达尔西利联合来曲唑/阿那曲唑或氟维司群治疗激素受体阳性、人表皮生长因子受体2阴性晚期乳腺癌：Ib期研究结果
Dalpiciclib in combination with letrozole/anastrozole or fulvestrant in HR-positive and HER2-negative advanced breast cancer: results from a phase Ib study.
作者信息
Zhang Qingyuan, Zhang Pin, Yan Min, Yan Xi, Wang Xian, Gu Yuanting, Qu Xiujuan, Li Shaorong, Xu Guoying, Zhu Xiaoyu, Xu Binghe
机构信息
Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
National Cancer Center and Clinical Trial Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
出版信息
Ther Adv Med Oncol. 2024 Sep 2;16:17588359241273026. doi: 10.1177/17588359241273026. eCollection 2024.
BACKGROUND
Dalpiciclib is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary efficacy as monotherapy for pretreated advanced breast cancer (BC).
OBJECTIVES
To further assess dalpiciclib with endocrine therapy (ET) in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC.
DESIGN
A multicenter, open-label, phase Ib trial.
METHODS
Patients with locally recurrent or metastatic BC were enrolled in five cohorts. Patients without prior treatment for advanced disease (cohorts 1-2) were given dalpiciclib (125 or 150 mg) plus letrozole/anastrozole; patients who progressed after ET (cohorts 3-5) were given dalpiciclib (125, 150, or 175 mg) plus fulvestrant. Dalpiciclib was administered orally once daily in 3-weeks-on/1-week off schedule. The primary endpoint was safety.
RESULTS
A total of 58 patients received dalpiciclib with letrozole/anastrozole and 46 received dalpiciclib with fulvestrant. No maximum tolerated dose of dalpiciclib was reached with letrozole/anastrozole or fulvestrant. Across all cohorts, 86.7%-93.8% of patients had a grade ⩾3 adverse event, with the most common being neutropenia (grade 3, 40.0% for dalpiciclib 175 mg and 61.8%-87.5% for lower doses; grade 4, 46.7% and 4.2%-20.6%, respectively) and leukopenia (grade 3, 80.0% for 175 mg and 33.3%-54.2% for lower doses; grade 4, 0% for all doses). At tested dose levels, steady-state areas under the concentration curve and peak concentration of dalpiciclib increased with dose when combined with letrozole/anastrozole and fulvestrant. Dalpiciclib at 150 mg was associated with a numerically higher objective response rate in both patients untreated for advanced disease (67.6%; 95% confidence interval (CI) 49.5-82.6) and patients progressing after ET (53.3%; 95% CI 26.6-78.7); as of July 30, 2022, the median progression-free survival with dalpiciclib 150 mg was 24.1 months (95% CI 16.9-46.0) with letrozole/anastrozole and 16.7 months (95% CI 1.9-24.1) with fulvestrant.
CONCLUSION
Dalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile. The recommended phase III dose of dalpiciclib was 150 mg.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT03481998.
背景
达尔西利是一种新型细胞周期蛋白依赖性激酶4/6抑制剂，作为单药治疗经治晚期乳腺癌（BC）显示出耐受性和初步疗效。
目的
进一步评估达尔西利联合内分泌治疗（ET）用于激素受体（HR）阳性/人表皮生长因子受体2（HER2）阴性乳腺癌的疗效。
设计
一项多中心、开放标签的Ib期试验。
方法
局部复发或转移性乳腺癌患者入组5个队列。未接受过晚期疾病治疗的患者（队列1-2）接受达尔西利（125或150mg）加来曲唑/阿那曲唑治疗；内分泌治疗后进展的患者（队列3-5）接受达尔西利（125、150或175mg）加氟维司群治疗。达尔西利口服给药，每日1次，采用3周给药/1周停药方案。主要终点是安全性。
结果
共有58例患者接受达尔西利联合来曲唑/阿那曲唑治疗，46例患者接受达尔西利联合氟维司群治疗。与来曲唑/阿那曲唑或氟维司群联合使用时，未达到达尔西利的最大耐受剂量。在所有队列中，86.7%-93.8%的患者发生≥3级不良事件，最常见的是中性粒细胞减少（3级，175mg达尔西利组为40.0%，较低剂量组为61.8%-87.5%；4级，分别为46.7%和4.2%-20.6%）和白细胞减少（3级，175mg组为80.0%，较低剂量组为33.3%-54.2%；4级，所有剂量组均为0%）。在测试的剂量水平下，与来曲唑/阿那曲唑和氟维司群联合使用时，达尔西利的稳态浓度曲线下面积和峰浓度随剂量增加。150mg达尔西利在未接受过晚期疾病治疗的患者（客观缓解率67.6%；95%置信区间（CI）49.5-82.6）和内分泌治疗后进展的患者（客观缓解率53.3%；95%CI 26.6-78.7）中均显示出数值上更高的客观缓解率；截至2022年7月30日，150mg达尔西利联合来曲唑/阿那曲唑治疗的中位无进展生存期为24.1个月（95%CI 16.9-46.0），联合氟维司群治疗的中位无进展生存期为16.7个月（95%CI 1.9-24.1）。
结论
达尔西利加来曲唑/阿那曲唑或氟维司群显示出可接受的安全性。达尔西利的推荐III期剂量为150mg。
试验注册
ClinicalTrials.gov标识符：NCT03481998。
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