Department of Medicine (Hematology/Oncology), UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
Lancet Oncol. 2022 Aug;23(8):995-1008. doi: 10.1016/S1470-2045(22)00326-6. Epub 2022 Jul 4.
Cabozantinib has shown clinical activity in combination with checkpoint inhibitors in solid tumours. The COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma.
COSMIC-312 is an open-label, randomised, phase 3 trial that enrolled patients aged 18 years or older with advanced hepatocellular carcinoma not amenable to curative or locoregional therapy and previously untreated with systemic anticancer therapy at 178 centres in 32 countries. Patients with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were not eligible. Tumours involving major blood vessels, including the main portal vein, were permitted. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), Barcelona Clinic Liver Cancer stage B or C disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A. Previous resection, tumour ablation, radiotherapy, or arterial chemotherapy was allowed if more than 28 days before randomisation. Patients were randomly assigned (2:1:1) via a web-based interactive response system to cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks, sorafenib 400 mg orally twice daily, or single-agent cabozantinib 60 mg orally once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were progression-free survival per RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population), and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib (ITT population). Final progression-free survival and concurrent interim overall survival analyses are presented. This trial is registered with ClinicalTrials.gov, NCT03755791.
Analyses at data cut-off (March 8, 2021) included the first 837 patients randomly assigned between Dec 7, 2018, and Aug 27, 2020, to combination treatment of cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188). Median follow-up was 15·8 months (IQR 14·5-17·2) in the progression-free survival ITT population and 13·3 months (10·5-16·0) in the ITT population. Median progression-free survival was 6·8 months (99% CI 5·6-8·3) in the combination treatment group versus 4·2 months (2·8-7·0) in the sorafenib group (hazard ratio [HR] 0·63, 99% CI 0·44-0·91, p=0·0012). Median overall survival (interim analysis) was 15·4 months (96% CI 13·7-17·7) in the combination treatment group versus 15·5 months (12·1-not estimable) in the sorafenib group (HR 0·90, 96% CI 0·69-1·18; p=0·44). The most common grade 3 or 4 adverse events were alanine aminotransferase increase (38 [9%] of 429 patients in the combination treatment group vs six [3%] of 207 in the sorafenib group vs 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), aspartate aminotransferase increase (37 [9%] vs eight [4%] vs 18 [10%]), and palmar-plantar erythrodysaesthesia (35 [8%] vs 17 [8%] vs 16 [9%]); serious treatment-related adverse events occurred in 78 (18%) patients in the combination treatment group, 16 (8%) patients in the sorafenib group, and 24 (13%) in the single-agent cabozantinib group. Treatment-related grade 5 events occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) patient in the sorafenib group (general physical health deterioration), and one (<1%) patient in the single-agent cabozantinib group (gastrointestinal haemorrhage).
Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed.
Exelixis and Ipsen.
卡博替尼联合检查点抑制剂在实体瘤中显示出临床活性。COSMIC-312 试验评估了卡博替尼联合阿替利珠单抗与索拉非尼作为晚期肝细胞癌的一线系统治疗。
COSMIC-312 是一项开放标签、随机、III 期试验，在 32 个国家的 178 个中心招募了年龄在 18 岁或以上的晚期肝细胞癌患者，这些患者不适宜进行根治性或局部区域治疗，且在之前没有接受过系统抗癌治疗。纤维板层癌、肉瘤样肝癌或肝细胞癌合并胆管癌患者不符合条件。允许涉及主要血管的肿瘤，包括主门静脉。要求患者符合实体瘤反应评估标准 1.1（RECIST 1.1）可测量的疾病、巴塞罗那临床肝癌分期 B 或 C 期、东部肿瘤协作组表现状态 0 或 1、足够的器官和骨髓功能以及 Child-Pugh 分级 A。如果随机分组前超过 28 天，则允许进行先前的切除术、肿瘤消融术、放疗或动脉化疗。患者通过基于网络的交互式反应系统以 2:1:1 的比例随机分配至卡博替尼 40 mg 口服每日一次联合阿替利珠单抗 1200 mg 静脉注射每 3 周一次、索拉非尼 400 mg 口服每日两次或单药卡博替尼 60 mg 口服每日一次。随机分组按病因、地理区域以及是否存在肝外疾病或大血管侵犯分层。双重主要终点是盲法独立放射学委员会评估的首次随机分配至卡博替尼联合阿替利珠单抗或索拉非尼治疗组的 372 例患者的无进展生存期（无进展生存期意向治疗[ITT]人群）和所有随机分配至卡博替尼联合阿替利珠单抗或索拉非尼治疗的患者的总生存期（ITT 人群）。目前报告了最终的无进展生存期和同时进行的总生存期中期分析。本试验在 ClinicalTrials.gov 注册，NCT03755791。
数据截止（2021 年 3 月 8 日）时，分析了 2018 年 12 月 7 日至 2020 年 8 月 27 日之间随机分配至卡博替尼联合阿替利珠单抗（n=432）、索拉非尼（n=217）或单药卡博替尼（n=188）治疗组的前 837 例患者。无进展生存期 ITT 人群的中位随访时间为 15.8 个月（IQR 14.5-17.2），ITT 人群的中位随访时间为 13.3 个月（10.5-16.0）。无进展生存期的中位时间为联合治疗组 6.8 个月（99%CI 5.6-8.3），索拉非尼组 4.2 个月（2.8-7.0）（风险比[HR]0.63，99%CI 0.44-0.91，p=0.0012）。联合治疗组的中位总生存期（中期分析）为 15.4 个月（96%CI 13.7-17.7），索拉非尼组为 15.5 个月（12.1-无法估计）（HR 0.90，96%CI 0.69-1.18；p=0.44）。最常见的 3 级或 4 级不良事件为丙氨酸氨基转移酶升高（联合治疗组 429 例患者中有 38 例[9%]，索拉非尼组 207 例中有 6 例[3%]，单药卡博替尼组 188 例中有 12 例[6%]）、高血压（联合治疗组 37 例[9%]、索拉非尼组 17 例[8%]、单药卡博替尼组 23 例[12%]）、天门冬氨酸氨基转移酶升高（联合治疗组 37 例[9%]、索拉非尼组 8 例[4%]、单药卡博替尼组 18 例[10%]）和手掌-足底红斑感觉异常（联合治疗组 35 例[8%]、索拉非尼组 17 例[8%]、单药卡博替尼组 16 例[9%]）；联合治疗组有 78 例（18%）患者发生严重治疗相关不良事件，索拉非尼组有 16 例（8%）患者，单药卡博替尼组有 24 例（13%）患者。联合治疗组有 6 例（1%）患者发生治疗相关 5 级事件（脑病、肝衰竭、药物性肝损伤、食管静脉曲张出血、多器官功能障碍综合征和肿瘤溶解综合征）、索拉非尼组有 1 例（<1%）患者发生一般健康恶化、单药卡博替尼组有 1 例（<1%）患者发生胃肠道出血。
卡博替尼联合阿替利珠单抗可能是晚期肝细胞癌的一种治疗选择，但需要进一步研究。
Exelixis 和 Ipsen。
