Transcript: Making evidence actionable: Applying NF1 therapies in practice
Eric Legius, MD, and Ignacio Blanco, MD, PhD
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- [Eric] Hello, welcome to this podcast on "Making evidence actionable: Applying NF therapies in practice". Welcome to Professor Ignacio Blanco from the Germans Trias Hospital in Barcelona. And I'm Eric Legius, Emeritus Professor from the Catholic University of KU Leuven, in Belgium. Hello. So what clinical factors, Professor Blanco, are important to you in your decision to decide on treatments in patients with NF1 and especially on the timing to initiate those treatments?
- [Ignacio] Hi Eric. This is a very tough question. I think that the appearance of medical treatment for some manifestations in NF1 has changed our way to address the disease. So far, when we have a patient with a manifestation like plexiform neurofibroma, we only have one possibility of treatment, that was surgery. Right now, we have to be sure if we can apply new modalities. But knowing this, the real action of these treatments, we have to have a complete evaluation of the patients. We have to know for how long the tumor is in the patient, what kind of symptoms is given to the patient, and how difficult is the possibility to proceed with surgery. This makes necessary the multidisciplinary approach. There is no possibility to have only one opinion. We need the opinion of different doctors that see the patient.
- [Eric] So, if I understand correctly, there is not one clinical sign or symptom that makes you decide to start treatment or not, but it is more the complexity and the whole setting in the patient, in a multidisciplinary team that makes you decide to treat. - Exactly. - Is that correct?
- [Ignacio] Yes, you are completely right. And also we have to think that if we are talking, for example, in adult patients, if the patient is giving us the information of the appearance of a new symptom, we should think about the possibility of malignant transformation. Not only treat with a single agent. For that, the multidisciplinary team approach, I think that is essential.
- [Eric] And in this multidisciplinary approach, Ignacio, what are the factors that are weighted against each other when you want to apply a specific standard of care therapeutic option?
- [Ignacio] Yes, I think that we have to evaluate the possibilities to make a safe surgery, it means, not that the tumor has to be an anatomically resectable, if it's a solitary lesion or a multiple lesions. Also, we have to know if the resection will be able, for example, to make a local relief of pain, for example. Also, we need to know, which are the comorbidities that the patient could have? And we have to also talk with the patients and define the objective of the truth because we have to talk with him in order to agree with some objectives in the long term treat.
- [Eric] So, in general, if you look at the standard of care therapies available in individuals with NF1, usually, there are not very many available for specific patients, but if you have several options available, how do you choose between the different options and what are the different aspects that makes you decide for one or the other? You mentioned already the interaction with the patient, so the parents of a child or an adult patient probably has an important say in what is going to happen because this is a chronic condition and the interaction with the patient is probably important, or not probably, but is certainly important. But what are the other factors that might be of relevance in this choice?
- [Ignacio] Hmm, this is very important, the information that we have about safety and the utility of the different drugs. I mean, the clinical evidence, we need to go through the literature to have all the information about trials that has been performed. We have to look very carefully about the results. We need to know in which patient has been used the specific treatment, which are the overall responses, the side effects and the time that has been used these medications. We need this clinical evidence. As you mentioned, there is only few possibilities right now and we have to be sure to have the best information in order to decide.
- [Eric] That's very clear. And as we know, in the last couple of years, there have been new targeted therapies that became available, such as the RAS/MAPK pathway inhibitors. And how do this fit in this whole, let's say consideration and a multidisciplinary team on when and how to treat a patient. How do they fit in?
- [Ignacio] That's again, a very tough question, when and how? Again, we have to discuss in a multidisciplinary team, when is the best moment to start treatment? For example, with the evidence that we have right now, we should start as soon as possible in the infancy because there is the possibility to change the natural history of the disease if we are able to decrease the growth of a tumor. However, the treatments are not completely without side effects and we have to make this balance. If the tumor is a small and is a unique tumor and can be safely removed, probably surgery is the best. If not, we can apply medical treatment. But, also, we can start thinking about applying different modalities of treatments for the same patients in a long period of time. I remember many years ago that, for example, surgeons didn't want to remove a tumor if they believe that it was not possible to remove completely. Later it was proved that you can make partial resections in order to improve quality of life of the patients. Right now, we can discuss the possibility to have surgery, medical treatment, surgery and so on. Another point that I want to make clear is that mainly in adult patients, as I said before, we have to remember the possibility to malignant transformation of a tumor. For that, when a patient, mainly adult patients, came to our clinic because they have new manifestations, increase of pain, increase of size, wherever, the first thing that we have to do is to rule out the possibility of malignant transformation because that will make more clear the decisions to be made.
- [Eric] Yeah, that's a very clear point. Thank you for that. And we have now been talking about the use of MEK inhibitors that target the RAS/MAPK pathway and there is quite a bit of data on the use of these MEK inhibitors for plexiform neurofibromas and also for some other tumors, but there are also other therapies being developed at the moment and how do you look at them, at other targeted therapies, such as mTOR pathway inhibitors or maybe systems that modulate the immune system or systems that target the tumor microenvironment. How do you look at those different therapies and how do you evaluate the potential use or benefit in treatment, in potential future treatment compared with the existing treatments?
- [Ignacio] When I have to talk with patients and I have to explain the possibilities, the new possibilities of treatment, I always say to my patients that we have to differentiate what has to be investigated in a clinical point or that we have enough information to be applied in a safety regime. So far, MEK inhibitors has clear evidence about the results that we can expect. However, the other modalities has to be still study in clinical trials, it's the potential to use these new drugs. However, we have to wait to have more information. Another important point that is changing our way to treat tumors is that probably the best way to apply treatments will be use a combination of treatment. So far, we use only one treatment, for example, MEK inhibitors, but probably, in the future, we will be able to use two or three treatments for the same patients because trying to target a tumor from different points, from different pathways, it will provide a better resolution. That is also seen in mainly malignant tumors that, right now, monotherapy is not the best way to treat tumors. Plexiform neurofibromas are not malignant tumors. The way to treat can be different from the malignant tumors, but a combination of tumors will be helpful. Right now, for example, we have evidence that MEK inhibitors, not all patients react in the same way. There are early responder and patients that respond later, they need to have more exposure to MEK inhibitors. And this is probably due to differences in the tumor because probably tumors that has more fibrotic constitution, it takes longer to respond to MEK inhibitors. And for that, if we use a treatment that can modify the structure of the tumor, then MEK inhibitors could act better. And for that combination of treatments probably will be the future of treatment of these patients.
- [Eric] So looking at those new modalities, some of them you mentioned already, but are also options such as gene therapy, you mentioned the combination therapies with the targeted treatments, you already mentioned also the malignant transformation, but there are people who are also trying to find ways to prevent malignant transformation or to stop it somewhere in the process of transformation. Looking at all these potential future treatments, which of those look most promising to you?
- [Ignacio] Before answering the question, I think that we have to be sure that we are changing the way that we address patients. So far, we used to respond when the patient has manifestations, symptoms, wherever, it's a reactive medicine. Now we have to change, we have to, as you mentioned, we have to be proactive, we have to look what we are expecting for the patients and to act as soon as possible. If want to be proactive, we have to identify, which are the characteristics of the tumor of the patients that make higher risk or lower risk? Which we have to look for biomarkers in order to know the risk of the patient to develop, for example, malignant transformation or growth of the tumor. And then, using all this information, we will be able to personalize the treatment for each patient. So far, we have identified some MRI characteristics of some tumors and we can use them to identify the best treatment. For example, right now, that the nodular lesions are less respondent to MEK inhibitors. If we have a patient with specific nodular lesions, probably surgery has to be the best decision and we need to identify these biomarkers to specific for each patients in order to be more specific in the treatment, so.
- [Eric] So if I understand you very, very well, it means moving from the damage control we do at the moment when things are already happened to a more proactive way of surveillance, of prevention and treatment of the patient in a more personalized way based on everything we know about surveillance, about MRI, about biomarkers and so on, so that for every individual patient, we can make a specific follow up strategy. That would be of course the ideal world, yeah. - [Ignacio] Exactly, you make a very clear reason. We need to change, we have to be proactive. We have to identify the risk of each individual in order to apply the best treatment at the best moment for each patient. That's the only way to change the way that we address these rare conditions, such as neurofibromatosis type one.
- [Eric] Thank you very much, Professor Blanco. And with this, we can conclude this podcast on "Applying NF1 therapies in practice: Making evidence actionable." Thank you very much for your participation.
- [Ignacio] Thanks to you, Eric.
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