Ribociclib Plus Fulvestrant Offers Improved PFS in Advanced Breast Cancer

The combination of the CDK4/6 inhibitor ribociclib and fulvestrant yielded an improvement in progression-free survival (PFS) compared with placebo plus fulvestrant in postmenopausal women with advanced breast cancer, according to the phase III MONALEESA-3 trial (abstract 1000) presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.

The MONALEESA-2 and MONALEESA-7 trials showed that adding ribociclib to endocrine therapy improves PFS compared with placebo and endocrine therapy, but no previous studies have examined de novo hormone receptor (HR)-positive/HER2-negative advanced breast cancer, or in those who relapsed more than 12 months after prior endocrine therapy, said Dennis J. Slamon, MD, PhD, of UCLA Medical Center. “MONALEESA-3 was designed to investigate this population in large part.”

The study included 726 postmenopausal women with HR-positive/HER2-negative advanced breast cancer, randomized 2:1 to receive either ribociclib plus fulvestrant (484 patients) or placebo plus fulvestrant (242 patients).

Patients either had de novo advanced/metastatic disease, with no prior exposure to endocrine therapy, or had relapsed more than 12 months since completion of adjuvant or neoadjuvant endocrine therapy. The median age in both groups was 63 years, most patients were white, and approximately half of the cohort had received prior endocrine therapy.

The median PFS was 20.5 months with ribociclib, compared with 12.8 months with placebo, for a hazard ratio of 0.593 (95% CI, 0.480–0.732; P = .00000041). This benefit was seen across a variety of subgroups, including those who had and had not received prior endocrine therapy, those with liver or lung metastases, those older or younger than 65 years, and others.

The response rate in the full cohort was 32.4% with ribociclib, compared with 21.5% with placebo (P = .000912). Restricted to patients with measurable disease, those rates were 40.9% and 28.7%, respectively (P = .003). The overall survival data were immature at the time of data cutoff; there were 70 deaths in the ribociclib group (14.5%), and 50 deaths in the placebo group (20.7%).

More patients in the ribociclib group required a dose reduction (37.9% vs 4.1%) or a dose interruption (75.4% vs 43.6%). Slamon said the safety of the combination was manageable, with toxicities similar to those seen in previously published trials.

“Patients receiving this combination had a statistically significant and clinically meaningful improvement in PFS,” he concluded. “This represents a new first- or second-line treatment option for postmenopausal women with HR-positive/HER2-negative advanced breast cancer.”

Angela DeMichele, MD, of the University of Pennsylvania in Philadelphia, was the discussant for the session. “I think the future of CDK inhibitors is bright,” she said, adding that the results of MONALEESA-3 are very consistent with previous data. Outstanding questions for these agents include the best way to integrate them into a therapeutic plan, which tumors are biologically most likely to respond, and what next steps should be upon progression of disease.