Ribociclib Regimen Elicits Longest Reported Median OS in HR+ Breast Cancer


New data support the use of ribociclib plus letrozole in the treatment of patients with postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer.

Susanne Schaffert, PhD

Susanne Schaffert, PhD

Postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer achieved a statistically significant improvement in overall survival (OS) following treatment with ribociclib (Kisqali) plus letrozole vs letrozole alone. The results, which show that this benefit continues to increase over time, shine favorably on the use of the CDK4/6 inhibitor as a frontline treatment for this patient population.1,2

Data from the phase 3 MONALEESA-2 trial (NCT01958021), which were published in the New England Journal of Medicine, showed that at a median follow-up of 6.6 years, the median OS achieved with ribociclib plus letrozole (n = 334) was 63.9 months (95% CI, 52.4-71.0) vs 51.4 months (95% CI, 47.2-59.7) with placebo plus letrozole (n = 334; HR, 0.76; 95% CI, 0.63-0.93; two-sided P = .008).

The Kaplan-Meier estimated 60-month OS rate with the doublet was 52.3% (95% CI, 46.5%-57.7%) vs 43.9% (95% CI, 38.3%-49.4%) with letrozole alone; at 72 months, these estimated rates were 44.2% (95% CI, 38.5%-49.8%) and 32.0% (95% CI, 26.8%-37.3%), respectively.

The OS benefit achieved with ribociclib plus letrozole over letrozole alone in exploratory patient subsets defined by patient and disease characteristics, geographic region, prior therapies received, and metastatic sites proved to be consistent with what had been observed in the overall patient population.

“What’s most compelling about these MONALEESA-2 data is to see that the OS benefit of [ribociclib] plus letrozole was improving over time for patients, regardless of disease characteristics,” Susanne Schaffert, PhD, president of Novartis Oncology, stated in a press release. “These meaningful outcomes are elevating the standard of care for people living with advanced breast cancer, who now have hope for a longer quality life. Data continue to show that [ribociclib] sets itself apart from other CDK4/6 inhibitors, and we look forward to continue studying all its potential benefits for patients living with hormone receptor–positive/HER2-negative breast cancer.”

MONALEESA-2 enrolled postmenopausal women with locally confirmed, hormone receptor–positive, HER2-negative recurrent or metastatic breast cancer who did not previously receive systemic therapy for advanced disease. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria or at least 1 predominantly lytic bone lesion, as well as acceptable bone marrow and organ function.

If patients received prior CDK4/6 inhibitors, systemic endocrine therapy, or chemotherapy for advanced disease, they were excluded. Notably, patients who received prior neoadjuvant or adjuvant endocrine therapy were permitted.

A total of 668 participants were randomized 1:1 to receive ribociclib at a daily dose of 600 mg or a matching placebo. Participants in both arms received letrozole at a daily dose of 2.5 mg on a continuous schedule.

The primary end point of the trial was investigator-assessed progression-free survival. A key secondary end point was OS. Other secondary end points included overall response rate and safety. Biomarker analysis served as an exploratory end point.

Earlier data from the trial showed that at a median follow-up of 26.4 months, the median PFS with ribociclib plus letrozole was 25.3 months (95% CI, 23.0-30.3) vs 16.0 months (95% CI, 13.4-18.2) with placebo plus letrozole (HR, 0.568; 95% CI, 0.457-0.704; log-rank P = 9.63 x 10-8).3

At the final analysis of OS, the median duration of exposure to trial treatment in the investigative and control arms was 20.2 months (interquartile range [IQR], 7.4-45.1) and 14.1 months (IQR, 7.1-28.9), respectively. The data cutoff date for OS was June 10, 2021.

Additional findings showed that among those who discontinued treatment, subsequent antineoplastic therapies were received by 87.8% of the 304 patients in the ribociclib/letrozole arm vs 90.2% of the 317 patients in the placebo/letrozole arm.

The most common subsequent therapy received was endocrine therapy alone, and this was received by 32.9% and 29.0% of those in the investigative and control arms, respectively. Fewer patients in the ribociclib arm vs the placebo arm received subsequent CDK4/6 inhibitors like palbociclib (Ibrance; 16.1% vs 31.5%), abemaciclib (Verzenio; 2.6% vs 3.8%), and ribociclib (Kisqali; 4.6% vs 1.9%) in any line of therapy, at 21.7% and 34.4%, respectively.

When adjusting for subsequent treatment with a CDK4/6 inhibitor, the estimated median OS in the placebo arm was 50.5 months (95% CI, 45.0-55.4) vs the 51.4 months (95% CI, 47.2-59.7) reported in the main analysis (HR, 0.73; 95% CI, 0.59-0.92).

In the intent-to-treat population, 28.9% of 621 patients who discontinued trial treatment subsequently received chemotherapy alone or as part of a combination; this included 28.0% and 29.7% of those in the investigative and control arms, respectively.

The median time to first subsequent chemotherapy received was 50.6 months and 38.9 months in the ribociclib/letrozole and letrozole/placebo arms, respectively (HR, 0.74; 95% CI, 0.61-0.91). Moreover, the median chemotherapy-free survival in the ribociclib arm was 39.9 months vs 30.1 months in the placebo arm (HR, 0.74; 95% CI, 0.62-0.89).

Regarding safety, the most frequently experienced toxicities that were grade 3 or 4 in severity and of special interest in the investigative and control arms, respectively, included neutropenia (63.8% vs 1.2%), hepatobiliary toxic effects (14.4% vs 4.8%), and prolonged QT interval (4.5% vs 2.1%). Additionally, 2 patients in the ribociclib arm experienced grade 3 interstitial lung disease (ILD) or pneumonitis vs no patients in the placebo arm. Notably, no grade 4 effects or deaths associated with ILD were reported in the investigative arm.

“This analysis of the MONALEESA-2 trial 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 hormone receptor–positive, HER2-negative breast cancer, with a 24% reduction in the risk of death, the study authors concluded. “Taken together, the MONALEESA trials of ribociclib have shown a consistent OS benefit regardless of accompanying endocrine therapy, line of therapy, or menopausal status.”


Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386(10):942-950. doi:10.1056/NEJMoa2114663

NEJM publication of Novartis Kisqali data shows longest median overall survival ever reported in HR+/HER2- advanced breast cancer. News release. Novartis; March 9, 2022. Accessed March 10, 2022. https://bit.ly/3CyWPag

Hortbagyi 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. 2018;29(7):1541-1547. doi:10.1093/annonc/mdy155

This article was originally published on OncLive as “NEJM Data Underscore OS Benefit With Ribociclib/Letrozole in HR+ Advanced Breast Cancer”

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