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The European Commission has approved the CDK 4/6 inhibitor ribociclib for use in combination with an aromatase inhibitor for the frontline treatment of postmenopausal women with hormone-receptor (HR)–positive, HER2-negative locally advanced or metastatic breast cancer.
Wolfgang Janni, MD, PhD
The European Commission (EC) has approved the CDK 4/6 inhibitor ribociclib (Kisqali) for use in combination with an aromatase inhibitor for the frontline treatment of postmenopausal women with hormone-receptor (HR)—positive, HER2-negative locally advanced or metastatic breast cancer.
The approval, which follows a positive recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use, is based on the phase III MONALEESA-2 trial, in which frontline treatment with ribociclib plus letrozole improved progression-free survival (PFS) by 9.3 months compared with letrozole plus placebo.
After a median follow-up of 26.4 months, the median PFS was 16.0 months (95% CI, 13.4-18.2) with letrozole plus placebo compared with 25.3 months (95% CI, 23.0-30.3) for ribociclib and letrozole, representing a 43% reduction in the risk of progression or death with the addition of the CDK4/6 inhibitor (HR, 0.568; 95% CI, 0.457-0.704; P <.0001). The 24-month PFS rate was 54.7% with ribociclib versus 35.9% for placebo.
The frontline ribociclib approval is applicable to all 28 European Union member states plus Iceland, Norway, and Liechtenstein.
“Advanced breast cancer remains incurable, so it’s important to start with a powerful treatment option at initial diagnosis,” MONALEESA-2 investigator Wolfgang Janni, MD, PhD, University of Ulm, said in a statement. “I am encouraged that women in Europe living with HR+/HER2- advanced breast cancer may be treated in first-line with ribociclib in combination with letrozole, which demonstrated strong progression-free survival of more than two years in the pivotal MONALEESA-2 trial.”
In the phase III study, 668 postmenopausal women with advanced breast cancer were randomized to letrozole plus ribociclib (n = 334) or placebo (n = 334). Letrozole was administered at 2.5 mg per day along and ribociclib was given at 600 mg per day for 3 weeks followed by 1 week off.
The benefits of ribociclib were consistent across patient subgroups for PFS. For those in the United States, the median PFS was 27.6 months with the ribociclib combination versus 15 months with placebo (HR, 0.527; 95% CI, 0.351-0.793). The reduction in the risk of progression or death with ribociclib versus placebo was also consistent for those with ECOG performance status 0 (42% reduction) and 1 (46% reduction) and for those above 65 years of age (34%) and those below 65 years (48%).
The objective response rate with ribociclib was 42.5% versus 28.7% with placebo. The response to ribociclib included a complete response (CR) rate of 3.9% and a partial response (PR) rate of 38.6%. In the placebo arm, 2.4% and 26.3% had a CR and PR, respectively. Overall, 26.9% and 32% of patients had stable disease in the ribociclib and placebo arms, respectively.
At the time of the analysis in January 2017, overall survival (OS) data remained immature. Based on 15% of events in the CDK4/6 inhibitor arm and 19.8% in the placebo group, there was an early 25% reduction in the risk of death observed with ribociclib, which was not statistically significant (HR, 0.746; 95% CI, 0.517-1.078; P = .059). The 24-month OS rate was 86.7% with ribociclib and 84.8% with placebo.
After 26.4 months of follow-up, 39.2% of patients continued to receive treatment with ribociclib and 26.3% continued in the placebo group. The most common cause for treatment discontinuation was disease progression (39.8% with ribociclib versus 60.8% with placebo). Adverse events (AEs) resulted in discontinuation for 8.1% of those in the ribociclib arm versus 2.4% of those in the placebo group.
The most common AEs with ribociclib versus placebo, respectively, were neutropenia (64.1% vs 4.8%), nausea (53.3% vs 30.6%), fatigue (41.3% vs 32.4%), diarrhea (38.3% vs 24.5%), alopecia (34.4% vs 16.1%), and vomiting (33.5% vs 16.7%). The most common grade 3/4 AEs were decreased neutrophils (62.6% vs 1.5%), decreased leukocytes (36.8% vs 1.5%), decreased lymphocytes (16.2% vs 3.9%), and elevated alanine aminotransferase (11.4% vs 1.2%).
In the United States, the FDA approved the frontline combination of ribociclib and an aromatase inhibitor for patients with HR+/HER2-negative advanced breast cancer in March 2017, also based on findings from the MONALEESA-2 study.
Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2—), advanced breast cancer (ABC). J Clin Oncol. 2017;35 (suppl; abstr 1038).