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Dalpiciclib in combination with letrozole/anastrozole or fulvestrant in HR-positive and HER2-negative advanced breast
Qingyuan Zhang1, Pin Zhang2, Min Yan3
1Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
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.
Insights
Dalpiciclib combined with endocrine therapy demonstrated tolerability and efficacy in advanced breast cancer (BC). The recommended Phase III dose of dalpiciclib is 150 mg for hormone receptor-positive/human epidermal growth factor receptor 2-negative BC.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Dalpiciclib, a novel cyclin-dependent kinase 4/6 inhibitor, showed preliminary efficacy and tolerability as a monotherapy for pretreated advanced breast cancer (BC).
- Further assessment of dalpiciclib in combination with endocrine therapy (ET) was warranted for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC.
Purpose of the Study:
- To evaluate the safety and preliminary efficacy of dalpiciclib combined with endocrine therapy (letrozole/anastrozole or fulvestrant) in patients with advanced breast cancer.
- To determine the recommended Phase III dose of dalpiciclib for further clinical investigation.
Main Methods:
- A multicenter, open-label, Phase Ib trial enrolled patients with locally recurrent or metastatic BC into five cohorts.
- Patients received dalpiciclib (125-175 mg) plus letrozole/anastrozole or fulvestrant, with dalpiciclib administered orally once daily on a 3-weeks-on/1-week-off schedule.
- The primary endpoint was safety, with dose-escalation and pharmacokinetic assessments conducted.
Main Results:
- No maximum tolerated dose of dalpiciclib was reached. Grade ⩾3 adverse events occurred in 86.7%-93.8% of patients, most commonly neutropenia and leukopenia.
- Steady-state pharmacokinetics showed dose-dependent increases in dalpiciclib exposure.
- The 150 mg dose of dalpiciclib demonstrated a numerically higher objective response rate and promising progression-free survival in both treatment-naïve and pretreated patient groups.
Conclusions:
- Dalpiciclib in combination with letrozole/anastrozole or fulvestrant exhibited an acceptable safety profile.
- The recommended Phase III dose for dalpiciclib in this setting is 150 mg.
- This combination therapy represents a potential treatment option for advanced HR+/HER2- BC.
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