Combining Norvartis‘ CDK4/6 inhibitor ribociclib with Femara (letrozole) may be a promising first-line therapy for hormone receptor (HR)-positive breast cancer patients, according to recent data from a Phase 3 clinical trial.
The results, recently presented at the European Society for Medical Oncology (ESMO) 2016 Congress, Oct. 7-11, in Copenhagen, show that the combination induced a 44 percent improvement in progression-free survival, compared to Femara alone.
“This was the definitive study to demonstrate the superiority of the combination of ribociclib and letrozole over letrozole alone,” principle investigator, professor Gabriel Hortobagyi, of the University of Texas MD Anderson Cancer Center in Houston, said in a press release.
The results are part of the first interim analysis of the randomized, double-blind MONALEESA2 study (NCT01958021), that enrolled 668 postmenopausal women with HR-positive, HER-negative advanced breast cancer who had not received any prior systemic treatment or undergone surgery. Participants were randomized to receive ribociclib (600 mg/day; 3 weeks on/1 week off) in combination with Femara once a day, or a placebo plus Femara.
Results revealed that the study met its primary endpoint, with ribociclib inducing a 44 percent improvement in progression-free survival compared to placebo. Median progression-free survival was 14.7 months in the placebo arm, and had not been reached in the ribociclib arm by the end of the study.
“The results of this trial represent a compelling proof of principle, and suggest a paradigm shift in metastatic, HR+ breast cancer. They also suggest that testing combinations of ribociclib with other inhibitors of various signaling pathways might lead to additional progress in the management of several subtypes of breast cancer,” said Hortobagyi.
Researchers also found, in patients with measurable disease at baseline, that the ribociclib arm showed significantly higher objective response rates, compared to the placebo arm (53% versus 37%). Clinical benefit rate was also higher in the ribociclib group (80% vs. 72%).
The impact of ribociclib therapy in overall survival could not be assessed due to the low number of deaths in the study.
“I believe the results of this study are significant because now we have a new CDK4/6 inhibitor for patients with estrogen-receptor positive metastatic breast cancer, in addition to palbociclib and abemaciclib,” said professor Giuseppe Curigliano, director of the New Drugs and Early Drug Development for Innovative Therapies Division at the European Institute of Oncology, in Milan, Italy. Palbociclib, marketed as Ibrance, has already been approved by the U.S. Food and Drug Administration for metastatic breast cancer. Abemaciclib is currently under development.
Although less than five percent of patients exhibited serious adverse effects in both arms, some adverse events increased in the ribociclib arm compared to the placebo arm. The effects included neutropenia (59% vs. 1%), leukopenia (21% vs. 1%), and lymphopenia (7% vs. 1%) — all of which refer to low numbers of particular types of blood cells.
“The addition of ribociclib to letrozole does increase the rate of toxicity, but overall, if we evaluate the magnitude of clinical benefit, there is definitely a benefit to be gained from adding ribociclib,” said Curigliano, adding that further studies are required to identify cancer biomarkers that help predict which patients are likely to benefit from the ribociclib, Femara combination.
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