Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors
Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors
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DOI：
10.1200/jco.19.01598
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发表时间：
2020-04-10
影响因子：
45.3
通讯作者：
Motzer, Robert J.
中科院分区：
文献类型：
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作者：
Taylor, Matthew H.;Lee, Chung-Han;Motzer, Robert J.
通过血管生成抑制调节血管内皮生长因子介导的免疫抑制可能会增加免疫检查点抑制剂的活性。我们报告的结果，从剂量发现和初始的Ib/II期研究，乐伐替尼加pembrolizumab在选定的晚期solid tumors.METHODSEligible患者的扩大有转移性肾细胞癌（RCC），子宫内膜癌，鳞状细胞癌的头部和颈部（SCCHN），黑色素瘤，非小细胞肺癌（NSCLC），或尿路上皮癌。Ib期试验的主要目的是确定乐伐替尼联合帕博利珠单抗（200 mg，静脉注射，每3周一次）的最大耐受剂量（MTD）。在预先计划的II期队列扩展中，主要目标是在推荐的II期剂量下第24周的客观反应率（ORR第24周）。总体而言，在Ib期（n = 13）和初始II期扩展（n = 124）期间招募了137名患者。在初始剂量水平（乐伐替尼24 mg/d+帕博利珠单抗）中报告了2起剂量限制性毒性（DLT; 3级关节痛和3级疲乏）。在随后的剂量递减队列中未观察到DLT，确立了乐伐替尼20 mg/d+帕博利珠单抗的MTD和推荐II期剂量。第24周ORR如下：碾压混凝土，63%（19/30; 95% CI，43.9%至80.1%）;子宫内膜癌，52%（12/23; 95% CI，30.6%-73.2%）;黑色素瘤，48%（10/21; 95% CI，25.7%-70.2%）; SCCHN，36%（8/22; 95% CI，17.2%-59.3%）; NSCLC，33%（7/21; 95% CI，14.6%-57.0%）;尿路上皮癌25%（5/20; 95% CI，8.7%-49.1%）。最常见的治疗相关不良事件是疲乏（58%）、腹泻（52%）、高血压（47%）和甲状腺功能减退症（42%）。结论乐伐替尼联合帕博利珠单抗在选定的实体瘤类型患者中表现出可管理的安全性和有希望的抗肿瘤活性。(c)2020年美国临床肿瘤学会
PURPOSEModulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We report results from the dose-finding and initial phase II expansion of a phase Ib/II study of lenvatinib plus pembrolizumab in patients with selected advanced solid tumors.METHODSEligible patients had metastatic renal cell carcinoma (RCC), endometrial cancer, squamous cell carcinoma of the head and neck (SCCHN), melanoma, non-small-cell lung cancer (NSCLC), or urothelial cancer. The primary objective of phase Ib was to determine the maximum tolerated dose (MTD) for lenvatinib plus pembrolizumab (200 mg intravenously every 3 weeks). In the preplanned phase II cohort expansion, the primary objective was objective response rate at week 24 (ORRweek 24) at the recommended phase II dose.RESULTSOverall, 137 patients were enrolled during phase Ib (n = 13) and the initial phase II expansion (n = 124). Two dose-limiting toxicities (DLTs; grade 3 arthralgia and grade 3 fatigue) were reported in the initial dose level (lenvatinib 24 mg/d plus pembrolizumab). No DLTs were observed in the subsequent dose-de-escalation cohort, establishing the MTD and recommended phase II dose at lenvatinib 20 mg/d plus pembrolizumab. ORRweek24 was as follows: RCC, 63% (19/30; 95% CI, 43.9% to 80.1%); endometrial cancer, 52% (12/23; 95% CI, 30.6% to 73.2%); melanoma, 48% (10/21; 95% CI, 25.7% to 70.2%); SCCHN, 36% (8/22; 95% CI, 17.2% to 59.3%); NSCLC, 33% (7/21; 95% CI, 14.6% to 57.0%); and urothelial cancer 25% (5/20; 95% CI, 8.7% to 49.1%). The most common treatment-related adverse events were fatigue (58%), diarrhea (52%), hypertension (47%), and hypothyroidism (42%).CONCLUSIONLenvatinib plus pembrolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with selected solid tumor types. (c) 2020 by American Society of Clinical Oncology