Washington, DC—Abemaciclib, a cyclin-dependent kinase (CDK)4/6 inhibitor, achieved an objective response in 1 of 5 heavily pretreated patients with metastatic hormone receptor–positive/HER2-negative (HR+/HER2–) breast cancer, according to the results of a phase 2 trial reported at the 2017 meeting of the American Association for Cancer Research. Responses to single-agent abemaciclib were durable, lasting for a median of approximately 9 months, and clinical benefit (ie, response plus stable disease) was achieved in >40% of patients.
These promising results of the phase 2 MONARCH-1 trial of single-agent abemaciclib have led to 2 phase 3 trials of this drug in combination with a hormonal drug in patients with HR+/HER2– breast cancer.
“Abemaciclib demonstrated single-agent activity in heavily pretreated patients with metastatic HR+/HER2– breast cancer. Few patients discontinued treatment due to adverse events,” said lead investigator Hope S. Rugo, MD, Director, Breast Oncology Clinical Trials Program, University of California San Francisco Helen Diller Family Comprehensive Cancer Center.
Two other CDK4/6 inhibitors are already approved by the FDA for the treatment of breast cancer—palbociclib and ribociclib in combination with an aromatase inhibitor.
Abemaciclib was given a “breakthrough therapy” designation by the FDA. Dr Rugo said that abemaciclib is distinct from its competitors because it is 14 times more potent against CDK4 than CDK6, it has single-agent activity, neutropenia is not a dose-limiting toxicity, and it can be continuously administered.
MONARCH-1 enrolled 132 women with HR+/HER2– breast cancer previously treated for metastatic disease with ≥2 previous chemotherapy regimens, 1 being taxane-based. Median age of participants was 58 years, with an upper age limit of 89 years. Approximately 50% of patients had ≥3 sites of metastatic disease. The median number of previous systemic regimens was 5 for all settings, and 3 for metastatic disease (including endocrine therapy).
Before the study entry, 67% of patients had received treatment with fulvestrant, and 37% with everolimus. Ninety-one percent had 2 previous lines of chemotherapy for metastatic disease (69% received taxane, and 55% capecitabine).
The overall response rate was 19.7%, and all of them were partial responses (these results were previously presented at the 2016 American Society of Clinical Oncology annual meeting). Clinical benefit (response plus stable disease) was 42.4%. Median duration of response was 8.9 months.
Subgroup analysis showed that overall response rate and clinical benefit were comparable regardless of the number of previous therapies, number of endocrine therapies, previous fulvestrant use, previous capecitabine use, and previous anthracycline use.
In earlier studies of patients with metastatic HR+/HER2– breast cancer treated with chemotherapy (ie, capecitabine, ixabepilone, or eribulin), overall response rates ranged from 11% to 25%, progression-free survival was 3 to 4 months, and overall survival was approximately 1 year. In MONARCH-1, single-agent abemaciclib demonstrated a median progression-free survival of 6 months and median overall survival of 22.3 months.
The most common adverse event of all grades was diarrhea. Grade 3 diarrhea was reported in 20% of patients, and grade 2 in 29% of patients. Serum creatinine was increased in all patients, but Dr Rugo emphasized that this had no impact on renal function according to assessment of glomerular filtration rate with cystatin C.
Dose reductions of abemaciclib were used in 49% of patients, most frequently because of diarrhea or neutropenia. Serious adverse events were reported in 25% of patients, and 10 patients (7.6%) discontinued therapy because of serious adverse events.
Ongoing phase 3 trials include MONARCH-2 (abemaciclib plus fulvestrant in endocrine pretreated HR+/HER2– breast cancer) and MONARCH-3 (abemaciclib plus nonsteroidal aromatase inhibitor as first-line treatment for metastatic HER+/HER2– breast cancer).