Dalpiciclib in combination with letrozole/anastrozole or fulvestrant in HR-positive and HER2-negative advanced breast cancer: results from a phase Ib study.

IF 4.3 2区医学 Q2 ONCOLOGY

Therapeutic Advances in Medical Oncology Pub Date : 2024-09-02 eCollection Date: 2024-01-01 DOI:10.1177/17588359241273026

Qingyuan Zhang, Pin Zhang, Min Yan, Xi Yan, Xian Wang, Yuanting Gu, Xiujuan Qu, Shaorong Li, Guoying Xu, Xiaoyu Zhu, Binghe Xu

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引用次数: 0

Abstract

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.

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Dalpiciclib 联合来曲唑/阿那曲唑或氟维司群治疗 HR 阳性和 HER2 阴性晚期乳腺癌：Ib 期研究结果。

背景：Dalpiciclib 是一种新型细胞周期蛋白依赖性激酶 4/6 抑制剂：Dalpiciclib是一种新型细胞周期蛋白依赖性激酶4/6抑制剂，作为单药治疗预处理晚期乳腺癌（BC）显示出耐受性和初步疗效：进一步评估dalpiciclib与内分泌治疗（ET）在激素受体（HR）阳性/人表皮生长因子受体2（HER2）阴性BC中的疗效：多中心、开放标签、Ib期试验：将局部复发或转移性 BC 患者分为五组。未接受过晚期疾病治疗的患者（1-2组）接受dalpiciclib（125或150毫克）加来曲唑/阿那曲唑治疗；ET后病情进展的患者（3-5组）接受dalpiciclib（125、150或175毫克）加氟维司群治疗。dalpiciclib每天口服一次，按3周开/1周停的时间表给药。主要终点是安全性：共有58名患者接受了dalpiciclib联合来曲唑/阿那曲唑治疗，46名患者接受了dalpiciclib联合氟维司群治疗。来曲唑/阿那曲唑或氟维司群均未达到dalpiciclib的最大耐受剂量。在所有组别中，86.7%-93.8%的患者发生了⩾3级不良事件，最常见的是中性粒细胞减少症（3级，dalpiciclib 175 mg为40.0%，低剂量为61.8%-87.5%；4级，分别为46.7%和4.2%-20.6%）和白细胞减少症（3级，175 mg为80.0%，低剂量为33.3%-54.2%；4级，所有剂量均为0%）。在测试的剂量水平上，dalpiciclib与来曲唑/阿那曲唑和氟维司群合用时，其稳态浓度曲线下面积和峰值浓度随剂量增加而增加。在未经治疗的晚期疾病患者（67.6%；95% 置信区间 (CI)：49.5-82.6）和 ET 后病情进展的患者（53.3%；95% 置信区间 (CI)：26.5-82.6）中，150 毫克剂量的 Dalpiciclib 与更高的客观应答率相关。3%；95% CI 26.6-78.7）；截至2022年7月30日，dalpiciclib 150 mg与来曲唑/阿那曲唑的中位无进展生存期为24.1个月（95% CI 16.9-46.0），与氟维司群的中位无进展生存期为16.7个月（95% CI 1.9-24.1）.结论：Dalpiciclib联合来曲唑/阿那曲唑或氟维司群的安全性可接受。III期推荐的dalpiciclib剂量为150毫克：试验注册：ClinicalTrials.gov identifier：NCT03481998。

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来源期刊

Therapeutic Advances in Medical Oncology ONCOLOGY-

CiteScore

8.20

自引率

2.00%

发文量

160

审稿时长

15 weeks

期刊介绍： Therapeutic Advances in Medical Oncology is an open access, peer-reviewed journal delivering the highest quality articles, reviews, and scholarly comment on pioneering efforts and innovative studies in the medical treatment of cancer. The journal has a strong clinical and pharmacological focus and is aimed at clinicians and researchers in medical oncology, providing a forum in print and online for publishing the highest quality articles in this area. This journal is a member of the Committee on Publication Ethics (COPE).