卡博替尼联合阿替利珠单抗治疗转移性去势抵抗性前列腺癌患者：多中心、开放标签、Ib 期试验（COSMIC-021）扩展队列的结果。
Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021).
机构信息
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
出版信息
Lancet Oncol. 2022 Jul;23(7):899-909. doi: 10.1016/S1470-2045(22)00278-9. Epub 2022 Jun 9.
BACKGROUND
Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer.
METHODS
COSMIC-021 is an ongoing, multicentre, open-label, phase 1b study with a dose-escalation stage followed by tumour-specific expansion stages. Expansion cohort 6 in metastatic castration-resistant prostate cancer was enrolled at 42 cancer research centres in France, Italy, the Netherlands, Spain, and the USA. Eligible patients were aged 18 years or older and had metastatic castration-resistant prostate cancer with radiographic soft tissue progression following treatment with either enzalutamide or abiraterone, or both; measurable soft tissue disease per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received oral cabozantinib 40 mg per day and intravenous atezolizumab 1200 mg once every 3 weeks. Study treatment continued until progressive disease or unacceptable toxicity. All enrolled patients were assessed for efficacy and safety. The primary endpoint was objective response rate per RECIST version 1.1 as assessed by the investigator. This study is registered with ClinicalTrials.gov, NCT03170960.
FINDINGS
Between April 24, 2018, and Aug 31, 2020, 132 patients were enrolled and received at least one dose of study treatment. At data cutoff (Feb 19, 2021), median duration of follow-up was 15·2 months (IQR 9·6-21·7). Objective response rate was 23% (95% CI 17-32; 31 of 132 patients), with three (2%) confirmed complete responses and 28 (21%) confirmed partial responses. 72 (55%) of 132 patients had grade 3-4 treatment-related adverse events, with the most common being pulmonary embolism (11 [8%] patients), diarrhoea (nine [7%]), fatigue (nine [7%]), and hypertension (nine [7%]). There was one grade 5 treatment-related adverse event (dehydration). 74 (56%) of 132 patients had serious adverse events of any causality. 28 (21%) of 132 patients had treatment-related adverse events leading to discontinuation of either study drug.
INTERPRETATION
Cabozantinib plus atezolizumab showed promising antitumour activity in patients with metastatic castration-resistant prostate cancer after novel hormonal therapy with an acceptable safety profile, supporting further evaluation of this combination.
FUNDING
Exelixis.
背景
接受新型激素治疗（如阿比特龙或恩扎鲁胺）后，转移性去势抵抗性前列腺癌患者的治疗选择有限。我们旨在评估卡博替尼（一种具有免疫调节特性的酪氨酸激酶抑制剂）联合 PD-L1 抑制剂阿替利珠单抗在转移性去势抵抗性前列腺癌中的疗效。
方法
COSMIC-021 是一项正在进行的、多中心、开放标签、1b 期研究，包括剂量递增阶段和肿瘤特异性扩展阶段。转移性去势抵抗性前列腺癌扩展队列 6 在法国、意大利、荷兰、西班牙和美国的 42 个癌症研究中心入组。符合条件的患者年龄在 18 岁及以上，且在接受恩扎鲁胺或阿比特龙或两者治疗后出现放射性软组织进展的转移性去势抵抗性前列腺癌；根据实体瘤反应评估标准（RECIST）版本 1.1 可测量软组织疾病；东部合作肿瘤学组（ECOG）体能状态为 0 或 1。患者每天口服卡博替尼 40mg，每 3 周静脉注射阿替利珠单抗 1200mg。研究治疗持续到疾病进展或不可接受的毒性。所有入组患者均进行疗效和安全性评估。主要终点为研究者评估的 RECIST 版本 1.1 客观缓解率。本研究在 ClinicalTrials.gov 注册，编号为 NCT03170960。
结果
2018 年 4 月 24 日至 2020 年 8 月 31 日，共有 132 例患者入组并接受了至少一剂研究药物治疗。数据截止日期（2021 年 2 月 19 日）时，中位随访时间为 15.2 个月（9.6-21.7）。客观缓解率为 23%（95%CI，17-32；132 例患者中有 31 例），3 例（2%）确认完全缓解，28 例（21%）确认部分缓解。132 例患者中有 72 例（55%）发生 3-4 级治疗相关不良事件，最常见的是肺栓塞（11 例[8%]）、腹泻（9 例[7%]）、疲劳（9 例[7%]）和高血压（9 例[7%]）。有 1 例（1%）5 级治疗相关不良事件（脱水）。132 例患者中有 74 例（56%）发生任何病因的严重不良事件。28 例（21%）患者因治疗相关不良事件而停止研究药物治疗。
结论
卡博替尼联合阿替利珠单抗在接受新型激素治疗后表现出有希望的抗肿瘤活性，安全性可接受，支持进一步评估该联合用药。
资金来源
Exelixis。
Zotero 插件