Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; August Pi i Sunyer Biomedical Research Institute, University of Barcelona Hospital Clinic Barcelona, Barcelona, Spain.
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
Lancet Oncol. 2023 Dec;24(12):1399-1410. doi: 10.1016/S1470-2045(23)00469-2.
BACKGROUND: Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. METHODS: In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. FINDINGS: Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0-72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4-35·3). Median overall survival was 21·2 months (95% CI 19·0-23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2-21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71-1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4-8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3-8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73-1·02; stratified log-rank p=0·047). The most common treatment-related grade 3-4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). INTERPRETATION: In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. FUNDING: Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck.
背景：系统疗法已经改善了肝细胞癌的治疗，但仍需要进一步提高一线晚期患者的总生存率。本研究旨在评估在不可切除的肝细胞癌一线治疗中，与仑伐替尼加安慰剂相比，仑伐替尼联合帕博利珠单抗的疗效。
方法：在这项全球性、随机、双盲、III 期研究（LEAP-002）中，年龄在 18 岁及以上、不可切除的肝细胞癌、Child-Pugh 肝功能 A 级、东部肿瘤协作组体能状态 0 或 1 级且无先前系统治疗的患者在 172 个全球地点入组。患者按 1:1 比例随机分配（采用中央交互式语音应答系统，分组大小为 4），接受仑伐替尼（体重<60kg，8mg/天；体重≥60kg，12mg/天）加帕博利珠单抗（每 3 周 200mg）或仑伐替尼加安慰剂治疗。随机分组按地理区域、大血管门静脉侵犯或肝外扩散或两者兼有、α-胎蛋白浓度和东部肿瘤协作组体能状态分层。主要终点是总生存期（最终总生存期分析的优越性阈值，单侧 p=0.019；在 532 例事件后进行最终分析）和无进展生存期（优越性阈值单侧 p=0.002；在 571 例事件后进行最终分析），均在意向治疗人群中进行。报告了最终分析的结果。该研究在 ClinicalTrials.gov 上注册，编号为 NCT03713593，目前处于活跃但不招募状态。
结果：在 2019 年 1 月 17 日至 2020 年 4 月 28 日期间，评估的 1309 例患者中，794 例被随机分配至仑伐替尼加帕博利珠单抗组（n=395）或仑伐替尼加安慰剂组（n=399）。中位年龄为 66.0 岁（IQR 57.0-72.0），794 例患者中，644 例（81%）为男性，150 例（19%）为女性，345 例（43%）为亚洲人，345 例（43%）为白人，22 例（3%）为多种族，21 例（3%）为美洲印第安人或阿拉斯加原住民，21 例（3%）为夏威夷原住民或其他太平洋岛民，13 例（2%）为黑人或非裔美国人，46 例（6%）没有种族数据。截至最终分析数据截止日期（2022 年 6 月 21 日）的中位随访时间为 32.1 个月（IQR 29.4-35.3）。仑伐替尼加帕博利珠单抗组的中位总生存期为 21.2 个月（95%CI 19.0-23.6；395 例死亡中有 252 例[64%]），仑伐替尼加安慰剂组为 19.0 个月（17.2-21.7；399 例死亡中有 282 例[71%]）（风险比[HR]0.84；95%CI 0.71-1.00；分层对数秩检验 p=0.023）。在无进展生存期最终分析数据截止日期（2021 年 4 月 5 日），仑伐替尼加帕博利珠单抗组的中位无进展生存期为 8.2 个月（95%CI 6.4-8.4；发生 270 例事件[42 例死亡；228 例进展]），仑伐替尼加安慰剂组为 8.0 个月（6.3-8.2；发生 301 例事件[36 例死亡；265 例进展]）（HR 0.87；95%CI 0.73-1.02；分层对数秩检验 p=0.047）。最常见的与治疗相关的 3-4 级不良事件是高血压（仑伐替尼加帕博利珠单抗组 395 例患者中有 69 例[17%]，仑伐替尼加安慰剂组 395 例患者中有 68 例[17%]）、天门冬氨酸氨基转移酶升高（27 例[7%] vs 17 例[4%]）和腹泻（25 例[6%] vs 15 例[4%]）。仑伐替尼加帕博利珠单抗组中有 4 例（1%）患者发生与治疗相关的死亡（胃肠道出血和肝肾综合征各 1 例[各占 1%]和肝性脑病 2 例[各占 2%]），仑伐替尼加安慰剂组中有 3 例（1%）患者发生与治疗相关的死亡（胃肠道出血、肝肾综合征和脑卒中等各 1 例[各占 1%]）。
结论：在早期研究中，仑伐替尼联合帕博利珠单抗作为晚期肝细胞癌的一线治疗已显示出有希望的临床活性；然而，仑伐替尼加帕博利珠单抗在总生存期和无进展生存期方面并未达到优于仑伐替尼加安慰剂的显著水平。我们的研究结果不支持改变临床实践。
资金来源：Eisai US 和默克公司的子公司 Merck Sharp & Dohme。
J Hepatocell Carcinoma. 2025-8-22
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