Findings of a recent multicenter randomized trial<sup> </sup>showed postmenopausal women with hormone receptor (HR)-positive metastatic breast cancer (MBC) had significant slowing of disease progression with the addition of the investigational cyclin-dependent kinase (CDK) 4/6 inhibitor ribociclib to endocrine therapy.
Gabriel N. Hortobagyi, MD
Findings of a recent multicenter randomized trial1showed postmenopausal women with hormone receptor (HR)-positive metastatic breast cancer (MBC) had significant slowing of disease progression with the addition of the investigational cyclin-dependent kinase (CDK) 4/6 inhibitor ribociclib to endocrine therapy.
The ribociclib arm had a 44% reduction in the hazard for progression or death compared with patients who received placebo in addition to hormonal therapy (HR, 0.556; 95% CI, 0.43-0.72;P= .00000329), and the difference satisfied prespecified statistical requirements for superiority.
“The treatment benefit was consistent across patient subgroups and for other secondary endpoints,” Gabriel N. Hortobagyi, MD, professor of Medicine at the University of Texas MD Anderson Cancer Center, said during a press conference announcing the results at the 2016 ESMO Congress in Copenhagen.
“Ribociclib was well tolerated. The combination of ribociclib and letrozole represents an important advance for patients with metastatic, hormone receptor-positive breast cancer.”
Results from the trial were published online simultaneously in theNew England Journal of Medicine.2
Inhibition of CDK 4/6 offers an attractive therapeutic strategy for hormone-receptor breast cancer. CDK 4 and 6, along with their protein regulator, cyclin D1, regulate cell-cycle progression. CDK4/6 overexpression and amplification of cyclin D1 gene occur frequently in HR-positive breast cancer, and increased CDK 4/6 activity, in particular, is associated with resistance to endocrine therapy, Hortobagyi explained.
The efficacy of antiCDK 4/6 therapy in advanced HR-positive breast cancer was demonstrated at the 2016 ASCO annual meeting in June. The addition of the CDK 4/6 inhibitor palbociclib to the endocrine agent fulvestrant significantly improved PFS in advanced breast cancer that had relapsed following first-line endocrine therapy.3
Hortobagyi reported findings from the MONALEESA-2 trial, a first-ever phase III study of a CDK 4/6 inhibitor and an endocrine agent as first-line therapy for advanced HR-positive breast cancer. The trial involved 668 postmenopausal women with untreated HR-positive, HER2-negative MBC.
All patients received the aromatase inhibitor letrozole at a dose of 2.5 mg/day, and investigators randomly assigned study participants evenly to ribociclib 600 mg/day (3 weeks on/1 week off) or placebo. The trial had a primary endpoint of PFS by investigator assessment. Secondary endpoints included overall survival, response rate, and safety.
The trial ended prematurely after an initial interim data analysis demonstrated a significant benefit in favor of the ribociclib arm. The analysis occurred after 243 qualifying events, including progression or death. Hortobagyi reported that 93 (27.8% of randomized patients) events occurred in the ribociclib arm compared with 150 (44.7%) in the placebo arm.
After a median follow-up of 15.3 months, the ribociclib group’s median PFS had yet to be reached, whereas the placebo group had an estimated median PFS of 14.7 months. Blinded PFS assessment by an independent review committee resulted in a hazard ratio of 0.59 in favor of the ribociclib arm (P= .002).
The 18-month PFS was 63.0% with ribociclib versus 42.2% for the placebo group. Among patients with measurable disease, the overall response rate was 52.7% with letrozole plus ribociclib and 37.1% with letrozole and placebo.
Ribociclib did add to treatment-associated toxicity, as 59.3% of patients who received the CDK 4/6 inhibitor developed grade 3/4 neutropenia, as compared with 0.9% of patients who received placebo. Grade 3/4 leukopenia occurred in 21.0% of the ribociclib arm and 0.6% of the placebo group. Hematologic adverse events were uncomplicated and resolved without incident in most cases, Hortobagyi said.
The most common nonhematologic adverse events (all grades) were nausea (51.5% with ribociclib, 28.5% with placebo), diarrhea (35.0% vs. 42.4%), fatigue (36.5% vs. 30.0%), and diarrhea (35.0% vs. 22.1%). The events were grade 1/2 severity in most cases. Rates of discontinuation were 7.5% with ribociclib and 2.1% with placebo.
Hortobagyi said the MONALEESA-2 trial and the PALOMA-3 trial involving palbociclib will have a paradigm-changing impact on management of HR-positive MBC. However, in the absence of reliable biomarkers to guide treatment decisions, the drugs’ role in disease management will continue to evolve.