Frontline Abemaciclib Receives FDA's Priority Review for HR+/HER2- Advanced Breast Cancer


Based on data from the phase III MONARCH 3 trial, a new drug application for abemaciclib (Verzenio) has been granted a priority review by the FDA for use in combination with an aromatase inhibitor for the frontline treatment of women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer.

Levi Garraway, MD, PhD

Levi Garraway, MD, PhD

Based on data from the phase III MONARCH 3 trial, a new drug application (NDA) for abemaciclib (Verzenio) has been granted a priority review by the FDA for use in combination with an aromatase inhibitor for the frontline treatment of 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.

In the phase III study, 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.

The median progression-free survival (PFS) was not yet reached in the abemaciclib arm versus 14.7 months with the NSAI alone (HR, 0.543; 95% CI, 0.409-0.723; P = .000021). In those with measurable disease, the objective response rate (ORR) was 59.2% with the CDK4/6 inhibitor and 43.8% in the control arm (P = .004).

The FDA grants priority review designation to drugs that have the potential to provide significant improvements in the safety or effectiveness in the treatment, diagnosis, or prevention of serious conditions compared to available therapies. Under priority review, the FDA typically takes action within 6 months of receiving a supplemental application rather than the standard 10 months.

“On the heels of our recent FDA approval of Verzenio, we are pleased with this important step forward in the agency's consideration to expand the use of Verzenio in metastatic breast cancer," Levi Garraway, MD, PhD, senior vice president, global development and medical affairs, Lilly Oncology, said in a press release. "We look forward to ongoing collaboration with the FDA to advance this important treatment across the spectrum of care for patients living with advanced or metastatic breast cancer." 

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.

Across all patients in the study, the ORR was 48.2% with abemaciclib versus 34.5% with placebo (P = .002). The complete response rate with the CDK4/6 inhibitor was 1.5% versus 0% with an NSAI alone. At the time of the analysis, data were immature for overall survival. There had been 49 total deaths, with 315 required for the final assessment.

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.


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.

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