Targeting autophagy plus high-dose CDK4/6 inhibitors in advanced HR+HER2- breast cancer: A phase 1b/2 trial.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2025-05-09 Epub Date: 2024-12-27 DOI:10.1016/j.medj.2024.11.012

Chang Gong, Qun Lin, Tao Qin, Yinduo Zeng, Fei Xu, Yaping Yang, Dong Yin, Zhuxi Duan, Chun-Long Chen, Louis Wing-Cheong Chow, Qiang Liu, Ahmed Hamaï, Maryam Mehrpour, Qianchong Lin, Jun Li, Erwei Song

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引用次数: 0

Abstract

Background: The unmet needs of managing patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer who progress after cyclin-dependent kinase (CDK)4/6 inhibitor (CDK4/6i) treatment remain unclarified.

Methods: This was a phase 1b/2, single-arm, open-label study that enrolled 29 patients with HR+/HER2- breast cancer who experienced first-line palbociclib treatment failure. The primary endpoint was the incidence of dose-limiting toxicity (DLT). The secondary endpoints were the objective response rate (ORR) and progression-free survival (PFS). The clinical trial registration number is ClinicalTrials.gov: NCT05953350.

Findings: The phase 1b study demonstrated no DLT in patients treated with hydroxychloroquine (HCQ; 600 mg, bis in die [bid]) plus increasing doses of palbociclib (100, 150, or 200 mg, quaque die [qd]). The plasma pharmacokinetics of palbociclib were not significantly affected by HCQ. The recommended phase 2 dose (RP2D) was HCQ (600 mg, bid) plus palbociclib (200 mg, qd). The dose-expansion cohort demonstrated that HCQ plus palbociclib (200 mg, qd) treatment was tolerable. Grade 3 treatment-emergent adverse events (TEAEs) with an incidence higher than 15.0% included neutropenia (25.0%), leukopenia (25.0%), fatigue (20.0%), and back pain (15.0%). The ORR of all enrolled patients in our present trial was 41.4% (12/29). In the dose-expansion cohort, with the last enrolled patient having a follow-up duration of 32.3 weeks, the median PFS was not reached. The clinical benefit rate (CBR) at 6 months was 90.0% (95% confidence interval [CI]: 68.3%-98.8%). These findings were supported by preclinical data.

Conclusions: Combined HCQ with high-dose CDK4/6i palbociclib (200 mg, qd) showed tolerable toxicity and promising efficacy for patients with advanced HR+/HER2- breast cancer after CDK4/6i failure.

Funding: This work was funded by the National Natural Science Foundation of China.

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靶向自噬加高剂量CDK4/6抑制剂治疗晚期HR+HER2乳腺癌：1b/2期试验

背景：在周期蛋白依赖性激酶（CDK）4/6抑制剂（CDK4/6i）治疗后进展的激素受体阳性/人表皮生长因子受体2阴性（HR+/HER2-）乳腺癌患者的管理需求尚未得到满足。方法：这是一项1b/2期、单臂、开放标签的研究，纳入了29例HR+/HER2-乳腺癌患者，这些患者经历了一线帕博西尼治疗失败。主要终点是剂量限制性毒性（DLT）的发生率。次要终点是客观缓解率（ORR）和无进展生存期（PFS）。临床试验注册号为ClinicalTrials.gov: nct00553350。结果：1b期研究表明，接受羟氯喹(HCQ；600mg，他在死亡[bid])加上增加剂量的palbociclib（100,150或200mg， quaque die [qd]）。帕博西尼的血浆药代动力学不受HCQ的影响。推荐的2期剂量（RP2D）为HCQ （600mg, bid）加palbociclib （200mg, qd）。剂量扩展队列显示，HCQ加帕博西尼（200mg, qd）治疗是可耐受的。3级治疗不良事件（teae）发生率高于15.0%，包括中性粒细胞减少（25.0%）、白细胞减少（25.0%）、疲劳（20.0%）和背痛（15.0%）。本试验中所有入组患者的ORR为41.4%（12/29）。在剂量扩大队列中，最后一名入组患者的随访时间为32.3周，中位PFS未达到。6个月时临床获益率（CBR）为90.0%（95%可信区间[CI]: 68.3% ~ 98.8%）。这些发现得到了临床前数据的支持。结论：HCQ联合大剂量CDK4/6i帕博西尼（200mg, qd）治疗CDK4/6i失效的晚期HR+/HER2-乳腺癌患者毒性可耐受，疗效良好。基金资助：本工作由国家自然科学基金资助。

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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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.