December 2016 VOL 7, NO 11

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ESMO 2016

Potentially Practice-Changing: Ribociclib/Letrozole Combo in Advanced Breast Cancer

The addition of the selective CDK4/6 inhibitor ribociclib to letrozole significantly improved progression-free survival (PFS) in hormone receptor–positive (HR+) advanced breast cancer. Compared with letrozole alone, the combination of ribociclib/letrozole improved PFS by 44%.

These results from the phase 3 MONALEESA-2 trial were presented at the European Society for Medical Oncology 2016 Congress and published simultaneously online to coincide with this presentation (N Engl J Med. 2016. DOI: 10.1056/NEJMoa1609709).

“The combination of ribociclib plus letrozole achieved a statistically 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+ breast cancer,” stated lead author Gabriel Hortobagyi, MD, The University of Texas MD Anderson Cancer Center in Houston.

Hormonal therapy is the cornerstone of treatment for HR+ primary and metastatic breast cancer, but resistance eventually develops.

“Cyclin-dependent kinase inhibitors [such as ribociclib] are a promising development to overcome resistance to hormonal therapy,” Dr Hortobagyi told listeners, and the availability of selective CDK4/6 inhibitors (ie, ribociclib and palbociclib) has jump-started research in this setting.

MONALEESA-2 enrolled 668 postmenopausal women with HR+, HER2-negative advanced breast cancer previously untreated for advanced disease. Women were randomized to receive ribociclib (600 mg/day, 3 weeks on and 1 week off) plus letrozole (2.5 mg/day given continuously), or letrozole plus placebo.

At a planned interim analysis, the study met its primary end point of PFS. After 18 months, the PFS rate was 63% for ribociclib/letrozole versus 42.2% for letrozole alone, for a highly statistically significant 44% improvement favoring the combination (P = .00000329). At the time of data cutoff, the median PFS had not yet been reached for the combination arm and was 14.7 months for letrozole alone.

The objective response rate was 53% for ribociclib/letrozole versus 37% for letrozole alone (P = .00028). Taking response rates plus stable disease together, the rate of clinical benefit was significantly higher in the ribociclib/letrozole arm compared with letrozole alone: 80% versus 72%, respectively (P = .02).

When PFS was analyzed across subgroups, ribociclib/letrozole was significantly superior to letrozole alone in every subgroup.

Both treatments were well tolerated. Serious adverse events were reported in fewer than 5% of patients on each arm. The addition of ribociclib increased the frequency of myelosuppression, neutropenia, anemia, and thrombocytopenia.

Neutropenia of any grade was reported in 75% of patients on the combination arm versus 5.2% on the letrozole arm, but the rate of febrile neutropenia was only 1.5% versus 0%, respectively.

Other adverse events seen more frequently in the combination arm, such as nausea, vomiting, diarrhea, alopecia, rash, and transaminase elevations, were mainly grade 1/2.

Two phase 3 trials are evaluating ribociclib plus other types of hormonal therapies: MONALEESA-3 (ribociclib plus fulvestrant versus placebo plus fulvestrant as first-line or second-line therapy in advanced breast cancer); MONALEESA-7 (ribociclib plus tamoxifen plus goserelin versus goserelin plus aromatase inhibitor in premenopausal and perimenopausal advanced breast cancer).

“The million dollar question is whether this study, along with PALOMA-2 [J Clin Oncol. 2016;34(suppl). Abstract 507], 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 explained.

“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.

The MONALEESA studies are funded by Novartis. Ribociclib was granted Breakthrough Therapy Designation by the FDA in September 2016.

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