George W. Sledge Jr, MD
In the international, double-blind phase III MONARCH 2 trial, the addition of abemaciclib led to an improvement in progression-free survival (PFS) of 7.1-months (HR, 0.553; 95% CI, 0.449-0.681; P <.0000001).1 The overall response rates (ORRs) among patients with measurable disease were 48.1% and 21.3% in the abemaciclib and control arms, respectively.
“Abemaciclib…plus fulvestrant was an effective treatment for women with HR+/HER2-negative advanced breast cancer whose disease progressed on prior endocrine therapy,” said lead study author George W. Sledge Jr, MD, professor of Medicine, Chief of the Division of Oncology, Stanford University Medical Center.
“This response rate is, to the best of our knowledge, the highest reported in an endocrine-resistant population,” added Sledge. “Based on these data, the combination of abemaciclib with endocrine therapy will be tested as adjuvant therapy for patients with HR+/HER2-negative high-risk breast cancer beginning later this year [in the phase III monarchE trial (NCT03155997)].”
In MONARCH 2, 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.
There are currently 170 patients remaining on treatment in the abemaciclib arm versus 45 in the fulvestrant-alone arm. The primary endpoint for the trial was PFS. Secondary endpoints included overall survival (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. The 48.1% ORR in the abemaciclib cohort included a complete response (CR) rate of 3.5%. There were no CRs 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 adverse events (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.
Single-agent abemaciclib has also shown promise in pretreated patients with HR+/HER2-negative breast cancer. In the phase II MONARCH 1 trial, abemaciclib induced a response rate of nearly 20%, with a median PFS of 6 months (95% CI, 4.2-7.5) and a median overall survival of 17.7 months (95% CI, 16 to not reached).2
The MONARCH 1 trial included 132 patients with HR+/HER2- metastatic breast cancer who progressed during or after endocrine therapy and chemotherapy.
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.
In April, Eli Lilly and Company, the manufacturer of abemaciclib, announced that another abemaciclib trial, MONARCH 3 (NCT02246621), had met its primary endpoint. In the study, adding abemaciclib to letrozole or anastrozole improved PFS compared with either aromatase inhibitor alone as a frontline treatment for women with HR+/HER2-negative breast cancer. The study included postmenopausal women with locoregionally recurrent or metastatic breast cancer and no prior systemic treatment for advanced disease. Lilly reported that the data from the trial will be presented at a medical conference later this year.
- Sledge GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy. J Clin Oncol 35, 2017 (suppl; abstr 1000).
- Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. J Clin Oncol 34, 2016 (suppl; abstr 510).