MONALEESA-2: the beauty of striving for overall survival goals in postmenopausal metastatic breast cancer

13 Dec 2021

Presented at ESMO 2021, the protocol-specified final analysis of the Phase III MONALEESA-2 trial demonstrated an overall survival (OS) benefit with CDK4/6 inhibitor ribociclib plus aromatase inhibitor letrozole in postmenopausal women with hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) negative advanced breast cancer.1-3 Following the presentation of the MONALEESA-2 data, the limbic spoke with Doctor Belinda Yeo, a Clinician Scientist (Translational Breast Cancer Program) and Medical Oncologist at the Olivia Newton-John Cancer Research Institute and Austin Health, to get her perspectives on the implications of this research in clinical practice.

“MONALEESA-2 is the first trial to show OS in the first-line setting. In metastatic disease, being able to say you live longer is very impressive and shows that we are getting better at treating this disease,” explained Dr Yeo. “Given the results of the MONALEESA trials, the question we’re left asking ourselves is why wouldn’t you treat, rather than why would you treat,” she added.

MONALEESA-2: Data presented at ESMO 2021

Hormone-receptor-positive (HR+) breast cancer is common – comprising up to three quarters of all breast tumours.1 The cyclin-dependent kinases 3 and 6 (CDK4/6) and their regulators are known to be mediators of drug resistance and a logical target for progressive disease. Ribociclib is an oral, small-molecule inhibitor of CDK4/6 that induces G1 phase arrest. It has demonstrated antitumour activity in xenograft models of oestrogen receptor positive breast cancer as monotherapy and in combination with the aromatase inhibitor letrozole and phosphatidylinositol 3-kinase (I3K) inhibitors.1 The efficacy and safety of ribociclib combined with letrozole for first-line treatment of advanced disease was assessed in the MONALEESA-2 trial.

Patients were randomised to receive either ribociclib 600 mg/day on a 4 week cycle (3 weeks on; 1 week off) plus letrozole 2.5 mg/day (n=334) or placebo plus letrozole 2.5 mg/day (n=334). The primary endpoint was investigator-assessed progression-free survival (PFS). Overall survival (OS) was a key secondary endpoint.1 A summary of the PFS at 15 and 26.4 months follow-up is shown in the table.

Summary of PFS in MONALEESA-2 at 15 and 26.4 months follow-up.1,2

Median duration of follow-up: Ribociclib + letrozole Placebo + letrozole
15 months Not reached

(95% CI: 19.3–NR)

14.7 months

(95% CI: 13.0–16.5)

26.4 months 25.3 months

(95% CI: 23.0–30.3)

16.0 months

(95% CI: 13.4–18.2)

“To patients, we’re able to say with the confidence of the data behind the MONALEESA-2 trial, that their treatment is going to last years,” said Dr Yeo.

The final OS analysis from the MONALEESA-2 trial was presented at ESMO 2021 by Professor Gabriel Hortobagyi (Professor of Medicine, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center). First-line ribociclib plus letrozole showed a statistically significant and clinically meaningful OS benefit versus placebo plus letrozole in post-menopausal HR+/HER2- advanced breast cancer patients. To summarise, median OS was prolonged by over 12 months at 79.7 months follow-up:3

  • OS 63.9 months with ribociclib plus letrozole
  • OS 51.4 months with placebo plus letrozole
  • HR: 0.76 (95% CI: 0.63-0.93); p=0.004

No new safety signals were seen after more than 6.5 years follow-up.3

“When you’ve got patients on treatment for that long, you want to be sure that it’s tolerable,” said Dr Yeo. “That’s something the MONALEESA-2 trial also gives us: reassurance in the safety and tolerability of long-term treatment,” she said.

CDK4/6+AI is used to treat the largest proportion of mBC patents

Commenting on the results, the investigators said, “To date, this is the first report of a statistically significant and clinically meaningful OS benefit with a [first-line] CDK4/6i in postmenopausal patients with HR+/HER2– ABC.3

Where does the MONALEESA-2 data fit?

The MONALEESA series of clinical trials aimed to expand the patient populations in which ribociclib has been assessed in combination with various therapies.4 Below, the different patient populations and treatment combinations in the MONALEESA trial series are shown.

Patient populations, prior treatments and treatment arms of the MONALEESA clinical trial series.4

Patient population Postmenopausal women with HR+/HER2- advanced breast cancer Men and postmenopausal women with HR+/HER2- advanced breast cancer Pre/perimenopausal women with HR+/HER2- advanced breast cancer
Prior treatment No prior therapy for advanced disease  

No prior chemotherapy for advanced disease


≤1 line of endocrine therapy for advanced disease

No prior endocrine therapy for advanced disease


≤1 line of chemotherapy for advanced disease

Treatment arms  

Ribociclib 600 mg/day + letrazole 2.5 mg/day


Placebo + letrozole 2.5 mg/day

Ribociclib 600 mg/day + fulvestrant 500mg*


Placebo + fulvestrant 500 mg*

Ribociclib 600 mg/day + tamoxifen/NSAI + goserelin


Placebo + tamoxifen/NSAI + goserelin

Starting dosage for tamoxifen was 20 mg/day, for anastrozole was 1 mg/day, for letrozole was 2.5 mg/day, and for goserelin was 3.6 mg every 28 days.

The latest data from MONALEESA-3 and MONALEESA-7 demonstrated a statistically significant OS benefit when ribociclib was added to endocrine therapy versus endocrine therapy alone.5,6 In MONALEESA-3, the median OS was 53.7 months (95% CI:46.9-NR) in the ribociclib arm compared to 41.5 months (95% CI: 37.4-49.0) in the placebo arm.5   For MONALEESA-7 after a median 53.5 months’ follow-up, the median OS was 58.7 months in the ribociclib arm and 48.0 months in the placebo arm (HR, 0.76; 95% CI, 0.61 – 0.96) with a 24% relative reduction in the risk of death with ribociclib.6  These findings, along with those of MONALEESA-2 support the OS benefit seen when ribociclib is added to endocrine therapies in HR+/HER2- advanced breast cancer in women who are pre-, peri- and postmenopausal, regardless of the line of therapy.3.5.6

“MONALEESA-7 changed the way we cared for our pre/perimenopausal patients. Now, an OS benefit in MONALEESA-2 gives that same game-changing opportunity for the postmenopausal population. It’s definitely going to impact treatment choices. What’s more, the consistency we’re seeing across the MONALEESA series of trials continues to give us confidence in the treatment decisions we’ll be making,” said Dr Yeo.


CI=confidence interval; ESMO=European Society for Medical Oncology; HR=hazard ratio; MONALEESA= Mammary Oncology Assessment of LEE011’s Efficacy and Safety; NSAI=non-steroidal aromatase inhibitor; NR=not reached.


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 via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.


  1. Hortobagyi GN, et al. N Engl  J  Med  2016;375:1738-48.
  2. Hortobagyi GN, et al. Ann Oncol. 2018;29(7):1541-1547.
  3. Hortobagyi GN, Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741
  4. Yardley DA, Future Oncol. 2019 Aug;15(23):2673-2686.
  5. Slamon DJ, et al. Ann Oncol. 202;32(8):1015-1024.
  6. Tripathy D, et al. Cancer Res 81 (Suppl 4)PD2-04; DOI: 10.1158/1538-7445.SABCS20-PD2-04


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