Oncologists have a new pharmacologic option for the treatment of women with advanced or metastatic breast cancer, in whom survival is much lower than for those with earlier stage disease. The drug, ribociclib, has been approved by the FDA as a first-line treatment in combination with an aromatase inhibitor for postmenopausal women with hormone receptor–positive, HER2-negative advanced or metastatic disease. Ribociclib is a cyclin-dependent kinase (CDK)4/6 inhibitor.
This approval was based in part on the findings of the international, randomized, phase 3 MONALEESA-2 trial, which met its primary end point of an improvement in progression-free survival (PFS) in patients randomized to ribociclib plus letrozole compared with letrozole alone at a preplanned interim efficacy analysis.
The estimated median PFS had not been reached in the ribociclib arm, and was 14.7 months in the placebo arm (hazard ratio [HR], 0.556; P <.0001). The objective response rate (ORR) in patients with measurable disease was 52.7% in the ribociclib plus letrozole arm versus 37.1% in the placebo plus letrozole arm.
At a subsequent analysis with an additional 11 months of follow-up, a median PFS of 25.3 months was achieved in patients assigned to ribociclib plus letrozole versus 16.0 months for letrozole alone. Overall survival data are not yet mature and will be available at a later date.
The combination of ribociclib plus letrozole was associated with improved results across all patient subgroups regardless of age, disease burden, or tumor location. In a subgroup of patients aged ≥65 years (median age, 71 years), median PFS was not reached in the ribociclib plus letrozole arm compared with 18.4 months in the placebo plus letrozole arm (HR, 0.608). The ORR in this subanalysis was 37% among patients assigned to ribociclib plus letrozole versus 31% in those randomized to placebo plus letrozole.
Ribociclib is also being assessed through the MONALEESA clinical trial program. These trials are evaluating ribociclib in multiple endocrine therapy combinations across a broad range of patients, including men and premenopausal women.
Other CDK4/6 inhibitors currently being assessed are the FDA-approved agent palbociclib and the investigational agent abemaciclib. Aside from MONALEESA-2, additional clinical trials that support the use of CDK4/6 inhibitors include PALOMA-1 and PALOMA-2 (palbociclib plus letrozole), PALOMA-3 (palbociclib plus fulvestrant), and MONARCH-1 (abemaciclib monotherapy).
The various CDK4/6 inhibitors “should not be assumed to be exactly the same—clinically, pharmacodynamically, or kinetically,” said William J. Gradishar, MD, FACP, Professor of Medicine, Division of Hematology and Medical Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, at the National Comprehensive Cancer Network (NCCN) 22nd Annual Conference, held in Orlando, FL. “We believe these drugs are not identical, either in terms of efficacy or side effects. We should learn more about their distinguishing features as we see more data from the pivotal trials.”
Biomarker development is essential to help determine which patients stand to benefit from CDK4/6 inhibition, said Dr Gradishar.
The latest NCCN guidelines for the management of advanced breast cancer include the regimens of palbociclib plus letrozole and palbociclib plus fulvestrant as options for endocrine therapy for postmenopausal women for recurrent or stage IV disease (category 1).
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