Yau Thomas, Galle Peter R, Decaens Thomas, Sangro Bruno, Qin Shukui, da Fonseca Leonardo G, Karachiwala Hatim, Blanc Jean-Frederic, Park Joong-Won, Gane Edward, Pinter Matthias, Peña Ana Matilla, Ikeda Masafumi, Tai David, Santoro Armando, Pizarro Gonzalo, Chiu Chang-Fang, Schenker Michael, He Aiwu, Chon Hong Jae, Wojcik-Tomaszewska Joanna, Verset Gontran, Wang Qi Qi, Stromko Caitlyn, Neely Jaclyn, Singh Prianka, Jimenez Exposito Maria Jesus, Kudo Masatoshi
Centre of Cancer Medicine and University Department of Medicine, The University of Hong Kong, Hong Kong.
University Medical Center, I Medical Department, Mainz, Germany.
Lancet. 2025 May 24;405(10492):1851-1864. doi: 10.1016/S0140-6736(25)00403-9. Epub 2025 May 8.
BACKGROUND: Patients with unresectable hepatocellular carcinoma have a poor prognosis, and treatments with long-term benefits are needed. We report results from the preplanned interim analysis of the CheckMate 9DW trial assessing nivolumab plus ipilimumab versus lenvatinib or sorafenib for unresectable hepatocellular carcinoma in the first-line setting. METHODS: This open-label, randomised, phase 3 trial enrolled patients aged 18 years or older with unresectable hepatocellular carcinoma without previous systemic therapy at 163 hospitals and cancer centres across 25 countries in Asia, Australia, Europe, North America, and South America. Patients had at least one measurable untreated lesion per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, a Child-Pugh score of 5 or 6, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) via an interactive response technology system to receive nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) intravenously every 3 weeks for up to four doses, followed by nivolumab 480 mg every 4 weeks or investigator's choice of either oral lenvatinib (8 mg or 12 mg mg daily depending on bodyweight) or oral sorafenib (400 mg twice daily). Randomisation was stratified by aetiology; the presence of macrovascular invasion, extrahepatic spread, or both; and baseline alpha-fetoprotein concentration. The primary endpoint was overall survival, which was assessed in all randomly assigned patients; safety was an exploratory endpoint and was assessed in all randomly assigned patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04039607 (ongoing). FINDINGS: Between Jan 6, 2020, and Nov 8, 2021, 668 patients were randomly assigned to nivolumab plus ipilimumab (n=335) or lenvatinib or sorafenib (n=333). Early crossing of the overall survival Kaplan-Meier curves reflected a higher number of deaths during the first 6 months after randomisation with nivolumab plus ipilimumab (hazard ratio 1·65 [95% CI 1·12-2·43]) but was followed by a sustained separation of the curves thereafter in favour of nivolumab plus ipilimumab (0·61 [0·48-0·77]). After a median follow-up of 35·2 months (IQR 31·1-39·9), overall survival was significantly improved with nivolumab plus ipilimumab versus lenvatinib or sorafenib (median 23·7 months [95% CI 18·8-29·4] vs 20·6 months [17·5-22·5]; hazard ratio 0·79 [0·65-0·96]; two-sided stratified log-rank p=0·018); respective overall survival rates were 49% (95% CI 44-55) versus 39% (34-45) at 24 months and 38% (32-43) versus 24% (19-30) at 36 months. Overall, 137 (41%) of 332 patients receiving nivolumab plus ipilimumab and 138 (42%) of 325 patients receiving lenvatinib or sorafenib had grade 3-4 treatment-related adverse events. 12 deaths were attributed to treatment with nivolumab plus ipilimumab and three were attributed to treatment with lenvatinib or sorafenib. INTERPRETATION: Nivolumab plus ipilimumab showed a significant overall survival benefit versus lenvatinib or sorafenib and manageable safety in patients with previously untreated unresectable hepatocellular carcinoma. These results support nivolumab plus ipilimumab as a first-line treatment in this setting. FUNDING: Bristol Myers Squibb.
背景：不可切除肝细胞癌患者预后较差，需要有长期获益的治疗方法。我们报告了CheckMate 9DW试验预先计划的中期分析结果，该试验评估了一线治疗中纳武利尤单抗联合伊匹木单抗与乐伐替尼或索拉非尼用于不可切除肝细胞癌的疗效。 方法：这项开放标签、随机、3期试验在亚洲、澳大利亚、欧洲、北美和南美洲25个国家的163家医院和癌症中心招募了18岁及以上、未曾接受过全身治疗的不可切除肝细胞癌患者。患者根据实体瘤疗效评价标准（RECIST）1.1版至少有一个可测量的未经治疗的病灶，Child-Pugh评分为5或6，东部肿瘤协作组体能状态为0或1。患者通过交互式应答技术系统随机分配（1:1），接受纳武利尤单抗（1 mg/kg）联合伊匹木单抗（3 mg/kg）静脉注射，每3周一次，最多4剂，随后每4周接受480 mg纳武利尤单抗，或研究者选择口服乐伐替尼（根据体重每日8 mg或12 mg）或口服索拉非尼（每日400 mg，分两次服用）。随机分组按病因、是否存在大血管侵犯、肝外转移或两者皆有以及基线甲胎蛋白浓度进行分层。主要终点为总生存期，在所有随机分配的患者中进行评估；安全性为探索性终点，在所有接受至少一剂研究药物的随机分配患者中进行评估。本试验已在ClinicalTrials.gov注册，编号为NCT04039607（正在进行）。 结果：在2020年1月6日至2021年11月8日期间，668例患者被随机分配至纳武利尤单抗联合伊匹木单抗组（n = 335）或乐伐替尼或索拉非尼组（n = 333）。总生存期的Kaplan-Meier曲线早期交叉反映出随机分组后前6个月内纳武利尤单抗联合伊匹木单抗组死亡人数较多（风险比1.65 [95%CI 1.12 - 2.43]），但此后曲线持续分离，有利于纳武利尤单抗联合伊匹木单抗组（0.61 [0.48 - 0.77]）。经过35.2个月（IQR 31.1 - 39.9）的中位随访，与乐伐替尼或索拉非尼相比，纳武利尤单抗联合伊匹木单抗显著改善了总生存期（中位生存期23.7个月 [95%CI 18.8 - 29.4] 对比20.6个月 [17.5 - 22.5]；风险比0.79 [0.65 - 0.96]；双侧分层对数秩检验p = 0.018）；24个月时的总生存率分别为49%（95%CI 44 - 55）和39%（34 - 45），36个月时分别为38%（32 - 43）和24%（19 - 30）。总体而言，332例接受纳武利尤单抗联合伊匹木单抗治疗的患者中有137例（41%）发生3 - 4级治疗相关不良事件，325例接受乐伐替尼或索拉非尼治疗的患者中有138例（42%）发生。12例死亡归因于纳武利尤单抗联合伊匹木单抗治疗，3例死亡归因于乐伐替尼或索拉非尼治疗。 解读：对于既往未经治疗的不可切除肝细胞癌患者，纳武利尤单抗联合伊匹木单抗显示出显著的总生存获益且安全性可控。这些结果支持纳武利尤单抗联合伊匹木单抗作为这一情况下的一线治疗方案。 资助：百时美施贵宝公司。
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