Frontline Abemaciclib Granted FDA Approval for HR+/HER2- Breast Cancer

Joyce O'Shaughnessy, MD

Joyce O'Shaughnessy, MD

Based on data from the phase III MONARCH 3 trial, abemaciclib has been granted FDA approval 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, according to Eli Lilly and Company, the manufacturer of the CDK4/6 inhibitor.

Results of the trial showed 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&nbsp;Medical&nbsp;Center, TexasOncology and US Oncology,&nbsp;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 &ge;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.

Reference:

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.