目的：阿帕替尼是血管内皮生长因子受体-2 (VEGFR2)的选择性抑制剂。本研究的目的是评估阿帕替尼联合卡瑞利珠单抗（完全人源化的抗PD-1单克隆抗体）在晚期宫颈癌患者中的疗效和安全性。
Method: In this open-label, single-arm, phase 2 study done at 4 centers in China, eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, progressed after at least 1 line of systemic chemotherapy for metastatic, recurrent, or persistent cervical cancer, and had measurable disease. Patients received oral apatinib 250 mg once daily and intravenous camrelizumab 200 mg every 2 weeks. Treatment continued until disease progression, unacceptable toxicity, and withdrawal of consent. The primary endpoint was the objective response rate (ORR) assessed by the Response Evaluation Criteria in Solid Tumor (RECIST, version 1.1). An optimal Simon 2-stage design was employed to test the null hypothesis of a 17% ORR versus 35% alternative (1-sided alpha 0.10, 80% power), if more than 3 responses out of the first 16 patients were observed, then the study will continue to enroll a total of 44 patients.
方法：在这项开标签、单臂, 4个中国中心的II期临床研究中，入组标准为：患者年龄在18岁以上，ECOG评分0或1，至少接受1线系统化疗后转移性、复发性或持续性宫颈癌，并需具有可衡量癌灶。患者每日1次口服阿帕替尼250mg，联合每2周1次静脉注射卡瑞利珠单抗200mg。治疗一直持续到疾病进展，不可接受的毒性反应或患者不同意继续参加研究。主要研究终点为RECIST1.1评估的客观反应率(ORR)。采用最优的Simon 2阶段设计来检验原假设17%的反应率VS替代方案35%的反应率(单侧α0.10, 80%效力)。如果观察到首批16例患者中有3例以上的缓解，本研究将继续纳入病例至总数44例。
Results: Between January 21, , and August 1, , 45 patients were enrolled and received at least 1 dose of camrelizumab (safety population). The median age was 51 years (range 33–67 years). Median previous treatment lines was 2 (range 1–4). In the first stage, 8 responses were noted among 16 patients, which met the first-stage criteria; then the study continued to stage 2. As of October 25, , the median follow-up was 6.7 months (range 1.7–9.23). Twenty-five (57.1%) of 42 patients who had at least 1 post-baseline tumor assessment (efficacy evaluable set) achieved an objective response, including 1 (2.2%) complete response and 24 (53.3%) partial response. The disease control rate was 88.1% (37/42). The median duration of response has not yet been reached. Thirty-one (68.9%) patients had grade ≥3 treatment-related adverse events (TRAEs). Grade ≥3 TRAEs occurring in ≥5% of patients were hypertension (22.2%), fatigue (15.6%), anemia (13.3%), and thrombocytopenia (6.7%). See Figure 1.
结果：1月21日至8月1日期间，共45名患者被纳入研究，并接受了至少1次卡瑞利珠单抗治疗(安全人群)。患者年龄中位数为51岁(范围33-67岁)。中位既往治疗线数为2(范围1-4)。在第一阶段，16例患者中有8例得到缓解，符合第一阶段的标准;此后研究第二阶段继续开展。截至10月25日，中位随访时间为6.7个月(范围1.7-9.23)。42例患者中有25例(57.1%)患者在基线后进行了至少一次肿瘤评估(疗效评估集)，评估了客观缓解。1例达到(2.2%)完全缓解，24例(53.3%)为部分缓解。疾病控制率为88.1%(37/42)。持续缓解时间的中位数尚未达到。31例(68.9%)患者出现≥3级治疗相关不良事件(TRAEs)。至少5%的患者出现≥3级改变为高血压(22.2%)、疲劳(15.6%)、贫血(13.3%)、血小板减少(6.7%)。如图1。
Conclusion: Apatinib plus camrelizumab showed promising antitumor activity and tolerable toxicities in patients with advanced cervical cancer.
结论:阿帕替尼联合卡瑞利珠单抗在晚期宫颈癌患者中具有良好的抗肿瘤活性和可耐受的毒副反应。
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