Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312) : a multicentre, open-label, randomised, phase 3 trial
Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312) : a multicentre, open-label, randomised, phase 3 trial
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DOI：
10.1016/s1470-2045(22)00326-6
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发表时间：
2022-07-25
期刊：
影响因子：
51.1
通讯作者：
Yau, Thomas
中科院分区：
文献类型：
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作者：
Kelley, Robin Kate;Rimassa, Lorenza;Yau, Thomas
背景：卡波赞替尼与检查点抑制剂联合治疗实体肿瘤显示出临床活性。COSMIC-312试验评估了Cabozantinib加atezolizumab与索拉非尼作为治疗晚期肝癌的一线系统疗法。方法COSMIC-312是一项开放的、随机的3期试验，纳入了年龄在18岁或以上的晚期肝癌患者，这些患者无法治愈或局部治疗，以前在32个国家和地区的178个中心没有接受过系统抗癌治疗。纤维板层癌、肉瘤样肝细胞癌或合并肝细胞胆管细胞癌的患者不符合条件。肿瘤涉及主要血管，包括主要的门静脉，是被允许的。患者被要求具有实体肿瘤1.1版(RECIST 1.1)的可测量疾病反应评估标准，巴塞罗那临床肝癌B期或C期疾病，东方合作肿瘤学小组的表现状态为0或1，足够的器官和骨髓功能，以及Child-Pugh A级，如果随机选择前28天以上，可以接受切除、肿瘤消融术、放射治疗或动脉化疗。患者通过基于网络的交互响应系统被随机分配到卡波赞替尼40毫克，每日1次，加阿替唑单抗1200毫克，每3周静脉注射，索拉非尼400毫克，每天2次，或单药卡波赞替尼60 mg，每天1次。根据疾病病因学、地理区域和肝外疾病或大血管侵犯的存在情况进行随机分组。双主要终点是根据RECIST 1.1标准，由一个盲目的独立放射委员会对前372名患者进行的无进展生存期评估，这些患者被随机分配到库赞替尼加阿达唑单抗或索拉非尼(无进展生存意向治疗[ITT]人群)的联合治疗中，以及随机分配到库赞替尼加阿达唑单抗或索拉非尼(ITT人群)的所有患者中的总存活率。给出了最终无进展生存和并发的中期总体生存分析。这项试验在ClinicalTrials.gov，NCT03755791注册。数据截止处(2021年3月8日)的结果分析包括在2018年12月7日至2020年8月27日期间随机分配的前837名患者，分别接受Cabozantinib+atezolizumab(n=432)、索拉非尼(n=217)或单药Cabozantinib(n=188)的联合治疗。无进展生存期ITT组和ITT组的中位随访期分别为15个月和13个月(IQR14个中间点5-17个中间点2)和13个月(10个中间点5-16个中间点0)。中位无进展生存期联合治疗组6个月中期8个月(99%CI 5中期6~8个月3个月)，索拉非尼组4个中期2个月(2个中期8~7个月0个月)(风险比[HR]0中期63，99%CI 0中期44~0中期91，p=0中期0012)。中位总生存期(中期分析)联合治疗组15个月中期4个月(96%CI 13中期7-17个月)，索拉非尼组15个月中期5个月(12个中期1-不可估量)(HR 0中期90，96%CI 0中期69-1中期18；最常见的3级或4级不良事件是丙氨酸氨基转移酶升高(联合治疗组429例患者中38例[9%]比索拉非尼组207例中6例[3%]比单药卡波扎替尼组188例中12[6%])，高血压(37[9%]比17[8%]比23[12%])，天冬氨酸转氨酶升高(37[9%]比8[4%]比18[10%])，掌底红肿感觉(35[8%]比17[8%]比16[9%])；联合治疗组78名患者(18%)、索拉非尼组16名患者(8%)和单药卡波赞替尼组24名患者(13%)发生了严重的治疗相关不良事件。联合治疗组有6例(1%)患者发生与治疗相关的5级事件(脑病、肝功能衰竭、药物性肝损伤、食道静脉曲张出血、多器官功能障碍综合征和肿瘤溶解综合征)、1例(
Background 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.Methods 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.Findings 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 15middot8 months (IQR 14middot5-17middot2) in the progression-free survival ITT population and 13middot3 months (10middot5-16middot0) in the ITT population. Median progression -free survival was 6middot8 months (99% CI 5middot6-8middot3) in the combination treatment group versus 4middot2 months (2middot8-7middot0) in the sorafenib group (hazard ratio [HR] 0middot63, 99% CI 0middot44-0middot91, p=0middot0012). Median overall survival (interim analysis) was 15middot4 months (96% CI 13middot7-17middot7) in the combination treatment group versus 15middot5 months (12middot1-not estimable) in the sorafenib group (HR 0middot90, 96% CI 0middot69-1middot18; p=0middot44).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 (