Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer A Phase 2 Nonrandomized Clinical Trial
Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer A Phase 2 Nonrandomized Clinical Trial
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DOI：
10.1001/jamaoncol.2020.5945
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发表时间：
2020-11-19
期刊：
影响因子：
28.4
通讯作者：
Odunsi, Kunle
中科院分区：
文献类型：
--
作者：
Zsiros, Emese;Lynam, Sarah;Odunsi, Kunle
重要性复发性卵巢癌的治疗选择是有限的临床效益和不利影响患者的生活质量，代表了一个未满足的需要，可耐受的有效therapy.Objective. Objective. Objective. Objective. Objective. Objective. Objective. Objective. Objective. Objective. Objective. Objective. Objective. Objective. Objective. Objective. Objective. Pembrolizumab与贝伐单抗和口服节拍环磷酰胺的组合在复发性铂敏感，铂耐药，或难治性上皮性卵巢，输卵管，设计、设置和参与者这项开放标签、单臂2期队列研究从2016年9月6日至2018年6月27日在美国的一家机构招募患者。符合条件的患者患有复发性卵巢癌，根据实体瘤免疫相关缓解评价标准（irRECIST）可测量的疾病，东部肿瘤协作组体能状态为0至1。数据分析时间为2016年9月6日至2020年2月20日。干预患者在治疗周期内接受静脉注射派姆单抗200 mg和贝伐单抗15 mg/kg，每3周一次，口服环磷酰胺50 mg，每日一次，直至疾病进展，出现不可接受的毒性反应，主要结果和测量主要结果是客观反应率（ORR）和无进展生存期（PFS）。30例（75.0%）铂类耐药，10例（25.0%）铂类敏感性卵巢癌，平均（SD）年龄为62.2（9.4）岁。根据irRECIST标准，3名女性（7.5%）完全缓解，16名（40.0%）部分缓解，19名（47.5%）疾病稳定，ORR为47.5%，38名（95.0%）临床获益，10名（25.0%）持久缓解。中位PFS为10.0（90% CI，6.5-17.4）个月。最常见的3 - 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 [45.0%]），腹泻（13 [32.5%]）和高血压（11 [27.5%]）.结论和相关性在这项2期非随机临床试验中，帕博利珠单抗与贝伐单抗和口服环磷酰胺的组合耐受性良好，并在95.0%和持久的治疗反应中证明了临床获益25.0%的复发性卵巢癌患者术后生存时间>12个月。这种组合可能代表复发性卵巢癌的未来治疗策略。
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.