Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017-09-01
MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy.
Abstract
Purpose MONARCH 2 ( ClinicalTrials.gov identifier: NCT02107703) compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, plus fulvestrant with fulvestrant alone in patients with advanced breast cancer (ABC). Patients and Methods MONARCH 2 was a global, double-blind, phase III study of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), ≤ 12 months from the end of adjuvant ET, or while receiving first-line ET for metastatic disease. Patients were randomly assigned 2:1 to receive abemaciclib or placebo (150 mg twice daily) on a continuous schedule and fulvestrant (500 mg, per label). The primary end point was investigator-assessed progression-free survival (PFS), and key secondary end points included overall survival, objective response rate (ORR), duration of response, clinical benefit rate, quality of life, and safety. Results Between August 2014 and December 2015, 669 patients were randomly assigned to receive abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223). Abemaciclib plus fulvestrant significantly extended PFS versus fulvestrant alone (median, 16.4 v 9.3 months; hazard ratio, 0.553; 95% CI, 0.449 to 0.681; P < .001). In patients with measurable disease, abemaciclib plus fulvestrant achieved an ORR of 48.1% (95% CI, 42.6% to 53.6%) compared with 21.3% (95% CI, 15.1% to 27.6%) in the control arm. The most common adverse events in the abemaciclib versus placebo arms were diarrhea (86.4% v 24.7%), neutropenia (46.0% v 4.0%), nausea (45.1% v 22.9%), and fatigue (39.9% v 26.9%). Conclusions Abemaciclib at 150 mg twice daily plus fulvestrant was effective, significantly improving PFS and ORR and demonstrating a tolerable safety profile in women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who progressed while receiving ET.
Related Questions
How far can you dose reduce abemaciclib for a patient who is having toxicity at starting doses?
I think this is an extremely important question with broad applicability to drug dosing in general, and particularly in the elderly who not uncommonly are both less tolerant and less forgiving of side effects. If drug efficacy is truly maintained over a range of dosing and not just dose related rela...
Mindful of the coming approval of abemaciclib, how would you decide between a CDK 4/6 inhibitor in either the first or second-line setting in HR-positive, HER2-negative postmenopausal metastatic breast CA?
Side effect profile is generally a good starting point since there is no head to head comparison (not will there likely be). Abemaciclib does have a higher incidence of diarrhea but also a lower incidence of neutropenia. It also has the advantage of daily dosing which can be less confusing for pati...
Would you use sequential CDK 4/6 inhibitors in HR-positive metastatic breast CA in successive lines of therapy?
There is no preclinical or clinical data to support this approach at this time. I would not use sequential therapy in the absence of data. Several studies are ongoing to evaluate whether continued suppression of this pathway in the face of disease progression benefits patients. Until those studies h...