Adding abemaciclib to fulvestrant significantly improved progression-free survival (PFS) compared with placebo plus fulvestrant in women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer enrolled in the phase 3 MONARCH 2 trial.1 The findings from this trial were released at the 2017 meeting of the American Society of Clinical Oncology.
With the results from MONARCH 2, abemaciclib is positioned to become the third inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) to come to the market for the treatment of women with advanced breast cancer. (The US Food and Drug Administration [FDA] granted breakthrough designation for abemaciclib for refractory metastatic breast cancer based on its activity as monotherapy observed in early trials.)
Pairing hormone therapy with cell cyclin inhibitors that target CDK4/6 was first employed successfully with palbociclib, which was approved by the FDA in 2015 as first-line therapy when combined with letrozole, and later with any aromatase inhibitor, based on results from the phase 2 PALOMA-1 trial.2 Following PALOMA-2 and PALOMA-3, the FDA approved palbociclib as second-line therapy in combination with an aromatase inhibitor or fulvestrant.
The randomized phase 3 MONARCH 2 trial compared abemaciclib 150 mg twice daily (as continuous dosing) plus fulvestrant 500 mg, as either first-line or second-line treatment, versus placebo plus fulvestrant in 669 women with advanced HR-positive, HER2-negative breast cancer. Abemaciclib was initially dosed at 200 mg twice daily but the dose was amended after enrollment of the first 178 patients, because of discontinuations over diarrhea-related toxicity. Perimenopausal women in this trial were also administered a gonadotropin-releasing hormone agonist.
Women enrolled in MONARCH 2 had progressed while receiving neoadjuvant or adjuvant endocrine therapy, within 12 months from the end of adjuvant endocrine therapy, or during first-line endocrine therapy for metastatic disease. Those who were administered chemotherapy or >1 endocrine therapy in the metastatic setting were excluded from the trial.
Overall, 82% of patients in MONARCH 2 were postmenopausal, 72% had measurable disease, 56% had visceral disease, and 25% had primary endocrine therapy resistance. Approximately 60% of patients had received chemotherapy in the adjuvant or neoadjuvant setting.
At a median follow-up of 19.5 months, the combination of abemaciclib plus fulvestrant significantly improved PFS from 9.3 months to 16.4 months (hazard ratio, 0.553; P <.0000001). The overall response rate (ORR) was also significantly superior with this regimen compared with placebo plus fulvestrant (35.2% vs 16.1%; P <.001). Among patients with measurable disease, the ORR increased from 23.1% to 48.1% with abemaciclib. At the time of the presentation, overall survival data were not mature.
“This response rate is, to the best of our knowledge, the highest reported in an endocrine-resistant population,” said lead investigator George W. Sledge Jr, MD, Professor of Medicine, Chief of the Division of Oncology, Stanford University Medical Center, California. “Of note, based upon these data, the combination of abemaciclib with endocrine therapy will be tested as adjuvant therapy for HR-positive, HER2-negative high-risk breast cancer beginning later this year.”
The median duration of response in the control group was 25.6 months; it has not yet been reached in the abemaciclib plus fulvestrant arm.
The most common all-grade, treatment-related adverse event associated with the use of abemaciclib plus fulvestrant versus fulvestrant alone was diarrhea (86.4% vs 24.7%). Grade 3/4 diarrhea occurred in 13.4% versus 0.4% of patients, respectively. “Diarrhea occurred early, typically in the first cycle of therapy, and both the intensity and frequency of diarrhea were strongly related to the starting dose,” said Dr Sledge. Discontinuation decreased from 24% before the abemaciclib dose reduction to 13% after the dose reduction. Diarrhea was manageable in most patients with the use of antidiarrheal medication.
Other adverse events that were more frequently observed in the abemaciclib plus fulvestrant arm were neutropenia (46.0% vs 4.0%), nausea (45.1% vs 22.9%), and fatigue (39.9% vs 26.9%). Aside from diarrhea, grade 3/4 toxicities of note in this trial included neutropenia (26.5% vs 1.7%), leukopenia (8.8% vs 0%), and anemia (7.2% vs 0.9%).
1. 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. Presented at the American Society of Clinical Oncology Annual Meeting; June 2-6, 2017; Chicago, IL. Abstract 1000.
2. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25-35.