Updated Results of MONALEESA-2 Trial Maintain Benefit of Ribociclib in HR+/HER2- Breast Cancer

Gabriel N. Hortobagyi, MD

Updated results from the phase III MONALEESA-2 trial presented during the 2017 ASCO Annual Meeting confirmed the benefit of frontline ribociclib (Kisqali) in combination with letrozole in patients with postmenopausal hormone receptor (HR)-positive, HER2-negative advanced breast cancer. The combination showed a progression-free survival (PFS) benefit of 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<.001). The 24-month PFS rate was 54.7% with ribociclib versus 35.9% for placebo.

"This new look at the MONALEESA-2 data, after an additional year of follow-up, demonstrates the continued efficacy of ribociclib plus letrozole," lead investigator Gabriel N. Hortobagyi, MD, Professor of Medicine, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, said in a statement. "With more than 2 years of follow-up, the PFS data confirm the inclusion of ribociclib plus an aromatase inhibitor as a strong option among first-line treatments for HR-positive, HER2-negative advanced breast cancer."

In the phase III trial, 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 (ORR) 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%).

The FDA approved the combination of ribociclib and an aromatase inhibitor for patients with HR+/HER2-negative metastatic breast cancer in March 2017, based on findings from the MONALEESA-2 study. Additional phase III trials are looking at ribociclib with other endocrine therapies, including fulvestrant (MONALEESA-3) and tamoxifen, anastrozole, and goserelin (MONALEESA-7). Additionally, studies are planned to explore ribociclib in the adjuvant setting (EarLEE-1 and EarLEE-2).

Reference:

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).