）。
结论和相关性：在这项 2 期非随机临床试验中，帕博利珠单抗联合贝伐珠单抗和口服环磷酰胺的联合治疗耐受性良好，95.0%的患者有临床获益，25.0%的患者有持续超过 12 个月的治疗反应。该联合方案可能成为复发性卵巢癌的未来治疗策略。
试验注册：ClinicalTrials.gov 标识符：NCT02853318。
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