MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2− Metastatic Breast Cancer

Abstract

Purpose The phase 2 MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor positive (HR+), HER2− metastatic breast cancer (MBC). Experimental Design MONARCH 1 was a phase 2 single arm open-label study. Women with HR+/HER2− MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS) and overall survival (OS). Results Patients (n=132) had a median of 3 (range 1–8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites. At the 12 month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI: 13.3, 27.5; 15% not excluded); clinical benefit rate (CR+PR+SD≥6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%). Conclusion In this poor-prognosis, heavily pre-treated population with refractory HR+/HER2- metastatic breast cancer, continuous dosing of single agent abemaciciclib was well tolerated and exhibited promising clinical activity.

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

“…This increase in SCr due to abemaciclib results from the inhibition of a molecular pump that transports creatinine from the blood to the urine. It occurs within the first 28-day cycle of abemaciclib, remains elevated but stable throughout the treatment period, and is reversible upon treatment discontinuation [12, 13]. Renal function (glomerular filtration rate [GFR]) is not affected by abemaciclib treatment, as are other measures of GFR that do not rely on SCr (such as cystatin C-calculated GFR) [14].…”

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

“…The orr was 19.7%, the clinical benefit rate was 42.4%, the median pfs was 6.0 months, and the median os was 17.7 months. The most common adverse events of any grade were diarrhea, fatigue, and nausea 45 .…”

Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer

“…This trial included ER+/HER2-ABC patients who had previ- Trial ID (NCT00721409) [27] (NCT01740427) [28] (NCT01942135) [29][30][31] (NCT02549430) [33] (NCT01958021) [36,37] (NCT02102490) [39] (NCT02107703) [40] Trial phase Echavarria/Jerez/Martin/López-Tarruella Breast Care 2017;12:296-302 300 ously received 1 or 2 lines of ET (only 1 for ABC). The primary endpoint was the clinical benefit rate, which was similar for both arms (54 and 60% in the combination and monotherapy groups, respectively).…”

“…The MONARCH-1 [39] phase II trial of single-agent abemaciclib included ER+/HER2-ABC women who had progressed on or after ET and had received no more than 3 lines of chemotherapy for advanced disease. The primary endpoint was the overall response rate (ORR).…”