The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up. COSMIC-312 was an open-label, randomised, phase 3 study done across 178 centres in 32 countries. Patients aged 18 years or older with previously untreated advanced hepatocellular carcinoma were eligible. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), and adequate marrow and organ function, including Child–Pugh class A liver function; those with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were ineligible. Patients were randomly assigned (2:1:1) using a web-based interactive response system to a combination of oral cabozantinib 40 mg once daily plus intravenous atezolizumab 1200 mg every 3 weeks, oral sorafenib 400 mg twice daily, or oral single-agent cabozantinib 60 mg once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were for cabozantinib plus atezolizumab versus sorafenib: progression-free survival per RECIST 1.1, as assessed by a blinded independent radiology committee, in the first 372 randomly assigned patients (previously reported) and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib. The secondary endpoint was progression-free survival in all patients randomly assigned to cabozantinib versus sorafenib. Outcomes in all randomly assigned patients, including final overall survival, are presented. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with , . Between Dec 7, 2018, and Aug 27, 2020, 432 patients were randomly assigned to combination treatment, 217 to sorafenib, and 188 to single-agent cabozantinib, and included in all efficacy analyses. 704 (84%) patients were male and 133 (16%) were female. 824 of these patients received at least one dose of study treatment and were included in the safety population. Median follow-up was 22·1 months (IQR 19·3–24·8). Median overall survival was 16·5 months (96% CI 14·5–18·7) for the combination treatment group and 15·5 months (12·2–20·0) for the sorafenib group (hazard ratio [HR] 0·98 [0·78–1·24]; stratified log-rank p=0·87). Median progression-free survival was 6·9 months (99% CI 5·7–8·2) for the combination treatment group, 4·3 months (2·9–6·1) for the sorafenib group, and 5·8 months (99% CI 5·4–8·2) for the single-agent cabozantinib group (HR 0·74 [0·56–0·97] for combination treatment sorafenib; HR 0·78 [99% CI 0·56–1·09], p=0·05, for single-agent cabozantinib sorafenib). Grade 3 or 4 adverse events occurred in 281 (66%) of 429 patients in the combination treatment group, 100 (48%) of 207 patients in the sorafenib group, and 108 (57%) of 188 patients in the single-agent cabozantinib group; the most common were hypertension (37 [9%] 17 [8%] 23 [12%]), palmar-plantar erythrodysaesthesia (36 [8%] 18 [9%] 16 [9%]), aspartate aminotransferase increased (42 [10%] eight [4%] 17 [9%]), and alanine aminotransferase increased (40 [9%] six [3%] 13 [7%]). Serious adverse events occurred in 223 (52%) patients in the combination treatment group, 84 (41%) patients in the sorafenib group, and 87 (46%) patients in the single agent cabozantinib group. Treatment-related deaths 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%) in the sorafenib group (general physical health deterioration), and four (2%) in the single-agent cabozantinib group (asthenia, gastrointestinal haemorrhage, sepsis, and gastric perforation). First-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals. 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)：随机 3 期研究的最终结果

COSMIC-312 试验的目的是评估卡博替尼加阿特珠单抗与索拉非尼治疗既往未经治疗的晚期肝细胞癌患者的疗效。在初步分析中，与索拉非尼相比，卡博替尼加阿特珠单抗显着延长了无进展生存期。在这里，我们报告了预先计划的最终总体生存分析以及长期随访后更新的安全性和有效性结果。COSMIC-312 是一项开放标签、随机、3 期研究，在 32 个国家的 178 个中心进行。年龄 18 岁或以上、患有先前未经治疗的晚期肝细胞癌的患者符合资格。患者必须具有根据实体瘤疗效评估标准 1.1 版 (RECIST 1.1) 可测量的疾病，并且具有足够的骨髓和器官功能，包括 Child-Pugh A 级肝功能；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。使用基于网络的交互式应答系统将患者随机分配（2:1:1），接受口服卡博替尼 40 mg 每日一次加静脉注射阿替利珠单抗 1200 mg 每 3 周、口服索拉非尼 400 mg 每日两次或口服单药的组合卡博替尼 60 mg，每日一次。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。卡博替尼加阿特珠单抗与索拉非尼的双重主要终点为：根据 RECIST 1.1，由盲法独立放射学委员会评估的前 372 名随机分配的患者（之前报告）的无进展生存期，以及随机分配至卡博替尼加阿特珠单抗的所有患者的总生存期阿特珠单抗或索拉非尼。次要终点是随机分配至卡博替尼组与索拉非尼组的所有患者的无进展生存期。列出了所有随机分配的患者的结果，包括最终总生存期。对接受至少一剂研究药物的所有随机分配的患者进行安全性评估。该试验已在 , 注册。2018年12月7日至2020年8月27日期间，432名患者被随机分配接受联合治疗，217名患者接受索拉非尼治疗，188名患者接受单药卡博替尼治疗，并纳入所有疗效分析。704 名患者（84%）为男性，133 名患者（16%）为女性。其中 824 名患者接受了至少一剂研究治疗，并被纳入安全人群。中位随访时间为 22·1 个月（IQR 19·3–24·8）。联合治疗组的中位总生存期为 16·5 个月 (96% CI 14·5–18·7)，索拉非尼组为 15·5 个月 (12·2–20·0)（风险比 [HR] 0） ·98 [0·78–1·24]；分层对数秩 p=0·87)。联合治疗组的中位无进展生存期为 6·9 个月（99% CI 5·7–8·2），索拉非尼组为 4·3 个月（2·9–6·1）。单药卡博替尼组为 5·8 个月 (99% CI 5·4–8·2)（联合治疗索拉非尼的 HR 0·74 [0·56–0·97]；索拉非尼的 HR 0·78 [99%） CI 0·56–1·09]，p=0·05，对于单药卡博替尼索拉非尼）。联合治疗组 429 名患者中有 281 名患者（66%）发生 3 级或 4 级不良事件，索拉非尼组 207 名患者中有 100 名患者（48%）发生 3 级或 4 级不良事件，卡博替尼单药治疗组 188 名患者中有 108 名患者（57%）发生 3 级或 4 级不良事件。团体; 最常见的是高血压 (37 [9%] 17 [8%] 23 [12%])、掌跖红肿感觉障碍 (36 [8%] 18 [9%] 16 [9%])、天冬氨酸转氨酶升高 (42 [10%] 8 [4%] 17 [9%]），丙氨酸转氨酶升高（40 [9%] 6 [3%] 13 [7%]）。联合治疗组有 223 名患者（52%）发生严重不良事件，索拉非尼组有 84 名患者（41%），卡博替尼单药组有 87 名患者（46%）发生严重不良事件。联合治疗组中有 6 名患者 (1%) 发生治疗相关死亡（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），其中 1 名患者 (<1%)索拉非尼组有 4 例（一般身体健康状况恶化），卡博替尼单药组有 4 例（2%）（虚弱、胃肠道出血、败血症和胃穿孔）。与索拉非尼相比，一线卡博替尼加阿特珠单抗并未改善晚期肝细胞癌患者的总生存期。与索拉非尼相比，该组合的无进展生存获益得以维持，且没有新的安全信号。Exelixis 和 Ipsen。与索拉非尼相比，该组合的无进展生存获益得以维持，且没有新的安全信号。Exelixis 和 Ipsen。与索拉非尼相比，该组合的无进展生存获益得以维持，且没有新的安全信号。Exelixis 和 Ipsen。