Copenhagen, Denmark—The addition of the selective cyclin-dependent kinase (CDK) 4/6 inhibitor ribociclib to letrozole (Femara) significantly improved progression-free survival (PFS) in patients with hormone receptor (HR)-positive advanced breast cancer. Compared with letrozole alone, the combination of ribociclib plus letrozole improved PFS by 44%.
These results of the phase 3 MONALEESA-2 clinical trial were presented at the 2016 European Society for Medical Oncology Congress, and were simultaneously published online (Hortobagyi GN, et al. N Engl J Med. 2016 Oct 8. Epub ahead of print).
“The combination of ribociclib plus letrozole achieved a significant and clinically meaningful increase in progression-free survival, with a consistent treatment benefit observed across all subgroups and for other secondary end points. Ribociclib was well-tolerated. This combination represents an important advance for patients with metastatic, HR-positive breast cancer,” said lead investigator Gabriel N. Hortobagyi, MD, FACP, Department of Breast Medical Oncology, M.D. Anderson Cancer Center, Houston.
Hormone therapy is the cornerstone of treatment for HR-positive, primary and metastatic breast cancer, but resistance is inevitable.
“Cyclin-dependent kinase inhibitors [such as ribociclib] are a promising development to overcome resistance to hormonal therapy,” Dr Hortobagyi said, adding that the availability of selective CDK4/6 inhibitors (ie, ribociclib and palbociclib [Ibrance]) has jump-started research in this setting.
The MONALEESA-2 clinical trial enrolled 668 postmenopausal women with HR-positive, HER2-negative, advanced, untreated breast cancer. Women were randomized to ribociclib 600 mg daily (3 weeks on, 1 week off) plus letrozole 2.5 mg daily (given continuously), or to letrozole plus placebo.
At a preplanned interim analysis, the study met its primary end point of PFS. After 18 months, the PFS rate was 63% in the ribociclib plus letrozole group compared with 42.2% in the letrozole plus placebo group; a significant 44% improvement favoring ribociclib plus letrozole. The median PFS had not yet been reached in the active combination arm at the time of data cut-off versus 14.7 months in the placebo arm.
The objective response rate was 53% with ribociclib plus letrozole versus 37% with letrozole and placebo. The clinical benefit was 80% with ribociclib plus letrozole versus 72% with letrozole plus placebo.
When PFS was analyzed across the subgroups, the use of ribociclib plus letrozole was significantly superior to letrozole plus placebo in every subgroup.
Both treatments were well-tolerated. Serious adverse events were reported in 21 patients who received ribociclib plus letrozole, and in 39 patients who received letrozole plus placebo. The addition of ribociclib to letrozole increased the frequency of myelosuppression, neutropenia, and anemia.
Neutropenia of any grade was reported in 74.3% of patients who received ribociclib plus letrozole versus 5.2% of patients who received letrozole plus placebo, but the rate of febrile neutropenia was only 1.5% versus none, respectively. Nausea, vomiting, diarrhea, alopecia, rash, and elevations in transaminase levels were also reported more frequently in the active combination arm than in the placebo arm, but they were primarily grade 1 or 2.
Ribociclib plus other types of hormone therapies are being studied in 2 ongoing phase 3 studies, including the MONALEESA-3 clinical trial (ribociclib plus fulvestrant vs placebo plus fulvestrant as first- or second-line therapy for patients with advanced breast cancer), and the MONALEESA-7 clinical trial (ribociclib and tamoxifen plus goserelin vs goserelin plus an aromatase inhibitor in patients with premenopausal and perimenopausal advanced breast cancer).
“The million-dollar question is whether this study, along with PALOMA-2, will change practice. Both trials are precedent-setting, showing the greatest magnitude of benefit seen in advanced breast cancer. We still need biomarkers for patient selection to identify those most likely to benefit, but we are working hard in this area,” Dr Hortobagyi said.
“In my view, this is a practice-changing study. When ribociclib is approved, this drug will be one of the major choices for advanced breast cancer,” he stated.
Rabociclib received a breakthrough therapy designation by the FDA in August 2016 for advanced breast cancer based on results from the MONALEESA-2 clinical trial.
