Hart Recaps Data With Abemaciclib in HR+/HER2- Breast Cancer


Abemaciclib (Verzenio) has emerged as a promising agent for patients with hormone receptor-positive, HER2-negative metastatic breast cancer, according to Lowell L. Hart, MD.

Lowell L. Hart, MD

Lowell L. Hart, MD

Lowell L. Hart, MD

Abemaciclib (Verzenio) has emerged as a promising agent for patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer, according to Lowell L. Hart, MD.

The CDK4/6 inhibitor was approved by the FDA for the frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer in February 2018. This followed the September 2017 approval of the agent for use in combination with fulvestrant (Faslodex) in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy.

In a presentation during the 17th Annual International Congress on the Future of Breast Cancer® East, Hart, scientific director of Clinical Research at Florida Cancer Specialists & Research Institute, discussed the recent data with abemaciclib in patients with HR-positive, HER2-negative metastatic breast cancer.1

The phase III randomized, double-blind MONARCH 2 trial combined abemaciclib plus fulvestrant in women who recurred or progressed on or after endocrine therapy.

The 16-month progression-free survival (PFS) of patients who received abemaciclib plus fulvestrant was 16.4 months (95% CI, 14.4-19.3) compared with 9.3 months (95% CI, 7.4-12.7) for placebo plus fulvestrant (HR, 0.553; 95% CI, 0.449-0.681; P <.001).2

Patients with clinical characteristics such as primary resistance and visceral disease had a less favorable prognosis, and often progressed within 2 years on therapy, Hart added.

"PFS results in subgroups, including those with concerning clinical characteristics, were consistent with the intent-to-treat (ITT) population," Hart explained. "Preplanned subgroup analyses of PFS were performed for stratification factors of disease site, endocrine resistance, and other potential prognostic factors that included measurable diseases at baseline, number of organs involved, age, region, race, progesterone receptor status, and an ECOG [performance] score."

Median PFS in patients with primary resistance was 15.3 months (95% CI, 12.4-24.1) with abemaciclib plus fulvestrant compared with 7.9 months (95% CI, 5.7-11.4) with placebo plus fulvestrant (HR, 0.454; 95% CI, 0.306-0.674).3

For those with visceral disease, the median PFS was 14.7 months (95% CI, 13.0-17.4) with abemaciclib plus fulvestrant compared with 6.5 months (95% CI, 5.6-8.7) with placebo plus fulvestrant (HR, 0.481; 95% CI, 0.369-0.627).

At the time of the primary PFS analysis, the overall survival (OS) data were not mature but 20 patients had died, reported Hart. The overall response rate (ORR) was 48.1% (95% CI, 42.6-53.6) in patients who received abemaciclib plus fulvestrant and progressed on or after endocrine therapy. Of those 153 patients, 3.5% achieved a complete response (CR) and 44.7% achieved a partial response (PR). For patients who received placebo plus fulvestrant, the ORR was 21.3% (95% CI, 15.1-27.6) and all responses (n = 35) were PRs.

The median duration of response (DoR) was a secondary endpoint of the trial. The combination of abemaciclib and fulvestrant had a median DoR of 22.8 months (95% CI, 15.8-26.4) compared with 13.9 months (95% CI, 11.2-25.6) for placebo plus fulvestrant.

The MONARCH 2 results led to the September 2018 FDA approval of the agent in combination with fulvestrant in women with HR-positive, HER2-negative advanced disease with progression following endocrine therapy.

Another use for CDK4/6 inhibitors is in the frontline setting along with an aromatase inhibitor (AI), Hart said.

"In general, most of the gurus in the field that I have talked to feel that an AI and a CDK4/6 inhibitor should be your default," said Hart. "As a default, it is hard to argue with the data."

MONARCH 3 was a phase III, randomized, double-blind, placebo-controlled trial that evaluated abemaciclib plus an AI as initial endocrine-based therapy. This study included patients with HR-positive, HER2-negative locoregionally recurrent or metastatic breast cancer. The primary endpoint of this trial was PFS, with secondary endpoints of OS, ORR, and DoR.

The combination of abemaciclib and an AI showed a median PFS of 28.2 months (95% CI, 23.5-not reached [NR]) compared with 14.8 months (95% CI, 11.2-19.2) for placebo plus an AI, (HR, 0.54; 95% CI, 0.418-0.698; P <.0001).4

In a preplanned subgroup analysis, patients with concerning clinical characteristics were evaluated. The PFS in patients with liver metastases treated with abemaciclib plus an AI was 15.0 months (95% CI, 7.4-23.7) versus 7.2 months (95% CI, 2.1-14.0) for placebo plus an AI, (HR, 0.477; 95% CI, 0.272-0.837).

Additionally, patients who had a treatment-free interval of <36 months were included in this subgroup analysis after completion of adjuvant endocrine therapy. The median PFS in this group was 29.5 months (95% CI, 11.6-NR) after treatment with abemaciclib plus an AI, compared with 9.0 months (95% CI, 3.7-14.2) with placebo plus an AI (HR, 0.441; 95% CI, 0.241-0.805).

The PFS in both the postmenopausal subgroups of patients with liver metastases and treatment-free interval <36 months were consistent with the ITT population, according to Hart.

In postmenopausal patients with measurable disease, abemaciclib plus an AI had an ORR of 55.4% after initial endocrine-based therapy (95% CI, 49.5-61.4). Of the 148 patients evaluated with the combination, 9 achieved a CR (3.4%), and 139 achieved a PR (52.1%). The ORR for the placebo-controlled group was 40.2%, and all 132 patients achieved a PR. Median DoR for abemaciclib plus an AI was 27.4 months (95% CI, 25.7-NR) compared with 17.5 months (95% CI, 11.2-22.2) for placebo plus an AI.

MONARCH 1 was the phase II, single-arm trial that led to the single-agent FDA approval in HR-positive, HER2-negative metastatic breast cancer. The study included 132 patients who progressed during or after endocrine therapy and chemotherapy. Patients received 200 mg of abemaciclib orally every 12 hours on a continuous schedule until progression or unacceptable toxicity.

Per investigator assessment, ORR was 19.7% (95% CI, 13.3-27.5) with a median time to response of 3.7 months, and a median DoR of 8.6 months (95% CI, 5.8-10.2).5 An independent review showed an ORR of 17.4% (95% CI, 11.4-25) and a median DoR of 7.2 months (95% CI, 5.6-NR).


Abemaciclib is the only CDK4/6 inhibitor approved across this population in combination with fulvestrant or an AI and as a single agent, Hart noted.The majority of patients on abemaciclib will experience diarrhea, and the onset of the adverse event (AE) is quick, with a median duration of 11 days.

"The side effects are a little bit different, and those who use it are probably aware that patients are going to get some diarrhea at the start—about 80%," said Hart. "In our practice, we give them all Imodium. Every patient who is on this drug should have an antidiarrheal available."

Diarrhea is often associated with dehydration and infection, so the AE management of a patient on abemaciclib is important. Hart advised to start patients on antidiarrheal therapy at the first sign of loose stools and to increase oral fluids. Patients should notify their primary care physician for next steps, as well as follow-up, he added.

In MONARCH 2, AEs of all grade were nausea (45%), abdominal pain (35%), vomiting (26%), and stomatitis (15%). Additionally, fatigue (46%), peripheral edema (12%), and pyrexia (11%) of all grades were experienced.

Nine percent of patients had to discontinue treatment of abemaciclib due to an AE versus 3% with fulvestrant alone, and 43% of patients required a dose reduction of abemaciclib due to an AE.

Neutropenia occurred in 41% of patients in MONARCH 3 receiving abemaciclib plus an AI, 46% of patients in MONACH 2 receiving abemaciclib plus fulvestrant, and 37% of patients who received single-agent abemaciclib in MONARCH 1, Hart reported.

The management recommendation for neutropenia as a result of abemaciclib is to monitor complete blood counts prior to the start of therapy every 2 weeks for 2 months, and then monthly for the next 2 months. For patients who develop grade 3/4 AEs, dosage may be reduced, interrupted, or delayed. Additionally, patients should report fevers to their primary care physician, Hart said.

In MONARCH 3, liver function test showed grade ≥3 increases in ALT of 6% for abemaciclib and 2% for placebo. AST increase was 3% and 1% for abemaciclib and placebo, respectively. In MONARCH 2, ALT increase was 4% in the abemaciclib arm and 2% in the placebo arm, while AST increase was 2% and 3%, respectively.

AEs of all grades observed in MONARCH 3 for abemaciclib/AI versus placebo/AI were diarrhea (81% vs 30%), neutropenia (41% vs 2%), fatigue (40% vs 32%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increase (19% vs 4%), constipation (16% vs 12%), ALT increase (16% vs 7%), AST increase (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decrease (10% vs 3%), flu-like symptoms (10% vs 8%), and thrombocytopenia (10% vs 2%).

As a single agent, the most common AEs of all grades with abemaciclib as observed in MONARCH 1 are diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), leukopenia (17%), constipation (17%), arthralgia (15%), dry mouth (14%), weigh decrease (14%), stomatitis (14%), creatinine increase (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%).

"As with many of these drugs, you have to look out for CYP3A inhibitors," said Hart. "Strong CYP3A inhibitors increase the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity."

Venous thromboembolic events were reported in 5% of patients treated with abemaciclib/AI compared with 0.6% of patients treated with an AI/placebo in MONARCH 3. Additionally, abemaciclib can cause fetal harm if pregnant.

Safety information also states that a dose reduction to once daily is necessary in the case of severe hepatic impairment (Child-Pugh Class C).

"Because it is less suppressive of neutrophil count, you can take it continuously. You continuously inhibit the cell cycle progression; you’re not taking a week off," Hart explained. “In vitro studies have shown that by inhibiting that Rb [retinoblastoma] pathway, that can lead to senescence and apoptosis of cancer cell."

Hart concluded that there is good evidence that abemaciclib crosses the blood-brain barrier, although the significance of that in patients is unknown.


  1. Verzenio [package insert]. Indianapolis, Indiana. Eli Lilly and Company; 2018.
  2. Sledge GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy. J Clin Oncol. 2017;35 (suppl; abstr 1000).
  3. Data on file. Lilly USA, LLC. ONC20180103a.
  4. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638-3646. doi: 10.1200/JCO.2017.75.6155.
  5. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. J Clin Oncol. 2016;34 (suppl; abstr 510).
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