The addition of the CDK4/6 inhibitor abemaciclib to fulvestrant significantly improved progression-free survival (PFS) and time to subsequent chemotherapy in pre- and perimenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer, according to results from an analysis of the phase III MONARCH-2 trial (abstract 1002) presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.
“[Abemaciclib’s] toxicity profile allows a continuous-based schedule, and continuous inhibition of CDK4 and 6 with abemaciclib leads to sustained cell cycle arrest and subsequent senescence or apoptosis,” said Patrick Neven, MD, PhD, of Universitaire Ziekenhuizen Leuven in Belgium. “However, short-term inhibition leads to reversible arrest with rebound effect.”
The full trial included 669 women of any menopausal status; he discussed results only of the 114 women who were pre- or perimenopausal.
All patients were endocrine therapy–resistant and had not received chemotherapy for metastatic breast cancer. They were randomized to receive either abemaciclib plus fulvestrant (72 patients) or placebo plus fulvestrant (42 patients), and all patients were required to also receive a gonadotropin-releasing hormone (GnRH) agonist. Patients had a median age of 46 and 47 years in the abemaciclib and placebo groups, respectively.
In the full study population including all menopausal statuses, the median PFS was 16.4 months with abemaciclib, compared with 9.3 months with placebo, for a hazard ratio (HR) of 0.553 (95% CI, 0.449–0.691; P < .0000001). In only the pre- and perimenopausal women, the median PFS was not reached with the study drug, compared with 10.5 months with placebo, for an HR of 0.446 (95% CI, 0.264–0.754; P = .002). A similar result was seen only in pre- and perimenopausal women who had not received prior aromatase inhibitor therapy.
The objective response rate with abemaciclib was 43.1%, and the clinical benefit rate was 77.8%. In the placebo group, those rates were 19.0% and 69.0%. The median time to subsequent chemotherapy was not reached in the abemaciclib group, compared with 19.2 months with placebo plus fulvestrant, for an HR of 0.61 (95% CI, 0.32–1.15; P < .123).
Four abemaciclib patients required a drug discontinuation due to an adverse event, compared with none with placebo; 39.4% of abemaciclib patients and 2.4% of placebo patients required a reduction of at least one dose. Serious adverse events occurred in 11.3% of the abemaciclib group and in 4.8% of the placebo group; there was one death due to an adverse event in the abemaciclib group, due to a cerebral infarction. Diarrhea was a common event with the study drug, and after 25% of the cohort was enrolled the study protocol was amended to lower the dose from 200 mg twice daily to 150 mg twice daily; Neven said the diarrhea was easily managed with standard therapy.
“I think it’s fair to say that the addition of abemaciclib to fulvestrant and a GnRH agonist improves the PFS and also leads to a better response rate,” Neven said. “It’s also clear that it delays the subsequent chemotherapy.”