Jason M. Broderick
Verzenio (abemaciclib) was granted a priority review to a new drug application (NDA) to be used 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 drug.
As its name suggests, a priority review expedites the process by which the FDA reviews and potentially approves a drug. With a priority review, the FDA must take action within six months, compared to 10 months with standard review.
The NDA was based on data from the phase 3 MONARCH 3 trial in which the addition of Verzenio to anastrozole or letrozole reduced the risk of progression or death by 46 percent compared with the nonsteroidal aromatase inhibitor (NSAI) alone for previously untreated patients with HER2-negative, HR-positive advanced breast cancer.
In the phase 3 study, the median progression-free survival (PFS) was not yet reached in the Verzenio arm versus 14.7 months with the NSAI alone. In those with measurable disease, the objective response rate (ORR) was 59.2 percent with the CDK4/6 inhibitor and 43.8 percent in the control arm.
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 six 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, M.D., Ph.D., 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 3 MONARCH 3 trial, 493 postmenopausal women with locoregionally recurrent or metastatic breast cancer were randomized in a 2-1 ratio to continuous Verzenio at 150 mg twice daily (328 patients) or placebo (165 patients). 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 percent had measurable disease at baseline. The majority had a metastatic recurrence (55.5 percent to 60 percent), although nearly 40 percent of patients had de novo metastatic disease. Approximately 54 percent of patients had visceral disease and nearly 22 percent 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 percent with Verzenio versus 34.5 percent with placebo. The complete response rate with the CDK4/6 inhibitor was 1.5 percent versus 0 percent 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 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 less than 36 months (42 patients in Verzenio arm versus 32 in the placebo group) had a median PFS that was not reached with Verzenio versus nine months with placebo. Those with a TFI 36 or more months (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 adverse event (AE) 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 grade 1/2 in both arms. With Verzenio there was no grade 4 diarrhea and grade 3 diarrhea occurred in 9.5 percent 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 percent of those treated with Verzenio versus 1.9 percent in the control arm. Only one patient developed febrile neutropenia in the Verzenio arm.
Other common AEs with Verzenio versus placebo, respectively, included fatigue (40.1 percent vs 31.7 percent), nausea (38.5 percent vs 19.9 percent), abdominal pain (29.1 percent vs 11.8 percent), anemia (28.4 percent vs 5.0 percent), vomiting (28.4 percent vs 11.8 percent), alopecia (26.6 percent vs 10.6 percent), decreased appetite (24.5 percent vs 9.3 percent) and leukopenia (20.8 percent vs 2.5 percent). Additionally, grade 2 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 AE versus 14.9 percent of those in the control arm. There were significantly more deaths from AEs in the Verzenio arm (2.4 percent) versus placebo group (1.2 percent). Deaths in the investigational arm were attributed to lung infection (three patients), embolism (two patients) cerebral ischemia (one patient), pneumonitis (one patient) and respiratory failure (one patient). 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 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.