帕博利珠单抗联合或不联合乐伐替尼作为晚期尿路上皮癌患者的一线治疗（LEAP-011）：一项3期随机双盲试验
Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial.
作者信息
Matsubara Nobuaki, de Wit Ronald, Balar Arjun Vasant, Siefker-Radtke Arlene O, Zolnierek Jakub, Csoszi Tibor, Shin Sang Joon, Park Se Hoon, Atduev Vagif, Gumus Mahmut, Su Yu-Li, Karaca Saziye Burcak, Cutuli Hernán Javier, Sendur Mehmet A N, Shen Liji, O'Hara Karen, Okpara Chinyere E, Franco Sonia, Moreno Blanca Homet, Grivas Petros, Loriot Yohann
机构信息
National Cancer Center Hospital East, Chiba, Japan.
Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
出版信息
Eur Urol. 2024 Mar;85(3):229-238. doi: 10.1016/j.eururo.2023.08.012. Epub 2023 Sep 29.
BACKGROUND
Pembrolizumab plus lenvatinib has shown antitumor activity and acceptable safety in patients with platinum-refractory urothelial carcinoma (UC).
OBJECTIVE
To evaluate pembrolizumab plus either lenvatinib or placebo as first-line therapy for advanced UC in the phase 3 LEAP-011 study.
DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced UC who were ineligible for cisplatin-based therapy or any platinum-based chemotherapy were enrolled.
INTERVENTION
Patients were randomly assigned (1:1) to pembrolizumab 200 mg intravenously every 3 wk plus either lenvatinib 20 mg or placebo orally once daily.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). An external data monitoring committee (DMC) regularly reviewed safety and efficacy data every 3 mo.
RESULTS AND LIMITATIONS
Between June 25, 2019 and July 21, 2021, 487 patients were allocated to receive lenvatinib plus pembrolizumab (n = 245) or placebo plus pembrolizumab (n = 242). The median time from randomization to the data cutoff date (July 26, 2021) was 12.8 mo (interquartile range, 6.9-19.3). The median PFS was 4.5 mo in the combination arm and 4.0 mo in the pembrolizumab arm (hazard ratio [HR] 0.90 [95% confidence interval {CI} 0.72-1.14]). The median OS was 11.8 mo for the combination arm and 12.9 mo for the pembrolizumab arm (HR 1.14 [95% CI 0.87-1.48]). Grade 3-5 adverse events attributed to trial treatment occurred in 123 of 241 patients (51%) treated with lenvatinib plus pembrolizumab and in 66 of 242 patients (27%) treated with placebo plus pembrolizumab. This trial was terminated earlier than initially planned based on recommendation from the DMC.
CONCLUSIONS
The benefit-to-risk ratio for first-line lenvatinib plus pembrolizumab was not considered favorable versus pembrolizumab plus placebo as first-line therapy in patients with advanced UC.
PATIENT SUMMARY
Lenvatinib plus pembrolizumab was not more effective than pembrolizumab plus placebo in patients with advanced urothelial carcinoma.
背景
帕博利珠单抗联合乐伐替尼已在铂类难治性尿路上皮癌（UC）患者中显示出抗肿瘤活性和可接受的安全性。
目的
在3期LEAP - 011研究中评估帕博利珠单抗联合乐伐替尼或安慰剂作为晚期UC的一线治疗方案。
设计、设置和参与者：纳入不符合基于顺铂治疗或任何铂类化疗条件的晚期UC患者。
干预措施
患者被随机分配（1:1）接受每3周静脉注射200mg帕博利珠单抗，同时每日口服20mg乐伐替尼或安慰剂。
结局测量和统计分析
双重主要终点为无进展生存期（PFS）和总生存期（OS）。一个外部数据监测委员会（DMC）每3个月定期审查安全性和疗效数据。
结果与局限性
在2019年6月25日至2021年7月21日期间，487例患者被分配接受乐伐替尼联合帕博利珠单抗（n = 245）或安慰剂联合帕博利珠单抗（n = 242）治疗。从随机分组到数据截止日期（2021年7月26日）的中位时间为12.8个月（四分位间距，6.9 - 19.3）。联合治疗组的中位PFS为4.5个月，帕博利珠单抗组为4.0个月（风险比[HR] 0.90 [95%置信区间{CI} 0.72 - 1.14]）。联合治疗组的中位OS为11.8个月，帕博利珠单抗组为12.9个月（HR 1.14 [95% CI 0.87 - 1.48]）。在接受乐伐替尼联合帕博利珠单抗治疗的241例患者中有123例（51%）发生了归因于试验治疗的3 - 5级不良事件，在接受安慰剂联合帕博利珠单抗治疗的242例患者中有66例（27%）发生了此类事件。根据DMC的建议，该试验比最初计划提前终止。
结论
对于晚期UC患者，一线使用乐伐替尼联合帕博利珠单抗的风险效益比与帕博利珠单抗联合安慰剂作为一线治疗相比不具优势。
患者总结
在晚期尿路上皮癌患者中，乐伐替尼联合帕博利珠单抗并不比帕博利珠单抗联合安慰剂更有效。
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