<br>Lenvatinib 联合 pembrolizumab 治疗晚期子宫内膜癌患者：一项多中心、开放标签、单臂、2 期试验的中期分析。,The Lancet Oncology

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Lenvatinib 联合 pembrolizumab 治疗晚期子宫内膜癌患者：一项多中心、开放标签、单臂、2 期试验的中期分析。
The Lancet Oncology ( IF 41.6 ) Pub Date : 2019-03-25 , DOI: 10.1016/s1470-2045(19)30020-8
Vicky Makker ₁ , Drew Rasco ₂ , Nicholas J Vogelzang ₃ , Marcia S Brose ₄ , Allen L Cohn ₅ , James Mier ₆ , Christopher Di Simone ₇ , David M Hyman ₁ , Daniel E Stepan ₈ , Corina E Dutcus ₈ , Emmett V Schmidt ₉ , Matthew Guo ₈ , Pallavi Sachdev ₈ , Robert Shumaker ₈ , Carol Aghajanian ₁ , Matthew Taylor ₁₀

Affiliation

背景

Lenvatinib 是 VEGFR1、VEGFR2 和 VEGFR3 以及其他受体酪氨酸激酶的多激酶抑制剂。Pembrolizumab 是一种靶向 PD-1 的抗体，对生物标志物未选择的子宫内膜癌具有中等疗效。在 1b 期研究中确定最大耐受剂量后，我们旨在评估 lenvatinib 加 pembrolizumab 联合治疗晚期子宫内膜癌患者的疗效。

方法

在美国 11 个中心进行的这项开放标签、单臂、2 期研究中，符合条件的患者年龄在 18 岁或以上，患有转移性子宫内膜癌（未因微卫星不稳定性或 PD-L1 而选择），东部肿瘤合作组体能状态为 0 或 1，既往接受过不超过两次全身治疗，根据实体瘤免疫相关反应评估标准（irRECIST）患有可测量的疾病，预期寿命为 12 周或更长时间。患者每天口服 20 mg lenvatinib 加 200 mg 静脉注射 pembrolizumab，每 3 周一次。治疗持续至疾病进展、出现不可接受的毒性作用或撤回同意。该中期分析的主要终点是研究人员根据 irRECIST 在符合方案的人群中评估的第 24 周时具有客观反应的患者比例。此试用版注册为，编号为。

发现

在 2015 年 9 月 10 日至 2017 年 7 月 24 日期间，共纳入 54 名患者，其中 53 名被纳入分析。在抗肿瘤活性数据的截止日期（2017 年 12 月 15 日），中位研究随访为 13·3 个月（IQR 6·7–20·1）。21 例（39·6% [95% CI 26·5–54·0]）患者在第 24 周时有客观反应。16 例（30%）患者发生严重治疗相关不良事件，并报告了 1 例治疗相关死亡（颅内出血）。最常报告的任意级别治疗相关不良事件是高血压（31 [58%]）、疲劳（29 [55%]）、腹泻（27 [51%]）和甲状腺功能减退症（25 [47%]）。最常见的 3 级治疗相关不良事件是高血压（18 例 [34%]）和腹泻（4 例 [8%]）。未报告与 4 级治疗相关的不良事件。5 例（9%）患者因治疗相关不良事件而停止研究治疗。

解释

Lenvatinib 联合 pembrolizumab 在晚期复发性子宫内膜癌患者中显示出抗肿瘤活性，除了甲状腺功能减退症的频率增加外，其安全性与先前报道的 lenvatinib 和 pembrolizumab 单药治疗相似。Lenvatinib 联合 pembrolizumab 可能代表该患者群体的新的潜在治疗选择，并且正在一项随机 3 期研究中进行研究。

资金

卫材和默克。

"点击查看英文标题和摘要"

Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial.

Background

Lenvatinib is a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected endometrial cancer. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma, after establishing the maximum tolerated dose in a phase 1b study.

Methods

In this open-label, single-arm, phase 2 study done at 11 centres in the USA, eligible patients were aged 18 years or older and had metastatic endometrial cancer (unselected for microsatellite instability or PD-L1), had an Eastern Cooperative Oncology Group performance status of 0 or 1, had received no more than two previous systemic therapies, had measurable disease according to the immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and had a life expectancy of 12 weeks or longer. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Treatment continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. The primary endpoint of this interim analysis was the proportion of patients with an objective response at week 24 as assessed by investigators according to irRECIST in the per-protocol population. This trial is registered with , number .

Findings

Between Sept 10, 2015, and July 24, 2017, 54 patients were enrolled, 53 of whom were included in the analysis. At the cutoff date for anti-tumour activity data (Dec 15, 2017), median study follow-up was 13·3 months (IQR 6·7–20·1). 21 (39·6% [95% CI 26·5–54·0]) patients had an objective response at week 24. Serious treatment-related adverse events occurred in 16 (30%) patients, and one treatment-related death was reported (intracranial haemorrhage). The most frequently reported any-grade treatment-related adverse events were hypertension (31 [58%]), fatigue (29 [55%]), diarrhoea (27 [51%]), and hypothyroidism (25 [47%]). The most common grade 3 treatment-related adverse events were hypertension (18 [34%]) and diarrhoea (four [8%]). No grade 4 treatment-related adverse events were reported. Five (9%) patients discontinued study treatment because of treatment-related adverse events.

Interpretation

Lenvatinib plus pembrolizumab showed anti-tumour activity in patients with advanced recurrent endometrial cancer with a safety profile that was similar to those previously reported for lenvatinib and pembrolizumab monotherapies, apart from an increased frequency of hypothyroidism. Lenvatinib plus pembrolizumab could represent a new potential treatment option for this patient population, and is being investigated in a randomised phase 3 study.

Funding

Eisai and Merck.

更新日期：2019-05-16

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