Abemaciclib/Fulvestrant Improves Survival in HR+ Advanced Breast Cancer

The addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to fulvestrant (Faslodex) led to a median 9.4-month overall survival benefit compared with fulvestrant with placebo in patients with hormone receptor–positive, HER2-negative advanced breast cancer who progressed on prior endocrine therapy.

George W. Sledge Jr, MD

The addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to fulvestrant (Faslodex) led to a median 9.4-month overall survival (OS) benefit compared with fulvestrant with placebo in patients with hormone receptor (HR)—positive, HER2-negative advanced breast cancer who progressed on prior endocrine therapy, according to results of the phase III MONARCH 2 trial that were presented at the 2019 ESMO Congress.1,2

At a median follow-up of 47.7 months, the median OS with the combination of abemaciclib and fulvestrant was 46.7 months compared with 37.3 months for placebo/fulvestrant (HR, 0.757; 95% CI, 0.606-0.945; P = .0137).

“The addition of abemaciclib to fulvestrant provided a statistically significant OS improvement in patients with HR-positive, HER2-negative breast cancer who had progressed on prior endocrine therapy,” said lead study investigator George W. Sledge Jr, MD, in a press conference during the meeting. “This OS benefit is consistent across subgroups, including patients with poor prognostic factors such as visceral metastasis and primary endocrine therapy resistance. Abemaciclib significantly delayed the receipt of subsequent chemotherapy in a subsequent analysis."

The FDA approved abemaciclib in combination with fulvestrant in this patient population in September 2017, based off of progression-free survival (PFS) data from the phase III MONARCH 2 study. The earlier findings showed that adding abemaciclib to fulvestrant led to a 45% reduction in the risk of disease progression or death compared with fulvestrant alone.3

In the MONARCH 2 trial, investigators randomized 669 pre/peri or postmenopausal patients with HR­-positive, HER2-negative advanced breast cancer resistant to endocrine therapy in a 2:1 ratio to receive abemaciclib plus fulvestrant (n = 446) or placebo/fulvestrant (n = 223). Abemaciclib was administered at 150 mg twice daily on a continuous schedule and fulvestrant was given at 500 mg twice daily continuously. Enrollment occurred between August 7, 2014, and December 29, 2015.

To be eligible for enrollment on MONARCH 2, patients must have relapsed on neoadjuvant endocrine therapy on or within 1 year of endocrine treatment in the adjuvant setting, or have progressed on frontline endocrine therapy for their advanced breast cancer. No prior chemotherapy for advanced disease was permitted, and patients could not have received ≥1 line of endocrine treatment. All patients had an ECOG performance status of ≤1.

The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint and time to chemotherapy (TTC) was evaluated as an exploratory analysis. Patients were stratified by site of metastasis and either primary or secondary endocrine therapy resistance. The data cut-off date was June 20, 2019.

At the median 47.7-month follow-up, 17% of patients on abemaciclib remain on treatment compared with 4% of those on placebo. The OS benefit was consistent across subgroups, including in patients with poor prognostic factors such as visceral metastasis (HR, 0.675; 95% CI, 0.511-0.891) and primary endocrine therapy resistance (HR, 0.686; 95% CI, 0.451-1.043).

Sledge, professor of medicine (oncology) at Stanford University Medical Center, also provided updated findings on PFS, with 297 events occurring on the abemaciclib arm versus 193 events on placebo. The median PFS with abemaciclib/fulvestrant and placebo/fulvestrant was 16.9 months and 9.3 months, respectively (HR, 0.536; 95% CI, 0.445-0.645; P <.0001). Moreover, the 3-year PFS rates were 29.9% and 10.1% with abemaciclib/fulvestrant and placebo/fulvestrant, respectively.

The time to second disease progression was also improved with the addition of abemaciclib at a median 23.1 months versus 20.6 months with fulvestrant/placebo (HR, 0.675; 95% CI, 0.558-0.816). Abemaciclib/fulvestrant also showed a statistically significant improvement in median chemotherapy-free survival compared with fulvestrant/placebo at 25.5 months and 18.2 months, respectively (HR, 0.638; 95% CI, 0.527-0.773).

In the exploratory TTC analysis, abemaciclib/fulvestrant also led to a 60% delay in TTC. The median TTC was 50.2 months compared with 22.1 months in the abemaciclib/fulvestrant and placebo/fulvestrant arms, respectively (HR, 0.625; 95% CI, 0.501-0.779; P <.0001).

Regarding safety, Sledge noted that the tolerability and associated adverse events (AEs) with abemaciclib was consistent with those previously reported in clinical trials.

Common hematologic grade ≥3 AEs in those who received abemaciclib included neutropenia (29.9%), anemia (9.1%), and leukopenia (11.1%). There were no new cases of febrile neutropenia that were reported relative to the primary analysis (n = 6). The most frequent nonhematologic AE reported was diarrhea (14.5%); most cases of this AE occurred during the

first 4 weeks of abemaciclib initiation and were effectively managed using loperamide or dose adjustments. A total 1.4% of patients discontinued treatment due to diarrhea.

Within a subset of patients who were on MONARCH 2 ≥1 year (abemaciclib, n = 240 vs placebo, n = 89), new any-grade treatment-emergent diarrhea events that appeared after ≥1 year of therapy were reported in 28.3% and 11.2% of patients who received abemaciclib/fulvestrant and placebo/fulvestrant, respectively.

Follow-up will continue in MONARCH 2 to further characterize the OS benefit with the treatment and exploratory efficacy endpoints, Sledge concluded.

Nadia Harbeck, MD, PhD, head of the Breast Center, Ludwig Maximilians University, provided perspective on these data during the press conference.

“Fifty months to chemotherapy—this is a game changer in metastatic breast cancer. The MONARCH 2 trial shows, for the first time, a significant OS advantage in a purely second-line cohort of pre- and postmenopausal patients,” explained Harbeck. “It's the first time we see OS data for abemaciclib, which is 1 of the 3 CDK4/6 inhibitors, and the delta of 10 months is really clinically meaningful. Also, [the fact that for] 46 months, patients live with their metastatic disease in the second-line [setting] with abemaciclib [is meaningful].”

Abemaciclib is also approved by the FDA for use as a single agent for patients with metastatic HR-positive/HER2-negative breast cancer who have previously received endocrine therapy and chemotherapy. The CDK4/6 inhibitor is also indicated for use in combination with an aromatase inhibitor for the frontline treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.


  1. Sledge Jr GW, Toi M, Neven P, et al. MONARCH 2: overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2 advanced breast cancer. Presented at: 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA6_PR.
  2. Sledge Jr GW, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor—positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial [published online ahead of print September 29, 2019]. JAMA Oncol. doi:10.1001/jamaoncol.2019.4782.
  3. 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(15 suppl; abstr 1000). doi: 10.1200/JCO.2017.73.7585.

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