Inhibitors of cyclin-dependent kinase 4/6 (CDK4/6) have become an important part of the treatment plan for patients with advanced, hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. One such agent, abemaciclib, recently demonstrated significantly improved efficacy in combination with fulvestrant (compared with placebo), and a tolerable safety profile, in the phase III MONARCH 2 trial of patients with advanced HR-positive, HER2-negative breast cancer whose disease had progressed on prior endocrine therapy.
At the second Presidential Symposium at the 2017 European Society for Medical Oncology (ESMO) annual congress, Angelo DiLeo, MD, PhD (Istituto Toscano Tumori, Prato, Italy), presented interim results from the randomized, placebo-controlled phase III MONARCH 3 trial, which is comparing abemaciclib plus aromatase inhibitor (either anastrozole or letrozole) to placebo plus aromatase inhibitor as initial treatment for postmenopausal patients with advanced, HR-positive, HER2-negative breast cancer (N = 493) (Presentation 236O_PR). The primary endpoint of the study is investigator-assessed progression-free survival (PFS). At a median follow-up of 17.8 months, abemaciclib significantly improved median PFS compared to placebo (not reached vs 14.7 months; HR 0.543, P = .000021).
The PFS benefit of abemaciclib was consistent across most prespecified patient subgroups, including patients with liver metastases. Patients with a treatment-free interval of three or more years appeared to not benefit from the addition of abemaciclib, though Dr DiLeo cautioned that this was an exploratory analysis looking at relatively small numbers of patients. The objective response rate (ORR) was significantly improved with abemaciclib, both in the entire treatment population (48.2% vs 34.5%; P = .002) and in patients with measurable disease at baseline (n = 397; 59.2% vs 43.8%; P = .004). Overall survival (OS) results are not yet mature and thus, were not reported.
Abemaciclib was associated with a higher rate of adverse events (AEs) and more severe AEs than placebo. Serious AEs occurred in 27.5% of patients treated with abemaciclib, compared with 14.9% of patients in the placebo group. The most common grade 3/4 treatment-related AEs in patients treated with abemaciclib included neutropenia, anemia, leukopenia, diarrhea, and laboratory abnormalities. One patient in the abemaciclib arm experienced nonserious febrile neutropenia and eight patients in the abemaciclib arm died due to AEs.
In his discussion of these results, Nicholas Turner, MA, MRCP, PhD (The Royal Marsden NHS Foundation Trust, London, United Kingdom), commented on the consistent efficacy and safety of CDK4/6 inhibitors in breast cancer, and indicated that abemaciclib will most likely join other agents of this class as treatment options for first-line HR-positive, HER2-negative advanced breast cancer. Moving forward, Dr Turner suggested it will be important to identify patients who can be treated with endocrine therapy alone versus those who should receive a first-line CDK4/6 inhibitor.