肝细胞癌 (HCC) 是癌症相关死亡的主要原因，需要额外的一线治疗。程序性细胞死亡蛋白 1 抑制剂 tislelizumab 作为二线 HCC 治疗显示出疗效和可耐受的安全性。旨在研究 tislelizumab 与甲苯磺酸索拉非尼一线治疗不可切除 HCC 的疗效和安全性。开放标签、全球、多区域阶段3 RATIONALE-301 随机临床试验纳入了未经全身治疗的成人，患有组织学确诊的 HCC，巴塞罗那临床肝癌 B 期或 C 期疾病，局部治疗后疾病进展（或患者不适合），东部肿瘤合作组表现状态为 1 2017年12月27日至2019年10月2日之间的Child-Pugh A级或以下。数据截止日期为2022年7月11日。患者以1:1的比例随机接受替雷利珠单抗，每3周静脉注射200毫克，或甲苯磺酸索拉非尼，400 mg，口服，每日两次。主要终点是总生存期 (OS)；次要终点包括客观缓解率、无进展生存期、缓解持续时间和安全性。分析中总共纳入了 674 名患者（570 名男性 [84.6%]；中位年龄 61 岁[范围 23-86 岁] ]）。截至 2022 年 7 月 11 日，最短研究随访时间为 33 个月。在意向治疗人群中达到了替雷利珠单抗与索拉非尼的 OS 非劣效性主要终点 (n = 674)；中位总生存期分别为 15.9 (95% CI, 13.2-19.7) 个月 vs 14.1 (95% CI, 12.6-17.4) 个月（风险比 [HR], 0.85 [95.003% CI, 0.71-1.02]），并具有优越性未满足替雷利珠单抗与索拉非尼的比较。替雷利珠单抗的客观缓解率为 14.3% (n = 49)，索拉非尼为 5.4% (n = 18)，中位缓解持续时间为 36.1（95% CI，16.8 至不可评估）个月 vs 11.0（95% CI，分别为 6.2-14.7) 个月。替雷利珠单抗与索拉非尼的中位无进展生存期分别为 2.1 (95% CI, 2.1-3.5) 个月和 3.4 (95% CI, 2.2-4.1) 个月 (HR, 1.11 [95% CI, 0.92-1.33])。替雷利珠单抗治疗中出现的不良事件 (AE) 发生率为 96.2%（338 名患者中的 325 名），索拉非尼为 100%（n = 324）。接受替雷利珠单抗治疗的 75 名患者（22.2%）和接受索拉非尼治疗的 173 名患者（53.4%）报告了 3 级或以上治疗相关 AE。与索拉非尼相比，替雷利珠单抗导致药物停药的治疗相关 AE 发生率较低（21 例 [6.2%] 对比 33 例 [10.2%]）和药物修改（68 例 [20.1%] 对比 187 例 [57.7%]）。 -301，替雷利珠单抗证明 OS 益处不劣于索拉非尼，具有更高的客观缓解率和更持久的缓解，而索拉非尼的中位无进展生存期更长。与索拉非尼相比，替雷利珠单抗具有良好的安全性。ClinicalTrials.gov 标识符：NCT03412773。

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment.To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC.The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy-naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022.Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily.The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety.A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib.In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib.ClinicalTrials.gov Identifier: NCT03412773.