Final Overall Survival Analysis of MONALEESA-2: Addition of Ribociclib to Letrozole in Postmenopausal Women With HR-Positive, HER2-Negative Advanced Breast Cancer

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As reported in The New England Journal of Medicine by Gabriel N. Hortobagyi, MD, and colleagues, the protocol-specified final overall survival analysis of the phase III MONALEESA-2 trial has shown a significant benefit with the addition of ribociclib to letrozole in the first-line treatment of postmenopausal women with hormone receptor (HR)-positive, HER2-negative advanced breast cancer.

Gabriel N. Hortobagyi, MD

Gabriel N. Hortobagyi, MD

Study Details

The double-blind trial included 668 patients from sites in 29 countries with recurrent or metastatic disease who had not received previous systemic therapy for advanced disease. Patients were randomly assigned between January 2014 and March 2015 to receive ribociclib at 600 mg once daily (n = 334) or placebo (n = 344) for 21 days on/7 days off in 28-day cycles, plus letrozole continuously at 2.5 mg once daily.

Random assignment was stratified according to the presence or absence of liver or lung metastases. Crossover between treatment groups was not permitted until completion of the final overall survival analysis. Overall survival, a key secondary endpoint, was analyzed when a total of 400 deaths had occurred.

Overall Survival

A previous report of updated progression-free survival results showed maintained superiority after the primary analysis, with median durations of 25.3 months in the ribociclib group vs 16.0 months in the control group (hazard ratio [HR] = 0.57, 95% confidence interval [CI] = 0.46–0.70, P < .001).

At data cutoff (June 2021), with a median follow-up of 80 months (6.6 years; minimum of 75 months), death had occurred in 181 patients (54.2%) in the ribociclib group vs 219 patients (65.6%) in the control group. Median overall survival was 63.9 months (95% CI = 52.4–71.0 months) in the ribociclib group vs 51.4 months (95% CI = 47.2–59.7 months) in the control group (HR = 0.76, 95% CI = 0.63–0.93, P = .008). Estimated rates at 48, 60, and 72 months were 60.9% vs 55.2%, 52.3% vs 43.9%, and 44.2% vs 32.0%, respectively.

In exploratory stratification subgroup analysis, hazard ratios were: 0.81 (95% CI = 0.54–1.24) among 131 patients with liver inolvement and 0.77 (95% CI = 0.62–0.97) among 537 patients without liver involvement; and 0.81 (95% CI = 0.61–1.09) among 302 patients with lung involvement and 0.72 (95% CI = 0.55–0.94) among 366 patients without lung involvement. Hazard ratios were 0.52 (95% CI = 0.36–0.74) among 227 patients with de novo metastatic disease and 0.91 (95% CI = 0.72–1.15) among 441 without de novo metastatic disease.

Subsequent Therapy and Additional Outcomes


  • Overall survival was significantly improved with the addition of ribociclib to letrozole.
  • Median overall survival was 63.9 months vs 51.4 months.

Subsequent antineoplastic therapy was received by 87.8% of 304 patients in the ribociclib group vs 90.2% of 317 patients in the control group who discontinued trial therapy. Endocrine therapy alone was received by 32.9% vs 29.0% of patients as the first subsequent therapy. Chemotherapy alone or in combination was the first subsequent therapy in 28.0% vs 29.7% of patients.

Subsequent use of CDK4/6 inhibitors (palbociclib, abemaciclib, and ribociclib) in any line of therapy occurred in 21.7% vs 34.4% of patients. A model accounting for subsequent use of CDK4/6 inhibitors showed an estimated median overall survival of 50.5 months (95% CI = 45.0–55.4 months) in the control group.

The median time to first subsequent chemotherapy was 50.6 months vs 38.9 months (HR =0.74, 95% CI = 0.61–0.91). Chemotherapy use or death before chemotherapy occurred in 229 patients (68.6%) vs 258 patients (77.2%), with a median chemotherapy-free survival of 39.9 months vs 30.1 months (HR = 0.74, 95% CI = 0.62–0.89). No new safety signals were observed.    

The investigators concluded, “First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo.”

Dr. Hortobagyi, of the Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Novartis. For full disclosures of the study authors, visit

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