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MONALEESA-3 demonstrates that ribociclib plus fulvestrant is an effective and safe first- and second-line treatment option for postmenopausal women with hormone-receptor positive, HER2-negative advanced breast cancer

Data from the MONALEESA-3 study presented at ASCO 2018 indicate that ribociclib plus fulvestrant is a new first- and second-line treatment option for postmenopausal women with hormone receptor (HR) positive, HER2-negative advanced breast cancer. In this study, the addition of ribociclib to fulvestrant resulted in a 40% reduction in the risk of disease progression or death. This progression free survival (PFS) benefit of ribociclib-fulvestrant over placebo-fulvestrant was seen in patients who received the therapy upfront (HR: 0.577) and in patients who were treated in the second-line setting (HR: 0.565). The safety profile of ribociclib in this trial was consistent with previous reports and was manageable. As such, MONALEESA-3 is the first study to show that the combination of a CDK4/6 inhibitor and fulvestrant is effective in patients with de novo advanced breast cancer and in patients who relapsed within 12 months after prior endocrine therapy.

CDK4 and 6 protein kinases play a crucial role in controlling cell cycle progression by binding to specific regulatory subunits, known as D-type cyclins. The resulting active cyclin-D-CDK4/6 complexes initiate hyperphosphorylation of the retinoblastoma protein (Rb). This hyperphosphorylation of Rb results in the inactivation of Rb, which allows the cell to progress from the G1 to the S phase in the cell cycle. In the previously reported MONALEESA-2 and MONALEESA-7 trials, the addition of the CDK4/6 inhibitor ribociclib to endocrine therapy significantly improved the PFS compared to placebo and endocrine therapy in pre-, peri- and postmenopausal women with HR-positive, HER2-negative advanced breast cancer. The combination of a CDK4/6 inhibitor and fulvestrant previously demonstrated efficacy in patients with HR-positive breast cancer who progressed on prior endocrine therapy, but to date there were no data on the use of such a combination in de novo HR-positive/HER2-negative advanced breast cancer, or in women who progressed within 12 months after prior endocrine therapy.

MONALEESA-3 is a phase III, randomised, double-blind, placebo-controlled study of ribociclib + fulvestrant in postmenopausal patients with HR-positive, HER2−negative advanced breast cancer who received no or up to 1 line of prior endocrine therapy for their advanced disease. Patients were randomized in a 2:1 fashion to receive ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus fulvestrant (500 mg) or placebo + fulvestrant. The primary endpoint of the study was investigator-assessed PFS, while secondary objectives included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety.

In total, 726 patients were enrolled in the trial and at the time of the analysis (median follow-up 20.4 months), 42.1% of patients in the ribociclib arm were still on treatment as compared to 31.4% in the control arm. MONALEESA-3 met its primary endpoint by demonstrating a median PFS of 20.5 months in the ribociclib-treated patients as compared to 12.8 months in the control arm (HR[95%CI]: 0.593[0.480-0.732]; p< 0.0001). This PFS benefit in favour of the ribociclib treatment was consistently seen in all investigated subgroups, irrespective of age, race, the number of metastatic sites, prior tamoxifen or aromatase inhibitor use and the presence of bone, liver or lung lesions. An analysis of the PFS in function of prior endocrine therapy use showed that the ribociclib + fulvestrant was associated with a statistically significant longer PFS than placebo + fulvestrant both in patients who receive the treatment in first-line (median not reached versus 18.3 months; HR[95%CI]: 0.577[0.415-0.802]) and in patients who received it in the second line setting (including early relapsers after endocrine therapy) (median 14.6 versus 9.1 months; HR[95%CI]: 0.565[0.428-0.744]). In patients with measurable disease at baseline, the ORR was 41% with the ribociclib treatment versus 29% in the control arm (p=0.003) (CBR: 69% versus 60%; p=0.015). At the time of the analysis, OS data were not yet mature.

The most common adverse event with the ribociclib-fulvestrant combination was neutropenia, which occurred in 69.6% of patients (versus 2.1% in the control arm). This neutropenia reached grade 3 or 4 severity in 46.6% and 6.8% of patients, respectively. Other common adverse events with the ribociclib regimen were nausea (45.3% versus 28.2%), fatigue (31.5% versus 33.2%), diarrhoea (29.0% versus 20.3%), leukopenia (28.4% versus 1.7%), vomiting (26.7% versus 12.9%) and arthralgia (24.0% versus 26.6%). However, these adverse events were mainly mild and rarely reached grade 3 or 4 in severity.

In summary, compared to placebo + fulvestrant, ribociclib + fulvestrant significantly prolongs the PFS of postmenopausal women with de novo HR-positive, HER2-negative advanced breast cancer and in patients who relapsed within 12 months after prior endocrine therapy. The combination also demonstrated a manageable safety profile.



D. Slamon, et al. Ribociclib (RIB) + fulvestrant (FUL) in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC): Results from MONALEESA-3. Presented at ASCO 2018; Abstract 1000.

Speaker Dennis Slamon


Prof. Dennis J. Slamon, MD, UCLA Medical Center, Santa Monica, CA, USA


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