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 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).

Interpretation

Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed.

Funding

Exelixis and Ipsen.

中文翻译：

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卡博替尼加阿特珠单抗与索拉非尼治疗晚期肝细胞癌 (COSMIC-312)：一项多中心、开放标签、随机、3 期试验

 背景

卡博替尼与检查点抑制剂联合治疗实体瘤已显示出临床活性。 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一线全身治疗的效果。

 方法

COSMIC-312 是一项开放标签、随机、3 期试验，在 32 个国家的 178 个中心入组年龄为 18 岁或以上、无法接受治愈性或局部治疗且之前未接受过全身抗癌治疗的晚期肝细胞癌患者。患有纤维板层癌、肉瘤样肝细胞癌或合并肝细胞胆管癌的患者不符合资格。允许肿瘤累及主要血管，包括主门静脉。患者需要符合实体瘤反应评估标准 1.1 版 (RECIST 1.1) 的可测量疾病、巴塞罗那临床肝癌 B 期或 C 期疾病、东部肿瘤合作组表现状态为 0 或 1、足够的器官和骨髓功能，以及Child-Pugh A 级。如果在随机分组前超过 28 天，则允许进行既往切除、肿瘤消融、放疗或动脉化疗。通过基于网络的交互式应答系统，患者被随机分配（2:1:1）：卡博替尼 40 mg 口服，每日一次加阿特珠单抗 1200 mg，每 3 周静脉注射，索拉非尼 400 mg 口服，每日两次，或单药卡博替尼 60 mg 口服每天一次。随机分组根据疾病病因、地理区域以及肝外疾病或大血管侵犯的存在进行分层。双重主要终点是根据 RECIST 1.1 的无进展生存期，由盲法独立放射学委员会对随机分配至卡博替尼加阿特珠单抗或索拉非尼联合治疗的前 372 名患者进行评估（无进展生存期意向治疗 [ITT] 人群） ），以及随机分配至卡博替尼加阿特珠单抗或索拉非尼（ITT 群体）的所有患者的总生存期。 提出了最终的无进展生存期和同时的中期总生存期分析。该试验已在 ClinicalTrials.gov 注册，NCT03755791。

 发现

数据截止日期（2021 年 3 月 8 日）的分析包括 2018 年 12 月 7 日至 2020 年 8 月 27 日期间随机分配的首批 837 名患者，接受卡博替尼加阿特珠单抗 (n=432)、索拉非尼 (n=217) 联合治疗，或单药卡博替尼 (n=188)。无进展生存 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）。联合治疗组的中位无进展生存期为 6·8 个月（99% CI 5·6–8·3），而索拉非尼组为 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），而索拉非尼组为 15·5 个月（12·1 - 不可估计）（HR 0· 90，96% CI 0·69–1·18；p=0·44）。最常见的 3 级或 4 级不良事件是丙氨酸转氨酶升高（联合治疗组 429 名患者中有 38 名患者 [9%]，索拉非尼组 207 名患者中有6 名患者 [3%]，单药治疗组 188 名患者中有12 名患者 [6%]。 -卡博替尼组）、高血压（37 [9%] vs 17 [8%] vs 23 [12%]）、天冬氨酸转氨酶升高（37 [9%] vs 8 [4%] vs 18 [10%]），和掌跖红肿感觉障碍（35 例 [8%] vs 17 例 [8%] vs 16 例 [9%]）；联合治疗组有 78 名患者（18%）发生了严重的治疗相关不良事件，索拉非尼组有 16 名患者（8%），卡博替尼单药组有 24 名患者（13%）。 联合治疗组中有 6 名 (1%) 患者发生与治疗相关的 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），1 例 (<1 %）索拉非尼组患者（一般身体健康状况恶化），单药卡博替尼组 1 例（<1%）患者（胃肠道出血）。

 解释

卡博替尼联合阿替利珠单抗可能是某些晚期肝细胞癌患者的治疗选择，但还需要进一步的研究。

 资金

 Exelixis 和 Ipsen。