Abemaciclib Data Reviewed as New Breast Cancer Indications Added

Abemaciclib (Verzenio) has quickly amassed several clinical indications for patients with metastatic breast cancer, and is the only CDK4/6 inhibitor approved as a single-agent. These approvals were based on findings from the phase III MONARCH2 and 3 trials, as well as the phase II MONARCH1 study, which each showed improvements in progression-free survival (PFS), particularly in patients with visceral disease and endocrine therapy resistance.

Given the rapid development of this novel agent, Andrew Koustenis, who has been involved in the development of abemaciclib since the initial phase I studies, reviewed all the pertinent efficacy and safety data for abemaciclib during a lunch symposium at the 2018 Miami Breast Cancer Conference^®.

"We now have 3 indications for this compound," said Koustenis, senior research advisor, Breast Cancer Development Team, Eli Lilly and Company. "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."

The most recent approval, on February 26, 2018, 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. This new indication was based on phase III data from the MONARCH3 trial, which was initially presented at the 2017 ESMO Annual Meeting and updated with the approval.

The median age of patients in the trial was 63 years, and approximately 80% had measurable disease at baseline. Overall, 51% had received prior systemic therapy, with 39% of patients receiving prior chemotherapy. Fifty-three percent of patients had visceral disease, with 16% having liver metastases and 22% having bone-only disease.

In the study, the median PFS with abemaciclib 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, representing a 52% reduction in the risk of progression or death (HR, 0.477; 95% CI, 0.272-0.837).

In patients with measurable disease, the objective response rate (ORR) 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 duration of response was 27.4 months with abemaciclib versus 17.5 months for the comparator.

The initial approvals for abemaciclib, which were both granted in September 2017, 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 who have previously received endocrine therapy and chemotherapy.

The approval of abemaciclib and fulvestrant was based on findings from the phase III MONARCH2 trial, which 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. For this group, patients received the gonadotropin-releasing hormone agonist goserelin throughout the trial and for at least 4 weeks prior to entering the study.

The 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). The ORRs among patients with measurable disease were 48.1% and 21.3% in the abemaciclib and control arms, respectively.

The benefit of abemaciclib and fulvestrant remained consistent in 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, the 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). In the visceral disease group, the median PFS 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, which enrolled 132 patients with HR+/HER2- metastatic breast cancer who progressed during or after endocrine therapy and chemotherapy. Overall, 90% of patients had visceral disease, and 51% had 3 or more metastatic sites. Seventy-one percent of patients had liver metastases.

The investigator-assessed ORR was 19.7% (95% CI, 13.3%-27.5%), with a median duration of response of 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

Diarrhea is one of the most common adverse events (AEs) associated with abemaciclib. In the MONARCH3 trial, 81% of patients experienced this event, of which 9% was grade 3. In the MONARCH2 trial, 86% of patients had all-grade diarrhea and 13% had a grade 3 event, and in the MONARCH1 trial, 90% of patients had diarrhea, with a grade 3 rate of 20%.

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

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

"It's important for those prescribing Verzenio to be aware of the diarrhea, so they can set expectations with patients," said Koustenis. "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."

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 ≥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.

Abemaciclib was associated with other AEs of interest, including hepatotoxicity, venous thromboembolism, and embryo-fetal toxicity. Management strategies for these events are defined in the prescribing information, Koustenis noted.

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