Expert Reviews Efficacy, Safety Data with Abemaciclib in Breast Cancer

Abemaciclib (Verzenio), the only CDK4/6 inhibitor approved as a single-agent, has amassed several clinical indications for patients with metastatic breast cancer. The findings from the phase III MONARCH2 and 3 trials, as well as the phase II MONARCH1 study led to these approvals. Each trial showed improvements in progression-free survival (PFS), especially in patients with visceral disease and endocrine therapy resistance.

Andrew Koustenis, involved in the development of abemaciclib since the initial phase I studies, presented his review of all the pertinent efficacy and safety data for abemaciclib during a symposium at the 2018 Miami Breast Cancer Conference^®.

"We now have 3 indications for this compound. Verzenio is the only CDK4/6 inhibitor approved across HR-positive, HER2-negative, metastatic breast cancer in combination with fulvestrant or an aromatase inhibitor (AI) and as a single agent," said Koustenis, senior research advisor, Breast Cancer Development Team, Eli Lilly and Company.

On February 26, 2018, the most recent approval was for abemaciclib in combination with an AI for the frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Based on phase III data from the MONARCH3 trial, this was presented initially at the 2017 ESMO Annual Meeting.

In the trial, median age of patients was 63 years with approximately 80% having measurable disease at baseline. 51% overall had received prior systemic therapy, while 39% received prior chemotherapy. 53% of patients had visceral disease, with 16% having liver metastases and 22% having bone-only disease.

Median PFS with abemaciclib in the trial was 28.2 months (95% CI, 23.5 to not reached) versus 14.8 months (95% CI, 11.2-19.2) with a nonsteroidal AI alone (HR, 0.54; 95% CI, 0.418-0.698;P<.0001). In those with liver metastases (n = 78), the median PFS was 15.0 months (95% CI, 7.4-23.7) in the abemaciclib arm compared with 7.2 months (95% CI, 2.1-14.0) in the placebo group. This represents a 52% reduction in the risk of progression or death (HR, 0.477; 95% CI, 0.272-0.837).

The objective response rate (ORR) in patients with measurable disease was 55.4% with the CDK4/6 inhibitor and 40.2% in the control arm. In the abemaciclib arm, 3.4% of patients had a complete response compared with none in the placebo group. The response duration was 27.4 months with abemaciclib versus 17.5 months for the comparator.

Both granted in September 2017, the initial approvals for abemaciclib were for the agent in combination with fulvestrant for women with HR+/HER2- advanced breast cancer with disease progression following endocrine therapy, and as a monotherapy for patients with HR+/HER2- breast cancer with metastatic disease that previously received endocrine therapy and chemotherapy.

Approval of abemaciclib and fulvestrant was based on findings from the phase III MONARCH2 trial. This trial randomized patients to abemaciclib plus fulvestrant (n = 446) or fulvestrant plus placebo (n = 223). The study primarily included postmenopausal women (82%), with the remainder being pre- or peri-menopausal. Patients received the gonadotropin-releasing hormone agonist goserelin throughout the trial as well as at least 4 weeks prior to the study.

Median PFS was 16.4 months (95% CI, 14.4-19.3) in the abemaciclib arm versus 9.3 months (95% CI, 7.4-12.7) in the fulvestrant-alone group (HR, 0.553; 95% CI, 0.449-0.681;P<.001). Among patients with measurable disease, the ORRs among were 48.1% and 21.3% in the abemaciclib and control arms, respectively.

Benefit of abemaciclib and fulvestrant remained consistent in both patients with primary resistance to endocrine therapy and those with visceral metastases, which consisted of 25% and 56% of patients, respectively. For those with primary resistance, median PFS was 15.3 months in the abemaciclib group and 7.9 months in the control arm (HR, 0.454; 95% CI, 0.306-0.674). The median PFS in the visceral disease group was 14.7 and 6.5 months, respectively (HR, 0.481; 95% CI, 0.369-0.627).

The monotherapy approval for abemaciclib was based on findings from the phase II MONARCH1 trial. This trial enrolled 132 patients with HR+/HER2- metastatic breast cancer who progressed during or after endocrine therapy and chemotherapy. 90% of patients overall had visceral disease, and 51% had 3 or more metastatic sites. 71% percent of patients had liver metastases as well.

The investigator-assessed ORR was 19.7% (95% CI, 13.3%-27.5%),while there was a median duration of response at 8.6 months. The independently reviewed ORR was 17.4% (95% CI, 11.4%-25.0%) with a median response duration of 7.2 months.

Safety Data

The most common adverse event (AE) was diarrhea, associated with abemaciclib. 81% of patients in the MONARCH3 trial experienced this AE, of which 9% was grade 3. 86% of patients in the MONARCH2 trial&nbsp;had all-grade diarrhea and 13% had a grade 3 event, while in the MONARCH1 trial, 90% of patients had diarrhea, with a grade 3 rate of 20%.

The frequency of diarrhea was greatest in the first month of treatment with abemaciclib. 32% of patients with grade 2 to 3 diarrhea experienced this event in the first cycle of treatment, in the MONARCH2 trial. Median time to onset of diarrhea was 6 to 8 days, and the duration ranged from 6 to 11 days. For management of diarrhea in 13% to 22% of patients, a dose reduction or omission was required. 85% of diarrhea events recovered with supportive treatment overall.

Given the frequency of this event, abemaciclib comes with a loperamide kit for patients as they begin treatment. The kit is offered free, as part of the patient support program for abemaciclib, Koustenis said.

"It's important for those prescribing Verzenio to be aware of the diarrhea, so they can set expectations with patients. What we have observed with loperamide is that diarrhea event duration is fairly self-limited, and there is a low discontinuation on our trials. Only 1 patient in the single-agent trial discontinued and there was approximately a 1% discontinuation rate for diarrhea in the 2 phase III trials,"&nbsp;said Koustenis.

Neutropenia represents another AE associated with CDK4/6, which occurred in 41%, 46%, and 37% of patients in the MONARCH3, 2, and 1 trials, respectively. Neutropenia of grade &ge;3 severity was experienced by 22%, 32%, and 27%, respectively. The median time to first episode onset was 29 to 33 days and the median duration ranged from 11 to 15 days.

"We do recommend that during the first 2 months of therapy that the complete blood counts be assessed every 2 weeks, and then monthly after that, and clinically indicated thereafter," said Koustenis.