Abemaciclib对晚期肾癌患者CDK4/6的抑制作用

IF 2.3 3区医学 Q3 ONCOLOGY

Clinical genitourinary cancer Pub Date : 2025-02-18 DOI:10.1016/j.clgc.2025.102318

Bradley A. McGregor , Wanling Xie , Stephanie A. Berg , Wenxin Xu , Srinivas R. Viswanathan , David McDermott , Sabina Signoretti , William G Kaelin Jr , Toni K. Choueiri

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引用次数: 0

摘要

临床前数据为周期蛋白依赖性激酶4和6 （CDK4/6）抑制剂单独或联合HIF-2α抑制剂治疗透明细胞肾细胞癌（ccRCC）提供了基本原理，目前正在进行的随机2期临床试验正在探索帕博西尼联合贝祖替芬与贝祖替芬联合治疗耐药的ccRCC （NCT05468697）。然而，CDK4/6抑制剂在ccRCC中的单药活性尚未报道。在这项多中心1b期临床试验（NCT04627064）中，我们研究了abemaciclib（一种口服CDK4/6抑制剂）单药治疗晚期预治疗的RCC患者的安全性和有效性。方法：在至少1次包括免疫治疗和VEGFR TKI在内的治疗方案后，透明细胞成分和ECOG状态≤2进展的成年晚期RCC患者接受阿贝美西利200 mg，每日2次，4周为一个周期，直到进展或不可接受的毒性。主要目的是评估abemaciclib的客观缓解率（ORR），次要终点是安全性。8周或2个周期后进行首次影像学检查。根据RECIST 1.1评估反应，根据CTCAE v5.0分级毒性。结果在2020年12月31日至2023年10月3日期间入组了6例患者。中位年龄为62岁（54-68岁）；73% （n = 8）为IMDC中危疾病，1例为易位性RCC伴透明细胞成分。先前治疗的中位数为4（范围1-9）。ORR为0% (0/11；8例进展性疾病，1例稳定疾病因临床进展而停止，2例不能用临床进展来评价)。约27% （n = 3）的患者出现≥3级治疗相关不良事件（腹泻n = 1，恶心n = 1，中性粒细胞减少n = 1）。结论在大量预处理的转移性RCC患者中，阿贝马昔利单药治疗没有临床意义的活性，没有新的毒性信号。这一数据将为正在进行的探索CDK4/6抑制与HIF-2α抑制剂和免疫治疗联合使用的试验结果的解释提供重要见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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CDK4/6 Inhibition With Abemaciclib in Patients With Previously Treated Advanced Renal Cell Carcinoma

Background

Preclincal data provide a rationale for cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors alone and in combination with HIF-2α inhibitors in treatment of clear cell renal cell carcinoma (ccRCC), with randomized phase 2 clinical trials currently open exploring the combination of palbociclib with belzutifan vs belzutifan in treatment resistant ccRCC (NCT05468697). However, single agent activity for CDK4/6 inhibitors in ccRCC has not been reported. In this multi-center phase 1b clinical trial (NCT04627064), we investigated the safety and efficacy of monotherapy with abemaciclib, an oral CDK4/6 inhibitor in patients with advanced pretreated RCC.

Methods

Adult patients with advanced RCC with a clear cell component and ECOG status of ≤ 2 progressing after at least 1 prior regimen including immunotherapy and a VEGFR TKI received abemaciclib 200 mg twice daily in 4-week cycles until progression or unacceptable toxicity. The primary objective was to evaluate the objective response rate (ORR) of abemaciclib with a secondary endpoint of safety. First imaging was performed after 8 weeks or 2 cycles. Response was assessed per RECIST 1.1 and toxicity graded per CTCAE v5.0.

Results

Eleven patients were enrolled between December 31, 2020 and October 03, 2023. Median age was 62 years (range 54-68); 73% (n = 8) had IMDC intermediate risk disease and 1 patient had translocation RCC with a clear cell component. Median number of prior therapies was 4 (range 1-9). ORR was 0% (0/11; 8 progressive disease, 1 stable disease stopping for clinical progression, 2 not evaluable with clinical progression). About 27% (n = 3) experienced grade ≥3 treatment-related adverse events (diarrhea n = 1, nausea n = 1, neutropenia n = 1).

Conclusion

In patients with heavily pretreated metastatic RCC, abemaciclib monotherapy had no clinically meaningful activity without new toxicity signals. This data will offer important insight into interpretation of results for ongoing trials exploring CDK4/6 inhibition in combination with HIF-2α inhibitors and immunotherapy.

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来源期刊

Clinical genitourinary cancer 医学-泌尿学与肾脏学

CiteScore

5.20

自引率

6.20%

发文量

201

审稿时长

54 days

期刊介绍： Clinical Genitourinary Cancer is a peer-reviewed journal that publishes original articles describing various aspects of clinical and translational research in genitourinary cancers. Clinical Genitourinary Cancer is devoted to articles on detection, diagnosis, prevention, and treatment of genitourinary cancers. The main emphasis is on recent scientific developments in all areas related to genitourinary malignancies. Specific areas of interest include clinical research and mechanistic approaches; drug sensitivity and resistance; gene and antisense therapy; pathology, markers, and prognostic indicators; chemoprevention strategies; multimodality therapy; and integration of various approaches.