Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study.

Sara M Tolaney,Andrew Lithio,Gregory L Price,Kevin Kalinsky,Alison Conlin,Lacey M Litchfield,Sonya C Chapman,Muralidhar Beeram,Matthew P Goetz,Kathleen N Moore,Teresa Helsten,Allison M Manuel,Komal Jhaveri,J Thaddeus Beck,Carlos Becerra,E Claire Dees,Howard A Burris,Shannon L Puhalla,Brent N Rexer

doi:10.3389/fonc.2021.810023

Abstract

BackgroundCyclin-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 MethodsWomen ≥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.ResultsSixty-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.ConclusionsAbemaciclib 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

Highlights

Endocrine therapy (ET) forms the foundation of treatment for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer
Evidence of a tolerable safety profile and antitumor activity was observed in a Phase 1 study, with abemaciclib administered either as a single agent or in combination with fulvestrant evaluating the 200 mg Q12H dose
Diarrhea (98.5%, any grade) was the most commonly reported Adverse events (AE), which was consistent with other studies of abemaciclib, and grade 3 diarrhea was observed in 35.8% of patients using a starting dose of abemaciclib of 200 mg Q12H

Summary

Introduction

Endocrine therapy (ET) forms the foundation of treatment for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. Subsequent Phase 3 studies evaluated abemaciclib in combination with nonsteroidal aromatase inhibitors (NSAI; letrozole or anastrozole) as initial therapy (MONARCH 3), or with fulvestrant after progression on ET (MONARCH 2), leading to approval of abemaciclib in combination with these ETs for the treatment of advanced or metastatic breast cancer [7,8,9]. 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

Methods

Results

Conclusion