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First-Line Treatment with Ribociclib plus Letrozole Shows a Significant Overall Survival Benefit in HR-positive, HER2-negative Advanced Breast Cancer

Findings from the final overall survival analysis in the MONALEESA-2 study
22 Mar 2022
Targeted Therapy;  Endocrine Therapy
Breast Cancer

First-line treatment with ribociclib plus letrozole showed a significant overall survival (OS) benefit as compared with placebo plus letrozole in postmenopausal patients with HR-positive, HER2-negative advanced breast cancer. Median OS was more than 12 months longer with ribociclib than with placebo in the MONALEESA-2 study. The findings from the protocol-specified final OS analysis were reported by Prof. Gabriel N. Hortobagyi of the Department of Breast Medical Oncology, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center in Houston, TX, US in the 10th March 2022 issue of The New England Journal of Medicine.

The authors wrote in the study background that the use of CDK4/6 inhibitors (ribociclib, abemaciclib, and palbociclib) improved progression-free survival (PFS) in this patient population, leading to regulatory approvals. Significant improvement in OS is one of the primary goals in the treatment of advanced breast cancer, in addition to maintaining or improving quality of life. However, evaluating OS among patients receiving first-line therapy is challenging owing to increasing survival after progression in this patient population.

To date, two studies evaluating ribociclib that included some patients receiving first-line therapy showed a significant OS benefit. Among premenopausal patients who had not received previous endocrine therapy for advanced disease but may have received up to one line of chemotherapy for advanced disease in the MONALEESA-7 study, OS was significantly longer with ribociclib plus endocrine therapy than with endocrine therapy alone. In addition, the MONALEESA-3 study showed significantly longer OS among postmenopausal patients with first- and second-line ribociclib plus fulvestrant than with fulvestrant alone. The MONARCH 3 study investigating first-line abemaciclib and the PALOMA-2 study investigating first-line palbociclib, both involving postmenopausal patients with HR-positive, HER2-negative advanced breast cancer, have yet to report final data on OS.

The MONALEESA-2 is a phase III study evaluating the efficacy and safety of ribociclib in combination with letrozole as the first-line treatment in postmenopausal patients with HR-positive, HER2-negative advanced breast cancer. In the primary and updated analyses of MONALEESA-2, PFS was significantly longer with ribociclib plus letrozole than with placebo plus letrozole (median in updated analysis, 25.3 months vs. 16.0 months; hazard ratio for disease progression or death 0.57; 95% confidence interval [CI] 0.46 to 0.70; p < 0.001). Data for OS were immature at the time of the primary and updated analyses.

Now, the study team reports findings from the protocol-specified final analysis of OS, a key secondary endpoint.

Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. OS was assessed with the use of a stratified log-rank test and summarised with the use of Kaplan–Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of PFS and OS to ensure the validity of the findings.

After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant OS benefit as compared with placebo plus letrozole. Median OS was 63.9 months (95% CI 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death 0.76; 95% CI 0.63 to 0.93; two-sided p = 0.008).

No new safety signals were observed.

The authors commented that the MONALEESA-2 study provides evidence of a significant improvement in OS with a nonsteroidal aromatase inhibitor plus a CDK4/6 inhibitor in postmenopausal women, as well as impressive median survival to date of 63.9 months among women with HR-positive, HER2-negative advanced breast cancer. This survival of more than 5 years in the ribociclib group supports the introduction of ribociclib as first-line therapy for postmenopausal patients with HR-positive, HER2-negative advanced breast cancer.

Previously, the MONALEESA-7, MONALEESA-3, and MONARCH 2 studies have shown a significant OS benefit with the addition of a CDK4/6 inhibitor (either ribociclib or abemaciclib) in broad groups of patients with HR-positive, HER2-negative advanced breast cancer. These studies showed a 29%, 28%, and 24% lower risk of death. The PALOMA-3 study showed a 19% lower risk of death, which was not considered to be significant. The latest analysis of the MONALEESA-2 study showed a significant and clinically meaningful difference in OS of 12.5 months with first-line ribociclib plus letrozole as compared with placebo plus letrozole in postmenopausal patients with advanced HR-positive, HER2-negative breast cancer, with a 24% relative reduction in the risk of death. Taken together, the MONALEESA trials of ribociclib have shown a consistent OS benefit regardless of accompanying endocrine therapy, line of therapy, or menopausal status.

The study was funded by Novartis. Ribociclib was discovered by the Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceuticals.


Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med 2022;386:942-950.

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