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This activity, titled “Applying Real-World Evidence to Improve Clinical Decision-Making for Patients with HR-positive/HER2-negative Metastatic Breast Cancer” is provided by AGILE and supported by an independent educational grant from Pfizer Incorporated.
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Here’s your host, Dr. Javier Cortes.
Skepticism regarding the use of real-world evidence continues to exist among oncologists, but the reality is that real-world studies can provide evidence that may aid clinicians in Europe who are treating patients with ER-positive HER2-negative metastatic breast cancer, especially regarding use of CDK4/6 inhibitors. That’s why today we will be focusing on the fundamental value that real-world evidence can provide in support of randomized clinical trials and how we can best incorporate those data into the current clinical practice.
This is CME on ReachMD. I’m Dr. Javier Cortes. Joining me in this discussion today are Dr. Peter Schmid from UK and Dr. Giuseppe Curigliano from Italy. Dr. Schmid, Dr. Curigliano, very welcome to you both.
Thank you, Javier.
Thank you, Javier.
To get started, I would like to focus on CDK4/6 inhibitors which have changed clearly the landscape of care for women with ER-positive HER2-negative metastatic breast cancer. So, Peter, let’s start with you. Can you talk about CDK4/6 inhibitors that have been approved by the FDA and/or by the EMA and how they have changed the landscape of care in Europe?
Thank you, Javier. CDK4/6 inhibitors clearly have transformed the way we are treating patients with hormone receptor-positive metastatic breast cancer. There is a number of randomized trials. There are 3 drugs out there that are at the moment licensed both in Europe and in the US called ribociclib, palbociclib and abemaciclib. And I think for me, the most fascinating part is how consistent the results, the benefits of these treatments are across the different trials and across the different indications. There are essentially 2 main indications where we have seen data so far in patients where we often say in an incorrect way as in a first-line setting, but is essentially an aromatase inhibitor-sensitive setting, where CDK4/6 inhibitors were combined with different aromatase inhibitors, and we have had a second group of studies in patients who had failed or showed resistance to prior aromatase inhibitor treatment where the backbone in these combination trials is the compound fulvestrant. Now, across all these studies, we see a substantial and significant benefit with the combination of CDK4/6 inhibitors and hormone therapy, and this is both in the first-line setting with aromatase inhibitors as well as in the pretreated setting with fulvestrant.
If you look at the first-line setting, we passed a magical threshold of a 2-year progression-free survival. In other words, we can say to patients who start on the first-line treatment for metastatic breast cancer, “If you start on a combination of a CDK4/6 inhibitor, you are likely—on average you will benefit for at least 2 years,” which is a massive step forward compared to where we were with aromatase inhibitor alone or hormone therapy alone where we were roughly around 12 to 14 months.
Thanks so much, Peter, for this brief and very comprehensive summary of these 3 CDK4/6 inhibitors in the clinical practice based on the randomized clinical trials we have.
Now, let’s turn our attention to real-world evidence, which comes from real-world studies. So, Giuseppe, can you please discuss for us what these represent and in what way they are different from the data which are coming from randomized controlled clinical trials?
Yes, of course.
So, which is the characteristics of the real-life study? The real-life or the real-world studies are comparative effectiveness trials in which you can compare real-life population receiving the treatment under investigation versus which was the standard of care with a different—completely different inclusion criteria. Just to give to you an example of a comparative effectiveness trial, we know the data from the Flatiron trial—it is an observational analysis of electronic health record from the Flatiron Health analytic database in which women with HR-positive HER2-negative metastatic breast cancer receiving palbociclib+letrozole have been compared to patients receiving letrozole alone. We included in this study elderly patients, so you should consider that in this real-world data set we have more than 40% of patients that are 70 years old or elderly. Many of them are patients with multiple comorbidities, so cardiovascular disease, diabetes. Many of them also may have access or not to the trial, so you can also obtain from real-world studies information on the social status. And if we look also to the characteristic of the disease, we have many of the patients with additional disease, some older patients with bone-only disease, but we have also a setting of patients with brain mets that were excluded from the prospective randomized trial. And other important information is having some patients with de novo metastatic disease that in these real-world studies are close to 40%.
So, which is finally the result of these real-world studies? It’s quite similar to the data that we have from the prospective randomized studies. In the Flatiron data set analysis, the median progression-free survival in the palbo+letrozole arm was 24 months versus 17 months in the letrozole alone arm. And when we look at the real-world overall survival, even if those patients were with multiple comorbidities, we have a benefit from the combination of letrozole+palbo versus the letrozole alone.
So, in conclusion, the type of study includes patients that are real life, so with multiple comorbidities, and you have a snapshot in the elderly population.
This is terrific, Giuseppe. Thank you so much. So now we have understood the characteristics of the data coming from randomized clinical trials compared with real-world studies and also the potential benefits of CDK4/6 inhibitors which are for the treatment of ER-positive HER2-negative metastatic breast cancer.
Now, let’s go back to you, Peter. So, can you briefly tell us which real-world evidence or what real-world evidence studies exist and the value which have been demonstrated for CDK4/6 inhibitors?
Thank you, Javier. There’s a number of studies out there, and Giuseppe already referred to this to some degree, and some of them, for example, focusing on cohorts of patients who are older or did not necessarily meet the slightly stringent eligibility criteria for trials. Now, I think there are some important considerations around those trials, is what level of evidence do they provide. One of the big downsides, obviously, is there is no formal randomization process involved. So, for example, if you compare a group of patients who received letrozole compared to a group of patients who received letrozole+palbociclib or CDK4/6 inhibitor, we cannot be certain that there hasn’t been an element of preselection that, for example, patients who are slightly frailer will get single-agent therapy or patients who possibly have an expected very good response to therapy. For example, we know patients who have bone-only disease tend to be doing better in the randomized trials. Now, if we have a nonrandomized comparison of 2 arms, that can lead to biases in one way or another.
The results of the trials are helpful. They are helpful in the way that they address some of the gaps, the large, very high-quality randomized trial data, greatly for us, but at the same time… I think it’s now consistent with the messages we saw before, but at the same time they bring up some challenges from a general point of view: in that way what endpoints are valid? is progression-free survival a reliable endpoint for a non-controlled trial where there’s no defined time points when scans are being done—there’s no monitoring of that? Overall survival, on the other hand, there’s a powerful endpoint that is very difficult to bias. Some of the response data, again, we need to be very careful because some of those trials do not use strict RECIST criteria.
What I’m trying to say, the devil is in the detail, and if we look at some of those trial results, they seem to be, in large, hugely supportive of what we see with CDK4/6 inhibitors across the randomized trials, but that is not surprising because we have never had a situation in oncology where 3 different drugs in 2 different settings has so remarkably consistent results, so it would be very unusual if then real-world data—some would be very, very different.
For those just tuning in, you are listening to CME on ReachMD. I am Javier Cortes, and today I’m speaking with Dr. Peter Schmid from UK and Giuseppe Curigliano from Italy about how we can apply the real-world evidence when managing patients with ER-positive HER2-negative metastatic breast cancer.
So, Giuseppe, in my opinion the critical comment, the critical question is: How can we best incorporate real-world data evidence into our clinical practice to supplement information which comes from our clinical studies?
So, Javier, this is really a very good question, I believe. We know very well, as Peter explained very well, that we have a lot of limitations of real-world studies.
But, how we can bring these in the real life? So I don’t believe the real-world evidence studies are enough to bring into the clinic a drug without a prospective randomized trial. In my opinion we need for any drug a prospective randomized trial that should be controlled, but real-world evidence trials are important because you can obtain a lot of information on special populations. So, when you treat the patient in a clinical trial and then you move into real life, you have a completely different population, because in the real life you have many patients that have multiple comorbidities, and you cannot extrapolate from the clinical trial to the real life on how to treat the patient with multiple comorbidities. So, real-world evidence trials would be much more important in the future because, if you know, many regulatory agencies are actually approving drugs based on a phase I, expanded phase II, and so you have directly the drug in real life, and many information cannot be obtained from a phase I phase II.
So, in conclusion, first, real-world data are not sufficient to bring in a clinic drug but can be very important to test the drug in the real life and to a patient population in which you have multiple comorbidities. And finally, if FDA, EMA, NICE or any other regulatory agencies would like to have data on comparative effectiveness, the only way to obtain those data are real-world studies.
I think, Giuseppe, this is a good summary of everything we have been discussing today. Just to finish, Peter—we are running out of time—just 1 or 2 key take-home messages for our audience.
I think the key message for me is, in the context of CDK4/6 inhibitors, we have impressive and amazingly consistent data from several randomized controlled trials in the first- and second-line setting. We have now additional supporting information from what we call real-world studies that basically give us insight in how these drugs are being applied and how effective they are outside clinical trials in populations that may be slightly less well-selected and controlled and therefore have possibly more comorbidities but also slightly different treatment indications. And again, that evidence is consistent with what we have seen from the randomized phase III trials and therefore provides a substantial evidence base for the use of CDK4/6 inhibitors in patients with ER-positive metastatic breast cancer.
Well, with these take-home messages in mind, I want to thank my guests, Dr. Peter Schmid and Dr. Giuseppe Curigliano, for helping us better to understand the importance of real-world studies in the management of ER-positive HER2-negative metastatic breast cancer.
Thanks a lot.
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