Nanjing Tianyinshang Hospital of China Pharmaceutical University, Nanjing, China.
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
JAMA Oncol. 2023 Dec 1;9(12):1651-1659. doi: 10.1001/jamaoncol.2023.4003.
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.
DESIGN, SETTING, AND PARTICIPANTS: 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.
肝细胞癌 (HCC) 是导致癌症相关死亡的主要原因，需要额外的一线治疗方法。程序性细胞死亡蛋白 1 抑制剂替雷利珠单抗作为二线 HCC 治疗方法，已显示出疗效和可耐受的安全性。
研究替雷利珠单抗与索拉非尼甲苯磺酸盐在不可切除 HCC 的一线治疗中的疗效和安全性。
设计、地点和参与者：这项开放标签、全球性、多区域的 3 期 RATIONALE-301 随机临床试验纳入了 674 例未经系统治疗的组织学证实的 HCC 、巴塞罗那临床肝癌分期 B 或 C 期、局部区域治疗后疾病进展（或患者不适合）、东部合作肿瘤学组体能状态为 1 或更低、Child-Pugh 分级为 A 的成年患者，于 2017 年 12 月 27 日至 2019 年 10 月 2 日入组，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，200 mg 静脉注射，每 3 周一次，或索拉非尼甲苯磺酸盐，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。
674 例患者纳入分析（570 例男性[84.6%]；中位年龄为 61 岁[范围：23-86 岁]）。截至 2022 年 7 月 11 日，最小随访时间为 33 个月。在意图治疗人群（n=674）中，替雷利珠单抗与索拉非尼的 OS 非劣效性主要终点得到满足；中位总生存期分别为 15.9（95%CI，13.2-19.7）个月和 14.1（95%CI，12.6-17.4）个月（风险比[HR]，0.85 [95.003%CI，0.71-1.02]），且替雷利珠单抗优于索拉非尼的假设不成立。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），中位缓解持续时间分别为 36.1（95%CI，16.8-不可评估）个月和 11.0（95%CI，6.2-14.7）个月，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（替雷利珠单抗 vs 索拉非尼 HR，1.11 [95%CI，0.92-1.33]）。替雷利珠单抗和索拉非尼治疗相关不良事件（AE）的发生率分别为 96.2%（338 例中的 325 例）和 100%（324 例）。接受替雷利珠单抗治疗的 75 例患者（22.2%）和接受索拉非尼治疗的 173 例患者（53.4%）发生了 3 级或更高级别的治疗相关 AE。替雷利珠单抗治疗相关 AE 导致停药（6.2%[21 例]）和药物调整（20.1%[68 例]）的发生率低于索拉非尼（10.2%[33 例]和 57.7%[187 例]）。
在 RATIONALE-301 中，替雷利珠单抗的 OS 获益不劣于索拉非尼，客观缓解率更高，缓解持续时间更长，而索拉非尼的无进展生存期更长。替雷利珠单抗的安全性优于索拉非尼。
ClinicalTrials.gov 标识符：NCT03412773。
