Clinically Meaningful Progression-Free Survival Benefit With Ribociclib and Fulvestrant in Advanced HR-Positive Breast Cancer

In recent years, cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors have become standard of care in combination with endocrine therapy for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). Ribociclib is a CDK 4/6 inhibitor that has recently been approved, in combination with an aromatase inhibitor, for first-line treatment of HR-positive/HER2-negative ABC.

At the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, Dennis Slamon, MD, PhD (UCLA Medical Center, Santa Monica, California, United States), presented results from the phase III MONALEESA-3 trial, which compared ribociclib and the estrogen receptor antagonist fulvestrant to fulvestrant plus placebo in postmenopausal women with HR-positive, HER2-negative ABC. Patients (N = 726) enrolled in the study could be previously untreated or have received up to one prior line of endocrine therapy for advanced disease.

The combination of ribociclib and fulvestrant resulted in significant improvement in progression-free survival (PFS) compared to fulvestrant alone (20.5 months vs 12.8 months; HR 0.593, P = .000000041) by investigator’s assessment. The benefit of ribociclib treatment was consistent across prespecified patient subgroups. In patients who had received no prior endocrine therapy, the median PFS was not reached with ribociclib plus fulvestrant, compared to 18.3 months with fulvestrant and placebo (HR 0.577). Patients who had received prior endocrine therapy had a median PFS of 14.6 months on ribociclib plus fulvestrant versus 9.1 months on placebo plus fulvestrant (HR 0.565). Ribociclib plus fulvestrant resulted in an improved overall response rate (ORR) in both the total patient population (32.4% vs 21.5%; P = .02) and in patients with measurable disease (40.9% vs 28.7%; P = .015). Overall survival data were not yet mature at the time of analysis.

Ribociclib plus fulvestrant was associated with a higher rate of adverse events (AEs) than placebo plus fulvestrant. These were primarily managed with dose reductions and dose interruptions. The safety profile was consistent with previous studies of ribociclib in that it comprised mostly of mild grade 1 and 2 AEs. The most common grade 3/4 AEs in patients receiving ribociclib were hematologic, including neutropenia (53.4%) and leukopenia (14.1%).

Dr Slamon concluded that ribociclib plus fulvestrant may be a new first- or second-line treatment option for postmenopausal women with HR-positive, HER2-negative ABC. In her discussion, Angie DeMichele, MD (Abramson Cancer Center, Philadelphia, Pennsylvania, United States), commented that this study, among many others, supports the role of CDK 4/6 inhibitors in combination with endocrine therapy in ABC. However, many unanswered questions remain, including when to best integrate CDK4/6 inhibitors into the treatment algorithm and what impact these agents may have on survival in the advanced setting. Future studies should evaluate potential predictive biomarkers of response, mechanisms of resistance to CDK 4/6 inhibitors, strategies beyond progression, and the role of these agents in HER2-positive and early breast cancer.

For more details on this trial and other trials on targeted therapy breast cancer presented at the 2018 ASCO meeting, please see the prIME Oncology Clinical Spotlight on Breast Cancer and Virtual Poster Session in Breast Cancer.

J Clin Oncol. 2018;36(suppl): Abstract 1000.