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Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative
Sara M Tolaney1, Muralidhar Beeram2, J Thaddeus Beck3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States.
Background:
Cyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen.
Patients And Methods:
Women ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0-1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1.
Results:
Sixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease.
Conclusions:
Abemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC.
Clinical Trial Registration:
https://clinicaltrials.gov/, identifier NCT02057133.
Insights
Abemaciclib combined with endocrine therapy shows manageable safety and promising antitumor activity in metastatic breast cancer patients. This combination therapy offers a new treatment option for hormone receptor-positive, HER2-negative advanced breast cancer.
Area of Science:
- Oncology
- Pharmacology
Background:
- Cyclin-dependent kinases (CDK) 4 and 6 are crucial regulators of cell cycle progression, frequently dysregulated in various cancers.
- Abemaciclib is an approved selective inhibitor of CDK4/6 for advanced or metastatic breast cancer treatment.
- This study investigated abemaciclib in combination with endocrine therapies for metastatic breast cancer (MBC).
Purpose of the Study:
- To evaluate the safety and tolerability of abemaciclib combined with endocrine therapy.
- To assess the pharmacokinetics of the combination therapy.
- To determine the antitumor activity of abemaciclib plus endocrine therapy in MBC patients.
Main Methods:
- A Phase 1b study enrolled women aged 18+ with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC.
- Patients received abemaciclib (200 mg every 12 hours) with letrozole, anastrozole, tamoxifen, or exemestane.
- Safety, tolerability, pharmacokinetics, and tumor response (RECIST v1.1) were assessed.
Main Results:
- Sixty-seven patients were enrolled across four treatment arms.
- The most frequent treatment-emergent adverse events included diarrhea, fatigue, nausea, and abdominal pain.
- Median progression-free survival was 25.4 months, with an objective response rate of 38.9% in patients with measurable disease.
Conclusions:
- Abemaciclib in combination with various endocrine therapies demonstrates a manageable safety profile.
- The combination therapy shows promising antitumor activity in patients with HR+, HER2- MBC.
- This regimen represents a potential therapeutic option for this patient population.
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