MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer

Abstract

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

Management of Adverse Events Due to Cyclin-Dependent Kinase 4/6 Inhibitors

“…Neutropenia has been identified as the class side effect of CDK4/6 inhibitors by AE assessment within the PALOMA, MONALEESA, and MONARCH clinical trials [1-5]. Even though grade 3 and grade 4 neutropenia were very common in these trials, the rate of febrile neutropenia did not exceed 2% (Table 6).…”

Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer: Redrawing the Lines

“…Subsequent phase iii trials in the first-line setting for postmenopausal patients were developed with palbociclib (paloma-2), ribociclib (monaleesa-2), and abemaciclib (monarch 3), as described in Table i [14][15][16][17][18][19] . Those trials excluded patients who had received prior therapy for advanced disease, but did not exclude patients who had been exposed to prior neoadjuvant or adjuvant treatment, including prior endocrine treatment, provided that the disease-free interval after exposure to a nonsteroidal ai was more than 12 months.…”

Profile of abemaciclib and its potential in the treatment of breast cancer

“…MONARCH 3 was a phase III, randomized, double-blind study that randomized previously untreated women with HR+ AMBC to receive a nonsteroidal AI with either abemaciclib or placebo 34. Prior endocrine therapy in the neoadjuvant or adjuvant setting was permitted if the patient had a disease-free interval of >12 months from its completion.…”