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

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 Registrationhttps://clinicaltrials.gov/, identifier NCT02057133

Circulating tumour DNA dynamics during alternating chemotherapy and hormonal therapy in metastatic breast cancer: the ALERT study

“…For the patients with detectable PIK3CA mutations in ctDNA (002, 006 008 and 011) a PIK3CA inhibitor may have indicated as detailed in the SOLAR-1 trail [21]. Alternatively, CDK4/6 inhibitor abemaciclib plus fulvestrant could be used regardless of PIK3CA or ESR1 mutation status [22]. Furthermore, it is possible that combining eribulin with CDK4/6 inhibitor could be an effective treatment strategy in overcoming resistance to CDK4/6 inhibitors, speci cally to block the escaped cells that pass the G1/S cell cycle phase irrespective of the CDK4/6 inhibitor treatment [23].…”

Stratification of Tamoxifen Synergistic Combinations for the Treatment of ER+ Breast Cancer

“…The mechanism by which simeprevir and tamoxifen combination therapy leads to a reduced tumor burden, and reduced HER2 expression, is currently unknown, and may necessitate further study. Additionally, many studies have shown the benefit of aurora kinase inhibitors, as well as other cell cycle inhibitors, in combination with antiestrogens [ 57 , 58 , 59 ]. Although both tamoxifen and aurora kinase inhibitors are cytostatic, to our knowledge, this is the first study to identify the additional benefit of reduction in HER2 upregulation provided by combination therapy when compared to tamoxifen monotherapy.…”

Cellular and molecular basis of therapeutic approaches to breast cancer

“…When the aromatase enzyme is blocked, estrogen production is ceased. When compared to tamoxifen, aromatase inhibitors (AIs) lower the risk of recurrence in postmenopausal women with ER-positive breast cancer [110]. Anastrozole and letrozole are reversible aromatase inhibitors that compete with one another to block the enzyme.…”