Select Topic:
Browse by Series:

MONALEESA-3: Ribociclib Plus Fulvestrant in HR+ mBC

Insights From: Debu Tripathy, MD, MD Anderson Cancer Center; Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center; Hatem Soliman, MD, H. Lee Moffitt Cancer Center & Research Institute
Published: Friday, Jul 27, 2018



Transcript: 

Sara Hurvitz, MD: MONALEESA-3 is a clinical trial looking at the combination of fulvestrant with ribociclib in patients who were either not previously treated for metastatic ER–positive breast cancer or had up to 1 prior line of therapy. So, the sort of unique feature about this study is the fact that it did have a subset population of patients who were first-line. Women received fulvestrant at the 500-mg dosing in combination with ribociclib or in combination with placebo. And not surprisingly, similar to the results that were already presented for palbociclib and abemaciclib in this setting, the hazard ratio was around 0.59 and in favor of the use of ribociclib.

In terms of actual median progression-free survival, patients who received ribociclib had over a 20-month median progression-free survival, and it was just over 12 months or so in patients who received placebo, so about an 8-month improvement.

There was no new safety signal from this data. The safety of ribociclib looks consistent with previously reported safety, with grade 3/4 neutropenia being the most common side effect. QTc prolongation was evaluated or patients were evaluated to make sure they weren’t having QTc prolongation. And actually, there were consistent results from this study. About 6% of patients had some prolongation. This was not serious. There were no new signals here in patients treated with ribociclib, and it was 3% in the placebo arm.

Hatem Soliman, MD: The rationale for starting with fulvestrant in the first-line therapy is based on a lot of data that have preceded in the past several years, stemming from multiple trials including FIRST and FALCON and also the SWOG trials, as well, that looked at the efficacy of fulvestrant in the first-line setting, either alone or in combination with an aromatase inhibitor. And those studies had shown that in particular subsets of patients, there was a benefit associated with starting off with fulvestrant compared with an aromatase inhibitor. And so, it led to the question being posed, during the conception of MONALEESA-3, to include those patients in the trial to see whether there was a benefit that could be seen with fulvestrant in combination with a CDK4/6 inhibitor in those de novo metastatic patients.

Debu Tripathy, MD: If you look at the general benefits when ribociclib is added to an endocrine therapy, we have seen consistent doubling of progression-free survival regardless of whether the partner is an aromatase inhibitor or fulvestrant, or even tamoxifen in the case of the MONALEESA-7 trial. All of them generated the same degree of benefit. Now, of course, what’s important in the outcome of the patient is the line of therapy in which they’re receiving it.

Most patients with endocrine therapy in the first line will have an expected PFS of about 12 months, and it’ll be doubled with a CDK inhibitor. But in the second-line setting, that is much shorter. So, if fulvestrant is given in the second-line setting, we typically see disease-free survivals that are more in the 4- to 5-month range.

Now, in the MONALEESA-3 study, fulvestrant was used either first- or second-line, so they were somewhere in between. They were actually closer to what we see in first-line therapy because some of those patients were first-line. Now what you use as your endocrine partner in first line has evolved a little bit. At the beginning of the CDK inhibitor trials, aromatase inhibitors were generally considered first-line and fulvestrant second-line. But in the past couple of years, since the publication of the FALCON trial, we’re now realizing that you can use fulvestrant in the first line and get equivalent results. And presumably when those patients progress, you can use aromatase inhibitors and use the reverse sequence, although we don’t have a lot of data on that yet because the whole idea of using fulvestrant up front is relatively new. Nevertheless, that gives us some flexibility as oncologists and as patients in making decisions. I feel that based on the data we have, one can use the endocrine partner of either an aromatase inhibitor or fulvestrant. In fact, in someone who’s intolerant of an aromatase inhibitor and fulvestrant, you could even use tamoxifen, even though we tend not to use that drug as much.

Hatem Soliman, MD: There do appear to be some subtle differences between the hormonal therapies, not so much the different aromatase inhibitor therapies. I think most physicians would feel that they’re relatively equivalent when it comes to the oral agents such as letrozole or anastrozole. However, with regards to fulvestrant, there is a thought that because of its mechanism of action being fundamentally different from aromatase inhibitors’, it actually may affect the natural history of the disease and treat certain types of hormone receptor–positive metastatic breast cancer better than an aromatase inhibitor.

Transcript Edited for Clarity 
Slider Left
Slider Right


Transcript: 

Sara Hurvitz, MD: MONALEESA-3 is a clinical trial looking at the combination of fulvestrant with ribociclib in patients who were either not previously treated for metastatic ER–positive breast cancer or had up to 1 prior line of therapy. So, the sort of unique feature about this study is the fact that it did have a subset population of patients who were first-line. Women received fulvestrant at the 500-mg dosing in combination with ribociclib or in combination with placebo. And not surprisingly, similar to the results that were already presented for palbociclib and abemaciclib in this setting, the hazard ratio was around 0.59 and in favor of the use of ribociclib.

In terms of actual median progression-free survival, patients who received ribociclib had over a 20-month median progression-free survival, and it was just over 12 months or so in patients who received placebo, so about an 8-month improvement.

There was no new safety signal from this data. The safety of ribociclib looks consistent with previously reported safety, with grade 3/4 neutropenia being the most common side effect. QTc prolongation was evaluated or patients were evaluated to make sure they weren’t having QTc prolongation. And actually, there were consistent results from this study. About 6% of patients had some prolongation. This was not serious. There were no new signals here in patients treated with ribociclib, and it was 3% in the placebo arm.

Hatem Soliman, MD: The rationale for starting with fulvestrant in the first-line therapy is based on a lot of data that have preceded in the past several years, stemming from multiple trials including FIRST and FALCON and also the SWOG trials, as well, that looked at the efficacy of fulvestrant in the first-line setting, either alone or in combination with an aromatase inhibitor. And those studies had shown that in particular subsets of patients, there was a benefit associated with starting off with fulvestrant compared with an aromatase inhibitor. And so, it led to the question being posed, during the conception of MONALEESA-3, to include those patients in the trial to see whether there was a benefit that could be seen with fulvestrant in combination with a CDK4/6 inhibitor in those de novo metastatic patients.

Debu Tripathy, MD: If you look at the general benefits when ribociclib is added to an endocrine therapy, we have seen consistent doubling of progression-free survival regardless of whether the partner is an aromatase inhibitor or fulvestrant, or even tamoxifen in the case of the MONALEESA-7 trial. All of them generated the same degree of benefit. Now, of course, what’s important in the outcome of the patient is the line of therapy in which they’re receiving it.

Most patients with endocrine therapy in the first line will have an expected PFS of about 12 months, and it’ll be doubled with a CDK inhibitor. But in the second-line setting, that is much shorter. So, if fulvestrant is given in the second-line setting, we typically see disease-free survivals that are more in the 4- to 5-month range.

Now, in the MONALEESA-3 study, fulvestrant was used either first- or second-line, so they were somewhere in between. They were actually closer to what we see in first-line therapy because some of those patients were first-line. Now what you use as your endocrine partner in first line has evolved a little bit. At the beginning of the CDK inhibitor trials, aromatase inhibitors were generally considered first-line and fulvestrant second-line. But in the past couple of years, since the publication of the FALCON trial, we’re now realizing that you can use fulvestrant in the first line and get equivalent results. And presumably when those patients progress, you can use aromatase inhibitors and use the reverse sequence, although we don’t have a lot of data on that yet because the whole idea of using fulvestrant up front is relatively new. Nevertheless, that gives us some flexibility as oncologists and as patients in making decisions. I feel that based on the data we have, one can use the endocrine partner of either an aromatase inhibitor or fulvestrant. In fact, in someone who’s intolerant of an aromatase inhibitor and fulvestrant, you could even use tamoxifen, even though we tend not to use that drug as much.

Hatem Soliman, MD: There do appear to be some subtle differences between the hormonal therapies, not so much the different aromatase inhibitor therapies. I think most physicians would feel that they’re relatively equivalent when it comes to the oral agents such as letrozole or anastrozole. However, with regards to fulvestrant, there is a thought that because of its mechanism of action being fundamentally different from aromatase inhibitors’, it actually may affect the natural history of the disease and treat certain types of hormone receptor–positive metastatic breast cancer better than an aromatase inhibitor.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: 1st Annual Paris Breast Cancer Conference™Dec 31, 20181.5
35th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® Clinical Vignette SeriesJan 31, 20192.0
Publication Bottom Border
Border Publication
x