FDA Approves Abemaciclib for Frontline Treatment of HR+/HER2- Advanced Breast Cancer

Based on data from the phase III MONARCH 3 trial, the FDA has approved abemaciclib (Verzenio) for use in combination with an aromatase inhibitor for the frontline treatment of postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer.

Eli Lilly and Company, the manufacturer of the CDK4/6 inhibitor, reported that the addition of abemaciclib to anastrozole or letrozole reduced the risk of progression or death by 46% compared with the nonsteroidal aromatase inhibitor (NSAI) alone for previously untreated patients with HER2-negative, HR-positive advanced breast cancer.

In the phase III study, the median progression-free survival (PFS) was 28.2 months (95% CI,23.5 to not reached) in the abemaciclib arm versus 14.8 months (95% CI,11.2-19.2) with the NSAI alone (HR, 0.54; 95% CI, 0.418-0.698; P <.0001). In those with measurable disease, the objective response rate (ORR) was 55.4% with the CDK4/6 inhibitor and 40.2% in the control arm.

"This approval is an important milestone, as it shows that Verzenio plus an aromatase inhibitor substantially reduced tumor size and delayed disease progression in women with HR+, HER2- metastatic breast cancer. Notably, the MONARCH 3 trial included patients with certain concerning clinical characteristics, such as a pattern of disease that spread to the liver," Joyce O'Shaughnessy, MD, Celebrating Women Chair in Breast Cancer Research and chair, Breast Cancer Research Program, Baylor University Medical Center, TexasOncology and US Oncology, said in a statement.

"This information will help inform treatment decisions for each patient, which can be complicated in advanced breast cancer," added O'Shaughnessy.

In the phase III MONARCH 3 trial, 493 postmenopausal women with locoregionally recurrent or metastatic breast cancer were randomized in a 2:1 ratio to continuous abemaciclib at 150 mg twice daily (n = 328) or placebo (n = 165). All patients also received either 1 mg of anastrozole or 2.5 mg of letrozole once daily. Patients had not received prior system therapy for metastatic disease, although adjuvant endocrine therapy was permitted. The median follow-up was 17.8 months.

The median age of patients in both groups was 63 years, and approximately 80% had measurable disease at baseline. The majority had a metastatic recurrence (55.5% to 60%), although nearly 40% of patients had de novo metastatic disease. Approximately 54% of patients had visceral disease and nearly 22% had bone-only disease. Nearly half of patients had received a prior neoadjuvant or adjuvant endocrine therapy.

Median PFS consistently favored the abemaciclib arm across preplanned subgroups. An exploratory analysis found that treatment-free interval (TFI), bone-only disease, and liver metastasis could potentially be utilized for treatment selection.

In the small exploratory analysis, those with a TFI of <36 months (42 patients in abemaciclib arm versus 32 in the placebo group) had a median PFS that was not reached with abemaciclib versus 9.0 months with placebo (HR, 0.48; 95% CI, 0.25-0.91). Those with a TFI ≥36 months (94 in the abemaciclib arm versus 40 in the placebo group), did not experience additional benefit with the addition of the CDK4/6 inhibitor (HR, 0.83; 95% CI, 0.46-1.52).

Additionally, the PFS increase with abemaciclib was not statistically significant in those with bone-only disease (HR, 0.58; 95% CI, 0.27-1.25), and in those without bone-only disease, there was a larger benefit with abemaciclib (HR, 0.51; 95% CI, 0.38-0.70). A benefit for abemaciclib was seen for those with and without liver metastases, although it was more dramatic for patients with visceral metastases (HR, 0.47; 95% CI, 0.25-0.87).

The most common adverse event (AE) associated with abemaciclib was diarrhea, which occurred in 81.3% of patients treated with the CDK4/6 inhibitor versus 29.8% of those in the control arm. These events were primarily grade 1/2 in both arms. With abemaciclib there was no grade 4 diarrhea and grade 3 diarrhea occurred in 9.5% of patients.

In addition to diarrhea, neutropenia was also common, which is a known AE associated with CDK4/6 inhibition. This AE was seen in 41.3% of those treated with abemaciclib versus 1.9% in the control arm. Only 1 patient developed febrile neutropenia in the abemaciclib arm.

Other common AEs with abemaciclib versus placebo, respectively, included fatigue (40.1% vs 31.7%), nausea (38.5% vs 19.9%), abdominal pain (29.1% vs 11.8%), anemia (28.4% vs 5.0%), vomiting (28.4% vs 11.8%), alopecia (26.6% vs 10.6%), decreased appetite (24.5% vs 9.3%), and leukopenia (20.8% vs 2.5%). Additionally, grade 2 creatinine increase was experienced by 52.9% of those in the abemaciclib arm versus 4.5% with placebo.

Overall, 27.5% of patients in the abemaciclib arm experienced a serious AE versus 14.9% of those in the control arm. There were significantly more deaths from AEs in the abemaciclib arm (2.4%) versus placebo group (1.2%). Deaths in the investigational arm were attributed to lung infection (n = 3), embolism (n = 2), cerebral ischemia (n = 1), pneumonitis (n =1), and respiratory failure (n = 1). Additionally, venous thromboembolic events occurred in 4.9% of patients treated with abemaciclib versus 0.6% with placebo.

In September 2017, the FDA approved abemaciclib for use in combination with fulvestrant in women with HR+/HER2- advanced breast cancer with disease progression following endocrine therapy, as well as for single-agent use for patients with HR+/HER2- breast cancer with metastatic disease who have previously received endocrine therapy and chemotherapy.

Di Leo A, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer. Presented at: 2017 ESMO Congress; Madrid, Spain; September 8-12, 2017. Abstract 236O_PR.