Abemaciclib, an oral CDK4/6 inhibitor, was the focus of several presentations at the 2017 American Society for Clinical Oncology Annual Meeting held in Chicago, Illinois.

The presentations demonstrated that abemaciclib provides clinical benefit for women with advanced or metastatic hormone-receptor positive (HR+)/HER2-negative breast cancer who progress on or are resistant to endocrine therapy.

Findings from the phase 3 MONARCH 2 study (ClinicalTrials.gov Identifier: NCT02107703) were presented on June 3 (and simultaneously published in the Journal of Clinical Oncology) by George W. Sledge, Jr, MD, chief of the division of oncology in the department of medicine at Stanford University in Stanford, California.1,2

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The study demonstrated that adding abemaciclib to fulvestrant produced improvements in progression-free survival (PFS) and objective responses in women with HR+/HER2-negative advanced or metastatic breast cancer who progressed on prior endocrine therapy in the adjuvant or metastatic setting.

This is an important group of women who are underserved by current therapy, according to Dr Sledge: “if we look at women who have metastatic disease and who go on to die of breast cancer, the majority have estrogen-sensitive disease. While these patients can respond to 1 or more hormonal therapies for metastatic disease, the disease eventually progresses and claims their lives.

MONARCH 2 was a double-blind study that randomly assigned 669 women 2:1 to receive 200 mg twice-daily oral abemaciclib (later reduced to 150 mg twice daily) plus fulvestrant (500 mg as labeled) or placebo plus fulvestrant.

Women who had received chemotherapy in the metastatic setting were not eligible.

Patients were stratified by metastatic site and whether they had primary or secondary resistance to endocrine therapy. The primary endpoint was PFS; a key secondary efficacy endpoint was objective response rate (ORR).

At baseline, 82% of women were postmenopausal, 56% had visceral metastases, 72% had measurable disease, and 25% had primary endocrine therapy resistance.

Median PFS with combined therapy was 16.4 months vs 9.3 months with fulvestrant monotherapy (hazard ratio, 0.553; 95% CI: 0.449-0.681; P < .0000001). Among patients with measurable disease at baseline, those in the combination therapy group had nearly double the ORR as those in the monotherapy group: 48.1% (including 3.5% complete responses) vs 21.3%, with no complete responses, respectively.

Benefit was seen across all patient subgroups. The clinical benefit rate, which is defined as complete and partial responses plus stable disease of at least 6 months’ duration, was about 70%, according to Dr Sledge. “There was an approximately 7-month improvement in PFS, and more than doubling of the ORR,” he said.

“For a fulvestrant-treated population in the metastatic setting, this is a very good result. The response rate seen in the patients with measurable disease is the highest response rate seen on a hormonal therapy in patients who had endocrine-resistant therapy.”

Consistent with earlier abemaciclib studies, diarrhea was a frequent adverse event, occurring in 86.4% of patients vs 24.7% in the placebo group. Other adverse events occurring more often with abemaciclib than placebo were neutropenia (46% vs 4.0%), nausea (45.1% vs 22.9%), and fatigue (39.9% vs 26.9%).

Although Dr Sledge noted that all members of the class of CDK4/6 inhibitors can cause neutropenia and neutropenic fever, “the rate with abemaciclib is lower than that seen with the others; for whatever reason, it has a somewhat less profound effect on the bone marrow than the others.”

Yet diarrhea is more of a concern with abemaciclib than with the others, Dr Sledge added. This concern led researchers to reduce the twice daily abemaciclib dose from 200 mg to 150 mg early in trial enrollment, which “markedly reduced the rate of diarrhea.”

Dr Sledge noted that abemaciclib-related diarrhea is “something that occurs early. Typically, if it is going to happen it happens during the first cycle, within the first month of therapy. It responds well to standard antidiarrheal medications and holding abemaciclib until diarrhea subsides. It’s certainly what oncologists would consider manageable diarrhea, but it is an additional side effect.”

In a poster presentation, Sara M. Tolaney, MD, MPH, of the Dana-Farber Cancer Institute in Boston, Massachusetts, detailed a small study (ClinicalTrials.gov Identifier: NCT02308020) for patients with HR+/HER2-negative brain-metastatic breast cancer, which found that abemaciclib produced confirmed partial responses (PRs) in intracranial tumors in 2 patients.3

The primary objective of the study was the objective intracranial response rate, which was defined using Response Assessment in Neuro-Oncology Brain Metastases response criteria.4