 The MONALEESA-2 randomized phase 3 trial was a clinical trial that initiated in January 2013 and completed accruing in March 2014. We reported the first progression-free survival data, which was the primary efficacy variable at the ESMO [European Society for Medical Oncology Congress] presidential session in 2016 showing highly significant prolongation in progression-free survival for the combination of ribociclib and letrozole compared with the letrozole plus placebo. Five years later, and earlier this year—actually, last month—I presented the overall survival results of the same clinical trial, which had close to 670 patients randomized to the letrozole plus placebo or letrozole plus ribociclib. The overall survival data are equally impressive with a 1-year prolongation of overall survival, with a median overall survival of 51 months for the placebo-plus-letrozole group and 64 months for the ribociclib-and-letrozole group. This represents about a 24% reduction in mortality events, which is a highly significant and highly relevant outcome.

This advantage in overall survival was accomplished with no change in the safety profile we reported 5 years ago, with some symptoms related to fatigue and some laboratory abnormalities, including myelosuppression and reversible liver function abnormalities and more rarely some other reversible safety events. After 6½ years of median follow-up, there have been no new safety signals, there has been no cumulative toxicity, and there have been no treatment-related deaths in this clinical trial.

The clinical implications of the MONALEESA-2 trial are several. No. 1, to date it is the only clinical trial that focuses on postmenopausal women with the metastatic hormone receptor–positive HER2 [human epidermal growth factor receptor 2]–negative breast cancer who haven’t received prior treatment for advanced disease. With the results presented and with the impressive prolongation in overall survival, it makes this combination of ribociclib and letrozole the preferred treatment for this group of patients. We’re awaiting the results of more phase 3 trials with the other CDK4/6 inhibitors in this space, but until similar or competing data becomes available they should be the preferred regimen in this group of patients.

The second implication of these results is that for the first time we’ve crossed a 5-year barrier in terms of median survival for any type of metastatic breast cancer. When I started oncology some 40 years ago, the median survival of patients with metastatic breast cancer was about 2 years. Today the hormone receptor–positive HER2- metastatic breast cancer group, as shown in the MONALEESA-2 trial, is in excess of 5 years. We’ve made significant progress, and this has resulted in an important benefit for our patients. Furthermore, the MONALEESA-2 trial has also shown that this benefit was accomplished without serious toxicity and with the maintenance of the quality of life and, in some cases, improvement of quality of life for those patients who started not with symptomatic disease. All in all, this has been an important step forward in the management of this group of patients.

Videos

Important takeaways from MONALEESA-2 trial updates on overall survival data corresponding with the use of ribociclib plus letrozole, as presented at ESMO 2021.

Updates to MONALEESA-2 Data in HR+ MBC

 The CDK4/6 inhibitors have been a major addition to our treatment of hormone receptor–positive primary breast cancer. At this point, we select treatments for this group of patients, based essentially on the expression of estrogen and progesterone receptors and the lack of expression or normal expression of HER2 [human epidermal growth factor receptor 2]. During the development of CDK4/6 inhibitors, there was a major effort expended in identifying biomarkers to enrich the population. We don’t have a good biomarker that identifies patients who will have a greater or smaller probability of response to a CDK4/6 inhibitor. For patients with metastatic breast cancer who have tumors that express hormone receptors and have a normal expression of HER2, a CDK4/6 inhibitor combined with endocrine therapy is the treatment of choice.

We have 3 CDK4/6 inhibitors available in North America and much of the Western world: ribociclib, palbociclib, and abemaciclib. The 3 CDK4/6 inhibitors were developed almost simultaneously, and all 3 have demonstrated similar efficacy in second- and third-line therapy of hormone receptor–positive HER2- metastatic breast cancer. The safety profiles of ribociclib and palbociclib are very similar. Abemaciclib is slightly different with less myelosuppression and somewhat more diarrhea characterizing its safety profile. Most North American physicians would choose either inhibitor as their first choice and perhaps reserve abemaciclib for somewhat later utilization. More recently, we’ve had clinical trials reporting on first-line therapy of hormone receptor–positive HER2- metastatic breast cancer showing that the 3 CDK4/6 inhibitors have a similar and highly significant effect on prolonging progression-free survival. More recently, the first of the 3, ribociclib, has been reported to show equally highly significant and clinically relevant prolongation of overall survival. That’s where we stand today.


The selection of endocrine partners for CDK4/6 inhibitors is relatively simple. We have 3 highly selective aromatase inhibitors available that have a somewhat equivalent therapeutic ratio or efficacy and safety profile; therefore, any of the 3 would provide an appropriate partner to the CDK4/6 inhibitors. Fulvestrant is a selective estrogen receptor down regulator that was initially partnered with the CDK4/6 inhibitors in the second and third lines after progression on aromatase inhibitor–based therapy and showed a similar highly significant advantage in progression-free survival and overall survival in those trials in which it was the endocrine backbone. More recently, additional randomized trials included fulvestrant as the endocrine partner in first-line therapy. The same therapeutic effect was observed with fulvestrant and with aromatase inhibitors as an endocrine backbone. One could say that it’s equally appropriate to choose either an aromatase inhibitor or fulvestrant as an endocrine partner for a CDK4/6 inhibitor in first- or second-line therapy depending on the prior endocrine therapy utilized. Having said that, some patients will prefer total oral therapy, while others will prefer an intramuscular administration of a drug once a month. It becomes a question more of patient preference than of medical evidence.

 In a patient with hormone receptor–positive advanced breast cancer who’s being treated initially in the frontline setting, I almost always recommend a CDK4/6 inhibitor–based therapy in combination with hormonal therapy. The decision among the 3 CDK4/6 inhibitors is a bit tricky because we have 3 available that show strikingly similar objective response rates and strikingly similar hazard ratios when it comes to progression-free survival.

However, we are beginning to see some differences among the 3 agents that may help us select among them. For example, there are differences in toxicity profiles. Abemaciclib is associated with more GI [gastrointestinal] toxicity and a lower rate of neutropenia. However, it also has associated with it a rate of venous thromboembolic events of around 4%. Ribociclib and palbociclib have higher rates of neutropenia, typically nonfebrile but still a more significant rate of neutropenia. With ribociclib, 1 has to watch the ECGs [electrocardiogram] for QTC prolongation and keep in mind concomitant medications.

We’re also beginning to see some differences in the survival benefits associated with these. We have survival benefits associated with ribociclib in the frontline setting from the MONALEESA-7 clinical trial. And then more recently, from the MONALEESA-2 clinical trial. We’re still waiting for survival benefits to be reported from the MONARCH 3 and PALOMA-2 trials. We’ll have to see if those trials end up showing a significant improvement in survival when it comes to those agents.

For now, I talk to a patient about the different regimens available and select the endocrine therapy based on what they’d received previously. If they’d recently been on an Agilent aromatase inhibitor, I’ll almost likely recommend fulvestrant as the endocrine partner. In some cases, I’ll suggest fulvestrant, even in a patient who is endocrine therapy-naïve, if they prefer not to have to take more pills. It’s a patient discussion regarding adverse-effect profiles: the benefits we’ve seen from each of them, the dosing regimen, and recent therapies that the patient has been on for their breast cancer.

Options available as first-line therapy for HR+ metastatic breast cancer and variables that impact which CDK4/6 inhibitor and endocrine partner is selected for a patient.

First-Line Approaches for HR+ Metastatic Breast Cancer

Gabriel N. Hortobagyi, MD, professor of Medicine at the University of Texas MD Anderson Cancer Center, discusses the MONALEESA-2 trial, which has shown that the addition of ribociclib to letrozole significantly improved progression-free survival (PFS) in postmenopausal women with hormone receptor (HR)&shy;-positive advanced breast cancer.  

Patients in the ribociclib arm had a 44% reduction in the risk of progression or death compared with patients who recieved placebo plus hormone therapy. This difference satisfied prespecified statistical requirements for superiority.

These findings are practice-changing, says Hortobagyi. Up until the development of the CDK4/6 inhibitors, the standard of care for managing patients with HR-positive metastatic breast cancer was an aromatase inhibitor such as letrozole or anastrozole. Based on these findings, going forward, the treatment of choice for these same postmenopausal women with HR-positive breast cancer will be a combination of a drug like letrozole with a CDK4/6 inhibitor such as ribociclib, he says.

This is a major change because with letrozole alone, the best data was about a 14-month PFS. With the addition of ribociclib, patients are expected to live significantly longer, says Hortobagyi.  

Dr. Gabriel Hortobagyi on the Impact of MONALEESA-2 Trial in HR+ Breast Cancer

Gabriel N. Hortobagyi, MD, professor of Medicine at The University of Texas MD Anderson Cancer Center, discusses findings from the phase III MONALEESA-2 trial, which looked at the addition of the CDK 4/6 inhibitor ribociclib to endocrine therapy in postmenopausal women with hormone receptor (HR)-positive metastatic breast cancer.

Patients were randomized to receive letrozole at a dose of 2.5 mg/day or ribociclib at 600 mg/day for 3 weeks on, 1 week off or placebo. Treatment was continued until disease progression, and the primary endpoint was progression-free survival, Hortobagyi says.

At a follow-up, there was such a significant difference between the two arms, it was decided that the trial had reached its primary endpoint. Results showed that there was a 44% reduction in the risk of progression, with a significant 

Dr. Hortobagyi on MONALEESA-2 Trial Results in HR+ Breast Cancer

Gabriel N. Hortobagyi, MD, professor of medicine, chair, Department of Breast Medical Oncology, director, Multidisciplinary Breast Cancer Research Program, University of Texas MD Anderson Cancer Center, discusses the BOLERO-2 trial that examined everolimus (Afinitor) plus exemestane (Aromasin) in hormone receptor-positive (HR+) breast cancer.

The trial was a prospective, double blind, placebo-controlled, phase III trial examining 724 postmenopausal women with HR+ metastatic breast cancer that had previously been treated with an aromatase inhibitor such as anastrozole or letrozole. Patients were randomized 2:1 to receive exemestane plus everolimus or exemestane plus placebo.

At the median follow-up of 12.5 months the progression-free survival (PFS) was 7.4 months for the everolimus arm and 3.2 in the control arm. The hazard ratio was 0.44 with a highly significant 

-value. At this point it is too early to determine an overall-survival benefit.

>>>Return to the main conference coverage page.

Dr. Gabriel Hortobagyi from the MD Anderson Cancer Center Discusses the BOLERO-2 Trial

Gabriel N. Hortobagyi, MD

Articles

Updates to MONALEESA-2 Data in HR+ MBC

First-Line Approaches for HR+ Metastatic Breast Cancer

Dr. Gabriel Hortobagyi on the Impact of MONALEESA-2 Trial in HR+ Breast Cancer

Dr. Hortobagyi on MONALEESA-2 Trial Results in HR+ Breast Cancer

Dr. Hortobagyi Discusses the BOLERO-2 Everolimus Trial