FDA Approves Frontline Verzenio for Advanced HR-Positive, HER2-Negative Breast Cancer

The Food and Drug Administration (FDA) has approved a targeted drug, Verzenio (abemaciclib), for use in combination with a hormonal therapy for initial treatment of postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer, according to the drug’s manufacturer, Eli Lilly and Company.

Verzenio is an inhibitor of the proteins CDK4 and 6, which help drive this type of cancer. The hormonal therapy it is paired with is known as an aromatase inhibitor, which stops the body from producing estrogen.

The approval was based on data from the phase 3 MONARCH 3 trial, in which the addition of Verzenio to aromatase inhibitors Arimidex (anastrozole) or Femara (letrozole) reduced the risk of disease progression or death by 46 percent compared with a nonsteroidal aromatase inhibitor (NSAI) alone for previously untreated patients with HER2-negative, HR-positive advanced breast cancer.

In the study, the median progression-free survival (PFS) was 28.2 months in the Verzenio arm versus 14.8 months with the NSAI alone. In those with measurable disease, the objective response rate (ORR) was 55.4 percent with the CDK4/6 inhibitor and 40.2 percent 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-positive, HER2-negative 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," said Joyce O'Shaughnessy, M.D., Celebrating Women Chair in Breast Cancer Research and chair of Breast Cancer Research Program at Baylor University Medical Center, TexasOncology and US Oncology.

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

In the trial, 493 postmenopausal women with locoregionally recurrent or metastatic breast cancer were randomized in a two-to-one ratio to continuous Verzenio at 150 mg twice daily (n = 328) or placebo (n = 165). All patients also received either 1 mg of Arimidex or 2.5 mg of Femara once daily. Patients had not received prior systemic therapy for metastatic disease, although post-surgical 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 percent had measurable disease at baseline. The majority had a metastatic recurrence (55.5 to 60 percent), although nearly 40 percent of patients had disease that was metastatic at diagnosis. Approximately 54 percent of patients had visceral disease and nearly 22 percent had bone-only disease. Nearly half of patients had received a prior pre- or post-surgical endocrine therapy.

The ORR among patients with measurable disease receiving Verzenio comprised a complete response rate of 3.4 percent (9/267) and a partial response rate of 52.1 percent (139/267). The 40.2 percent ORR in the control arm consisted of all partial responses. The median duration of response was 27.4 months for the Verzenio arm compared with 17.5 months in the control arm.

Median PFS consistently favored the Verzenio 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 more than 36 months (42 patients in Verzenio arm versus 32 in the placebo group) had a median PFS that was not reached during the study’s follow-up period with Verzenio, versus nine months with placebo. Those with a TFI 36 months or less (94 in the Verzenio arm versus 40 in the placebo group) did not experience additional benefit with the addition of the CDK4/6 inhibitor.

Additionally, the PFS increase with Verzenio was not statistically significant in those with bone-only disease, and in those without bone-only disease, there was a larger benefit with Verzenio. A benefit for Verzenio was seen for those with and without liver metastases, although it was more dramatic for patients with visceral metastases.

The most common side effect associated with Verzenio was diarrhea, which occurred in 81.3 percent of patients treated with the CDK4/6 inhibitor versus 29.8 percent of those in the control arm. These events were primarily mild or moderate in both arms. With Verzenio, there was no severe diarrhea, and serious diarrhea occurred in 9.5 percent of patients.

In addition to diarrhea, neutropenia (a low white blood cell count) was common; it is a known side effect associated with CDK4/6 inhibition. This was seen in 41.3 percent of those treated with Verzenio versus 1.9 percent in the control arm. Only one patient developed a fever with neutropenia in the Verzenio arm.

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

Overall, 27.5 percent of patients in the Verzenio arm experienced a serious side effect versus 14.9 percent of those in the control arm. There were significantly more deaths from side effects in the Verzenio arm (2.4 percent) versus placebo group (1.2 percent). Deaths in the investigational arm were attributed to lung infection (n = 3), embolism (n = 2), inadequate blood supply to the brain (n = 1), lung inflammation (n =1) and respiratory failure (n = 1). Additionally, venous thromboembolic events occurred in 4.9 percent of patients treated with Verzenio versus 0.6 percent with placebo.

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