Addition of Ribociclib to Letrozole Improves Survival in Women With HR-Positive, HER2-Negative Advanced Breast Cancer

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Gabriel N. Hortobagyi, MD

Gabriel N. Hortobagyi, MD

As reported in The New England Journal of Medicine by Gabriel N. Hortobagyi, MD, of the Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, 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.1

Study Details

In the double-blind trial, 668 patients from sites in 29 countries with recurrent or metastatic disease who had not received previous systemic therapy for advanced disease 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. Randomization 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).2,3

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.1 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%.


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

In an exploratory stratification subgroup analysis, hazard ratios were 0.81 (95% CI = 0.54–1.24) among 131 patients with 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 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

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 first subsequent therapy. Chemotherapy alone or in combination was 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).

Adverse Events

No new safety signals were observed, with adverse event profiles in both groups being consistent with previously reported findings. The most common grade 3 or 4 adverse event of special interest was neutropenia, occurring in 63.8% of patients in the ribociclib group and 1.2% of the control group. Other grade 3 or 4 adverse events of special interest in the ribociclib and control groups were hepatobiliary toxicity (14.4% vs 4.8%) and prolonged QT interval (4.5% vs 2.1%). Grade 3 interstitial lung disease or pneumonitis occurred in two patients (0.6%) vs no patients; no grade 4 events or deaths due to interstitial lung disease or pneumonitis occurred in the ribociclib group.

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.” 

DISCLOSURE: The study was funded by Novartis. For full disclosures of the study authors, visit Dr. Hortobagyi has served as a consultant for Novartis.


1. Hortobagyi GN, Stemmer SM, Burris HA, et al: Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med 386:942-950, 2022.

2. Hortobagyi GN, Stemmer SM, Burris HA, et al: Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375:1738-1748, 2016.

3. Hortobagyi GN, Stemmer SM, Burris HA, et al: Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 29:1541-1547, 2018.