{"title":"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。","authors":"Qingyuan Zhang, Pin Zhang, Min Yan, Xi Yan, Xian Wang, Yuanting Gu, Xiujuan Qu, Shaorong Li, Guoying Xu, Xiaoyu Zhu, Binghe Xu","doi":"10.1177/17588359241273026","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Dalpiciclib is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary efficacy as monotherapy for pretreated advanced breast cancer (BC).</p><p><strong>Objectives: </strong>To further assess dalpiciclib with endocrine therapy (ET) in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC.</p><p><strong>Design: </strong>A multicenter, open-label, phase Ib trial.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>Dalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile. The recommended phase III dose of dalpiciclib was 150 mg.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier: NCT03481998.</p>","PeriodicalId":23053,"journal":{"name":"Therapeutic Advances in Medical Oncology","volume":"16 ","pages":"17588359241273026"},"PeriodicalIF":4.3000,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369877/pdf/","citationCount":"0","resultStr":"{\"title\":\"Dalpiciclib in combination with letrozole/anastrozole or fulvestrant in HR-positive and HER2-negative advanced breast cancer: results from a phase Ib study.\",\"authors\":\"Qingyuan Zhang, Pin Zhang, Min Yan, Xi Yan, Xian Wang, Yuanting Gu, Xiujuan Qu, Shaorong Li, Guoying Xu, Xiaoyu Zhu, Binghe Xu\",\"doi\":\"10.1177/17588359241273026\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Dalpiciclib is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary efficacy as monotherapy for pretreated advanced breast cancer (BC).</p><p><strong>Objectives: </strong>To further assess dalpiciclib with endocrine therapy (ET) in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC.</p><p><strong>Design: </strong>A multicenter, open-label, phase Ib trial.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>Dalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile. The recommended phase III dose of dalpiciclib was 150 mg.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier: NCT03481998.</p>\",\"PeriodicalId\":23053,\"journal\":{\"name\":\"Therapeutic Advances in Medical Oncology\",\"volume\":\"16 \",\"pages\":\"17588359241273026\"},\"PeriodicalIF\":4.3000,\"publicationDate\":\"2024-09-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369877/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Therapeutic Advances in Medical Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1177/17588359241273026\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Therapeutic Advances in Medical Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/17588359241273026","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
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。
Dalpiciclib in combination with letrozole/anastrozole or fulvestrant in HR-positive and HER2-negative advanced breast cancer: results from a phase Ib study.
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.
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).