For patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, combination therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor and endocrine therapy (ET) is standard first-line therapy for both postmenopausal and premenopausal patients based on substantial improvement of progression-free survival (PFS) in randomized phase III trials. However, significant improvement in overall survival (OS) with this combination has not been demonstrated thus far. Despite the fact that young, premenopausal patients have more aggressive disease and poorer prognosis compared to older postmenopausal patients, they are often underrepresented in clinical trials. Phase III MONALEESA-7 trial evaluated the safety and efficacy of the CDK4/6 inhibitor ribociclib in combination with ET and ovarian suppression in premenopausal patients with HR-positive, HER2-negative advanced breast cancer. Initial results from this trial showed an impressive improvement of more than 10 months in median PFS with ribociclib plus ET compared to ET alone (HR 0.55, P<.0001). At the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, Sara Hurvitz, MD (University of California, Los Angeles, California, United States), presented data on the key secondary endpoint of OS from this trial (Abstract LBA1008). These results were also simultaneously published in The New England Journal of Medicine.
At a median follow-up of 34.6 months, combination ribociclib and ET resulted in a significant improvement in overall survival (OS) compared to ET alone, corresponding to a 29% reduction in the risk of death (not reached vs 40.9 months; HR 0.712, P = .00973). The estimated 42-month OS rate was 70.2% in patients receiving ribociclib plus ET, compared to 46.0% in patients receiving ET plus placebo. The OS benefit with ribociclib in patients who received aromatase inhibitors was similar to that in the overall population. In addition, a subgroup analysis demonstrated consistent benefit across most patient subgroups. Patients receiving ribociclib plus ET had a longer time to subsequent chemotherapy than those receiving ET plus placebo (not reached vs 36.9 months; HR 0.596). Furthermore, the time to second progression (PFS2) was prolonged in patients receiving ribociclib (not reached vs 32.3 months; HR 0.692). The median treatment duration was approximately 2 years in patients receiving ribociclib compared to 1 year in those receiving ET alone. The adverse event (AE) profile was consistent with the known safety profile of ribociclib. Grade 3/4 adverse events of special interest associated with ribociclib included neutropenia (63.5% vs 4.5%), hepatobiliary toxicity (11% vs 6.8%), and prolonged QT interval (1.8% vs 1.2%).
In her conclusion, Dr Hurvitz highlighted the role of this trial, conducted exclusively in premenopausal patients, in confirming the importance of adding CDK4/6 inhibitors to ET to ensure best patient outcomes. Additionally, this is the first study to demonstrate a significant improvement in survival with a CDK4/6 inhibitor in combination with ET in patients with HR-positive, HER2-negative advanced breast cancer. The discussant of this abstract, Angelo Di Leo, MD, PhD (Istituto Toscani Tumori, Prato, Italy), agreed that these data represent a major advance in breast cancer treatment, particularly for endocrine naïve patients, who were 60% of the population of the MONALEESA-7 trial.
For more information on these data and findings from other trials in HR-positive, HER2-negative metastatic breast cancer, see this conference data review from 2019 ASCO Annual Meeting.