The FDA has granted a priority review to a new drug application for the CDK4/6 inhibitor abemaciclib as a treatment for patients with advanced hormone receptor–positive, HER2-negative breast cancer.
Levi Garraway, MD, PhD
The FDA has granted a priority review to a new drug application (NDA) for abemaciclib as a treatment for patients with advanced hormone receptor (HR)­­—positive, HER2-negative breast cancer, according to Eli Lilly and Company, the manufacturer of the CDK4/6 inhibitor.
Lilly’s NDA is for 2 indications. The first is as monotherapy for patients with HR+/HER2- advanced breast cancer previously treated with endocrine therapy and chemotherapy for metastatic disease. Support for this indication comes from the single-arm phase II MONARCH 1 trial, in which the median progression-free survival (PFS) in this patient population was 6 months (95% CI 4.2-7.5) and the median overall survival (OS) was 17.7 months (95% CI, 16 to not reached).1
The second indication is for abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer with disease progression following endocrine therapy. The support for this indication comes from the phase III MONARCH 2 trial, in which adding abemaciclib to fulvestrant reduced the risk of disease progression or death by 45% versus fulvestrant alone in this patient population.2
In a press release, Lilly reported that it anticipates the FDA will make its decision on the application by the first quarter of 2018.
“We are pleased that the FDA has granted abemaciclib priority review, both as a potential monotherapy and combination therapy [with fulvestrant] for patients with advanced breast cancer,” Levi Garraway, MD, PhD, senior vice president, global development and medical affairs, Lilly Oncology, said in a press release. “Breast cancer is a complex disease, and the need still exists for new treatment options as patients face a significant disease burden. We look forward to working with the FDA and bringing this important potential treatment option to patients as soon as possible.”
The MONARCH 1 trial included 132 patients with HR+/HER2- metastatic breast cancer who progressed during or after endocrine therapy and chemotherapy. The median age was 58 years (range, 36-89), 44.7% of patients had an ECOG performance status of 1, 90.2% had visceral disease, and 85.6% had at least 2 metastatic sites. Patients with CNS metastases were excluded from enrollment.
Patients had received a median of 3 (range, 1-8) prior lines of therapy—including a median of 2 lines of chemotherapy—for metastatic disease. Sixty-seven patients (50.8%) had received fulvestrant in the metastatic setting. With chemotherapy, 68.9% (n = 91) of patients had received a taxane and 55.3 % (n = 73) of patients had received capecitabine in the metastatic setting.
Abemaciclib was administered at 200 mg orally every 12 hours on a continuous schedule until progression or unacceptable toxicity. At the 8-month interim analysis, 35.6% of patients had received at least 8 cycles of the CDK4/6 inhibitor.
Objective response rate (ORR) was the primary outcome measure. Secondary endpoints included duration of response, PFS, OS, clinical benefit rate, and safety.
The investigator-assessed, confirmed ORR was 19.7% (n = 26; 95% CI, 13.3-27.5), which included all partial responses (PR). The rate of patients with stable disease (SD) ≥6 months was 22.7%, leading to a clinical benefit rate (complete response + PR + SD ≥6 months) of 42.4%. The median time to response was 3.7 months and the median duration of response was 8.6 months. Thirty-four patients had progressive disease.
The most common non-laboratory, all-grade adverse events (AEs) were diarrhea (90.2%), fatigue (65.2%), nausea (64.4%), decreased appetite (45.5%), and abdominal pain (38.6%). The grade 3 rates of these events were 19.7% for diarrhea, 12.9% for fatigue, 4.5% for nausea, 3.0% for decreased appetite, and 2.3% for abdominal pain.
Leukopenia (27.4%) and neutropenia (22.3%) were the most common laboratory AEs. The only grade 4 AE of any kind in the trial was neutropenia, which occurred in 4.6% of patients.
Serious AEs occurred in 24.2% (n = 32) of patients, with AEs leading to treatment discontinuation in 7.6% (n = 10) of patients. Dose reductions were required for 49.2% of patients (n = 65). The most common reason for dose reductions were diarrhea (20.5%) and neutropenia (10.6%). There were 2 patient deaths during treatment and 1 patient death within 30 days after study discontinuation.
In the international, double-blind phase III MONARCH 2 trial, 669 patients were randomized in a 2:1 ratio to abemaciclib plus fulvestrant (n = 446) or fulvestrant plus placebo (n = 223). Patients had progressed during neoadjuvant or adjuvant endocrine therapy, within 12 months of adjuvant endocrine therapy, or during frontline endocrine treatment for metastatic disease. Individuals were excluded from enrollment if they were administered chemotherapy or more than 1 endocrine therapy in the metastatic setting.
Patient characteristics were well-balanced between the 2 arms. Overall, 82% of patients were postmenopausal, 72% had measurable disease, 56% had visceral disease, and 25% had primary endocrine therapy resistance. About 60% of patients had received chemotherapy in the adjuvant or neoadjuvant setting.
Patients received 500 mg (per label) of fulvestrant plus placebo or 150 mg of abemaciclib twice daily. The initial abemaciclib dose was 200 mg twice daily; however, the dose was amended after the first 178 patients were enrolled, due to diarrhea-related toxicity concerns. A GnRH agonist was given to pre/perimenopausal patients. The primary endpoint for the trial was PFS. Secondary endpoints included OS, response, clinical benefit rate, and safety.
Following 379 PFS events in the intent-to-treat population, the median PFS was 16.4 months in the abemaciclib arm versus 9.3 months in the fulvestrant-alone group (HR, 0.553; 95% CI, 0.449-0.681; P <.0000001). The ORRs among patients with measurable disease were 48.1% and 21.3% in the abemaciclib and control arms, respectively.
The 48.1% ORR in the abemaciclib cohort included a complete response rate of 3.5%. There were no complete responses in the control arm. The median duration of response was 25.6 months in the placebo arm and had not yet been reached in the fulvestrant arm. The OS data are not yet mature.
The most common all-grade treatment-related AEs with the abemaciclib combination versus fulvestrant alone were diarrhea (86.4% vs 24.7%), neutropenia (46.0% vs 4.0%), nausea (45.1% vs 22.9%), and fatigue (39.9% vs 26.9%).
The most frequently reported grade 3 AEs in the abemaciclib versus fulvestrant-alone arms were neutropenia (23.6% vs 1.3%) and diarrhea (13.4% vs 0.4%). Grade 4 neutropenia occurred in 2.9% versus 0.4% of the abemaciclib and fulvestrant-alone groups, respectively. There were 3 deaths in the abemaciclib arm linked to treatment-related AEs, compared with none in the control arm.
In April, Lilly announced that another phase III abemaciclib trial, MONARCH III, met its primary endpoint, showing that adding the CDK4/6 inhibitor to letrozole or anastrozole improved PFS compared with either aromatase inhibitor alone in women with HR+/HER2- breast cancer. The company intends to present the detailed findings from the MONARCH 3 trial at a medical conference later this year.
In October 2015, the FDA granted abemaciclib a breakthrough therapy designation as a monotherapy for heavily pretreated patients with refractory HR-positive advanced breast cancer.
Lilly plans to submit applications for abemaciclib to regulatory authorities in Europe and Japan before the end of the year.