Exploratory update on the MONALEESA-3 Phase III trial

Tuesday, 26 Jul 2022

An exploratory analysis from the phase III MONALEESA-3 trial,1 presented at the May 2022 ESMO Breast Cancer Conference, found that at a median follow-up of 70.8 months, first-line ribociclib plus fulvestrant resulted in a median overall survival (mOS) of 67.6 months, a difference of 15.8 months compared to placebo plus fulvestrant (mOS 51.8 months; Hazard Ratio (HR) 0.67; confidence interval [CI] 0.67: 0.50–0.90).1  Consistent with prior analyses, ribociclib also continued to demonstrate an overall survival (OS) benefit in the second-line population.1 The exploratory analysis reported no new safety signals in the first-line setting.1

The MONALEESA-3 trial evaluated ribociclib plus fulvestrant in first line (treatment naïve) and second line therapy in post-menopausal patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative HR+/HER2-  advanced breast cancer (ABC).2 In the final protocol-specified analysis at 39.4 months’ medium duration of follow-up, ribociclib was associated with a statistically significant OS benefit over placebo (HR 0.72; 95% CI: 0.57–0.92; p=0.00455) in the overall population.3 An exploratory OS analysis update at a median follow-up of 56.3 months confirmed the consistent OS benefit of ribociclib (mOS 53.7 months vs 41.5 months with placebo; HR 0.73; 95% CI: 0.59–0.90) in the intention-to-treat population; however, the mOS was not reached in the ribociclib arm for the first-line population (versus 51.8 months for placebo; HR 0.640; 95% CI: 0.46–0.88).4

“With median follow-up out to 70.8 months (nearly 6 years) for patients treated in the first-line setting, patients who received ribociclib with fulvestrant had a 15 month overall survival advantage compared to those patients who received fulvestant alone is clinically meaningful,” noted Dr Belinda Yeo, a Medical Oncologist at the ONJ Centre, Austin Health, Melbourne.

Dr Yeo cautioned that while the new data provides further useful information, its exploratory nature needs to be taken into account. No one would question that the results here are clinically meaningful, but it is an exploratory analysis of the study, in around a third of the patient population. So, the data is useful, but exploratory,” she said.

No new safety signals were observed with first-line ribociclib, and frequency of adverse events remained generally consistent with earlier analyses: neutropenia occurred in 73.8% of patients (versus 4.7% for placebo and fulvestrant), leukopenia in 32.5% (versus 1.6% for placebo and fulvestrant), hepatobiliary toxicity in 26.6% (versus 17.2 for placebo and fulvestrant), prolonged QT interval in 10.5% (versus 0.8% for placebo and fulvestrant) and interstitial lung disease/pneumonitis in 3.4% (versus 0.8% for placebo and fulvestrant).1

Dr Yeo pointed out that data is also available for other first-line therapy options in HR+/HER2- ABC patients. “We have several studies which have shown an overall survival advantage with the use of ribociclib in combination with an endocrine therapy backbone, whether that be an aromatase inhibitor or fulvestrant,” she explained.

The MONALEESA-2 trial investigated ribociclib plus letrozole versus letrozole and placebo in the treatment of postmenopausal HR+/HER- ABC patients. After a median follow-up of 6.6 years, there was a significant OS benefit in the ribociclib arm (63.9 months versus 51.4 months for placebo plus letrozole; HR for death, 0.76; 95% CI: 0.63–0.93; two-sided p=0.008).5

Both trials [MONALEESA-2 AND MONALEESA-3] have clinically significant OS data and it really comes down to a choice for the clinician and patient as to which endocrine therapy backbone is best for them,” said Dr Yeo. “Both are very effective therapies and it is nice to be able to offer patients a choice. If there has been prior aromatase inhibitor exposure, then fulvestrant is generally my preference,” she explained.

While caution is needed when comparing trials due to differences in patient populations and prior treatments, the investigators noted that, at a median follow-up of 70.8 months, the exploratory analysis of MONALEESA-3 reports the longest mOS observed for a first-line setting in postmenopausal HR+/HER2- ABC patients.1


This article was sponsored by Novartis. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Kisqali product information here. For PBS information, click here. Treatment decisions based on these data are the responsibility of the prescribing physician.


  1. Neven P, et al. Annals of Oncol 2022; 33(Suppl 3): S194-S223.
  2. Slamon DJ et al. J of Clin Oncol 2018;36(4): 2465-72.
  3. Slamon DJ, et al. N Eng J Med 2020; 382(6): 514-24.
  4. Slamon DJ, et al. Annals of Oncol 2021;32(8): 1015-24.
  5. Hortobagyi GN, et al. N Engl J Med 2022; 386: 942–950.

Item No: AU-20931. Date of preparation: July 2022




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