CM: Welcome. I’m very pleased to welcome you to this ecancer session concerning FGFR as an indicator of tumour agnostic indication in different tumour types in this precision medicine approach. My name is Christophe Massard, I’m the Head of the Phase 1 Department at Gustave Roussy; I’m a medical oncologist focussing on GU cancer and glioblastoma.
EC: Hello everybody, my name is Eva Compérat. I’m a uropathologist, so I’m more specialised on the bladder, of course, and we are implicated in this kind of FGFR3 testing, especially in the bladder where it seems to be pretty interesting. I’m pleased to have a discussion with Christophe Massard.
CM: I guess the idea is probably to have an overview of the recent RAGNAR trial that was completed and communicated during the last ASCO meeting. This trial is a histology agnostic trial; that means that the idea is to enrol patients with different tumour types and we try to identify patients with FGFR alterations. The important thing is we try also to identify FGFR positive tumours where FGFR seems to be oncogene addictive. So we use an algorithm to define different FGFR1, FGFR2, FGFR3 alterations, it could be mutations or alterations. The idea of this trial came from bladder cancer because we know that in bladder cancer FGFR fusion or mutation drives cancer and erdafitinib, an FGFR inhibitor, demonstrates significant activity in patients with metastatic bladder cancer. So the goal of the trial is to screen a large amount of patients, so we screened thousands and thousands of patients, to identify the 5-10% of patients with FGFR positive tumours. It could be different tumour types so, for example, colon carcinoma, glioblastoma, but also pancreatic cancer or breast cancer. All these patients with these different tumours, if the tumour is FGFR positive with different and very specific FGFR mutations or translocations, we propose to the patient to be enrolled in the clinical trial and treated by the FGFR inhibitor erdafitinib. There are different FGFR inhibitors in the field, erdafitinib seems very promising activity with a manageable toxicity and safety. The trial is ongoing. We know that in some tumour types like colon carcinoma or glioma patients with FGFR positive tumours seem to have some benefit from FGFR inhibitors. In this trial it’s very important also to have the expertise of bladder cancer experts because they know better than us how to manage the drug and they know also how to implement FGFR screening in patients because they have already done this screening in bladder cancer in the past in the trial in bladder cancer. So that’s the reason why it’s also important to have Eva Compérat in this session, just maybe to give some information about the FGFR screening in bladder cancer.
EC: The problem is of course we know that FGFR3 is overexpressed in these luminal papillary tumours which we know now from the molecular guidelines or consensus which was published in 2020. The problem is that we do not recognise, for example, in the bladder all the FGFR3 mutations by histology. We have quite a good idea if a tumour is extremely papillary, which of course happens, especially in non-muscle invasive bladder cancers where we know that FGFR3 mutations and alterations exist in nearly 50% of the tumours. Of course we can suspect and then we can lead the patient towards screening. Of course we do not do screening for everybody. The most important thing is to do the screening in muscle invasive bladder cancers but very often they are not really papillary so we do not know very well who to screen. Either you have the approach that you screen really everybody, which is not done, it is not really done. Maybe in Gustave Roussy because you are very rich over there but otherwise it’s not done in France and it’s not done in Austria where I’m actually working. So the problem is whom really we should choose and this is, in my opinion, a little bit where the pathologist can guide you towards saying, well, this is a really papillary, even invasive tumour but you should try. On the other hand you have to be very careful also afterwards with the removed cells and I think, Christophe, you know much better than I do, but you have these hard to spot mutations which are really very well known, especially in the bladder. You have fusions also in the bladder but you have these fusions much more in the gliomas which is pretty well known. So you really have to have a look at what you’re looking at and what you’re getting out because you also have, for example, mutations like the V333M which is a kind of mutation but it is resistant. So if you treat these patients with FGFR3 it will not work at all. So you really have to be very careful with what you take and what you treat.
CM: It’s very important because we know that it’s quite difficult and challenging to address patients for molecular screening. At this time most of the patients are enrolled in molecular screening in clinical trials. There is now a large programme in France with the France Genomic Programme but also in different countries to have access more largely to this screening. Clearly to have access to molecular screening is a challenge and the physician needs to address the challenge in their own hospital and discuss this option with patients. The second point is because FGFR is very challenging to analyse we have different mutations and sometimes the mutations are not oncogenic addictive or you have mutations of resistance. So it’s very important to have an interaction with molecular biologists or pathologists to have this expertise on the oncogene addiction of FGFR alterations. So that means probably in each hospital or each region you need to have this molecular tumour board to have a stronger interaction between physicians, patients and the molecular pathologists. The last point, we need to have access to tumour tissue or to the blood so this is clearly also an issue in some tumour types, for example for glioma. Sometimes it’s quite difficult to access tissue, for example when you have only a small biopsy – this can be the case in bladder cancer but also in a lot of tumour types. Sometimes we need these patients to have a re-biopsy or to have a blood test that are in development. From my point of view this is clearly a very promising approach in all these tumour types. All the experience of bladder cancer experts are very important because you worked in the field five years before everybody so we probably need to have more interaction with bladder cancer experts, pathologists and physicians because they treated also a lot of patients with erdafitinib. There are other FGFR inhibitors in development and this kind of approach is probably interesting for rare cancers, so we talk about colon cancer, glioma, it’s also true in children. So in some paediatric cancers you have FGFR alterations, in particular in glioma or in sarcoma. It could be also interesting to develop these FGFR inhibitors in very rare cancers like children’s cancers.
EC: Yes, that’s for sure. What you said is the sample size is one of the problems; the second problem is the tumour heterogeneity, not so much in gliomas but very much in bladder cancer. We know, after lung cancer and melanoma, it’s really one of the most heterogeneous tumours. So our problem is, for example, which sample we shall take because you can have one sample and it’s really a wonderful mutation, fusion, whatever you want of FGFR3 and by bad luck you take the other block and there is nothing in it. It’s just you don’t find anything. So that’s a little bit problematic, especially in bladder and also in lung cancer where sometimes there are some trials. The second problem is, of course, if you have a very small sample. In bladder very often you have huge tumours, you can do re-biopsy, but in gliomas, as you said, it’s really problematic because we have to make a diagnosis first and then we can only do the screening. So histology always is first, I’m sorry to say it’s so, but you have at least a correct diagnosis. So that’s really a very huge problem.
CM: For sure. The last point is to have access to FGFR inhibitors. So you have a clinical trial ongoing but also in different countries, like in France, you have access to compassionate use. I think in these molecular tumour boards or in these multidisciplinary tumour boards it is important a lot to discuss compassionate use access because it’s very frustrating for physicians, pathologists and also patients to identify a mutation but not have access to the drugs. So we need probably to educate ourselves, physicians, but also patients to give this information that FGFR inhibitors are available with compassionate use outside of proper clinical trials. So it’s always good to enrol patients in clinical trials but sometimes it’s not possible or it’s not feasible so you have this possibility to have compassionate access.
EC: I just wanted to ask you one thing because there are trials which have shown that if you treat the patients before with a checkpoint inhibitor, then you give an FGFR3 inhibitor, these patients react better. We know that for the bladder, this is also true for choriocarcinoma and all these gliomas and all these kinds of tumours where you treat them.
CM: Yes, the question is how to choose the best treatment.
EC: Yes, because we know from the bladder that sometimes you have these immune-excluded tumours in the bladder and you give them before immune checkpoint inhibitor and afterwards you give them FGFR3 and then you see they react pretty well. We don’t know exactly the mechanism, maybe there’s an activation of the T-cell lymphocytes, but do you know something about this?
CM: So it’s a very good question, we don’t have an answer. In this RAGNAR trial this is very advanced cancer patients so that means patients with refractory cancer. So there is no better option than clinical trial or compassionate use. But at some point, and I think it’s a good lesson from bladder cancer how to choose the better drugs in this field, we don’t know and at some point we will need to have some combination trial. Sometimes it’s not so easy to do, or to have some sequential trial. Because you are advanced in the field we will have some lessons from you in bladder cancer maybe to try to extrapolate to other tumour types.
So another point important to consider in the FGFR inhibitor development is the efficacy and the level of efficacy of this drug. We have some demonstrations of activity of this drug in different tumour types with different drugs from different companies. Most of these drugs have been focused on patients with FGFR positive tumours. Clearly these drugs do not have any activity in patients with non-FGFR activated tumour types. So it’s very important because the development of these drugs is clearly linking to molecular screening. We also need to consider that most of the patients enrolled in clinical trials are enrolled in second or third line or further lines of treatment. That means patients with very advanced and refractory tumour types. So most of the time we have an activity with 25-30% response rates which is quite high in patients with advanced tumour type and who have a duration of treatment between 6-9 months. That means it’s probably very close to what we see in lung cancer in second and third line with EGFR inhibitors. We don’t have a lot of data concerning FGFR inhibitors in earlier lines because we believe that in early lines probably FGFR mutants will be more active but we have also the discussion concerning the best treatment for patients. Because the other option, in particular in bladder cancer, is not so easy to have data on patients with naïve bladder cancer or other tumour type and FGFR activation. So what we can say is that we have different FGFR inhibitors in development. Their activity seems promising and what we see in these oncogenes, their addictions, and we need to demonstrate first the activity in different tumour types with no standard of care. Then we will have the question of the combination or a sequence of treatment. For me it’s clearly an option for patients and this option is only available if we have access to molecular screening for patients.
EC: There are some trials just starting so we don’t have any data. But the non-muscle invasive tumours, for example, in the bladder overexpress very frequently FGFR3 and BCG there’s a kind of shortage. So it would be interesting instead of giving maybe pembrolizumab but giving something like an FGFR3 inhibitor in these kinds of stages, so pTa and pT1 stages, but we still do not have any data, really reliable data, on this but that’s something which is certainly upcoming.
CM: Yes, for sure it will be very interesting to have this data and, once again, bladder cancer will probably show us the path because you have more data and so I think you will have more data for this earlier stage. For us it will be very important to have this data in bladder cancer. Thank you. Thank you everybody. Thank you Dr Compérat and I wish you a very good day. Thank you so much.
