2021 Genitourinary Cancers Symposium
Diagnosis, testing and biomarkers in the individualisation of patient care with FGFR mutated bladder cancer
Prof Andrea Necchi – Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Prof Eva Compérat – Medical University of Vienna, Vienna, Austria
AN: Welcome everyone. It’s a great pleasure to be here and thanks to ecancer TV for inviting me to present and to discuss the issue of FGF receptor alteration and potential targeting of the gene and the gene alteration in bladder cancer. I’m Andrea Necchi, I’m a medical oncologist and Associate Professor at Vita-Salute University in Milan in San Raffaele. It’s really a pleasure for me to be here discussing with Professor Eva Compérat from Vienna, from the University of Vienna, who doesn’t need an introduction. She’s an experienced and expert and top leader pathologist mainly in the field of GU cancer.
Today we will be discussing regarding many aspects and potential concerns of FGFR targeting and treatment in bladder cancer, basically based on the data that have been generated with FGFR targeting in this disease. So, first of all I would like to share with Eva some comments regarding the way to assess the FGFR3 alteration in bladder cancer. We know that there are several ways of assessing this alteration; we have a way of assessing the alteration with NGS, with next generation sequencing, with commercial platforms or internally developed platforms. So looking at the gene mutations or rearrangement. The other way we may test this alteration is at the mRNA level or even at the immunohistochemistry level. So, Eva, what is your feeling as a pathologist, or what would be the future in terms also of reliability and feasibility of genomic testing, FGFR testing, in bladder cancer?
EC: The most common thing is, of course, the sequencing and RT-PCR and so on. There have been several papers, especially around 2016, where they showed that immunohistochemistry is something which works pretty well. The only problem of these tumours is that very often if you have a mutation or whatever of FGFR2/3 very often you find these mutations and alterations in the upper part of the tumour but if you go down into the tumour the tumour, as it’s very heterogeneous, very often does not have these alterations. So this is kind of a problem. If you want to do immunohistochemistry, for example, you really have to do whole mount, the whole section, and not only TMAs.
The second thing, probably, which is not very good to do, is the FISH. You can do, for example for the gene fusions, you can do FISH but as the FGFR3 and the most important fusion, the TACC, is very, very close, it can be extremely tricky to make a report, a correct report, because you don’t see the signals very well. So probably, for me, immunohistochemistry is really underemployed because it really works very well; it’s an immune antibody which is easy to employ. But the actual standard, of course, is molecular biology.
AN: Great. A question that I have to you is related to the fact that we know already that luminal type tumours are enriched in FGFR 3 alterations. So I wonder whether the assessment of the molecular subtyping and the assessment, for example, of tumour as a luminal tumour may be a good surrogate for FGFR testing and potential activity of FGFR targeting in this disease. I would like to know your view.
EC: It’s a little bit complicated because you know you have different types of luminal tumours and the luminal-papillary are those which have these FGFR3 alterations. So it’s not every luminal tumour. The second thing is we’re just writing… the GUPS, Genitourinary Pathology Society, is writing a paper at the very moment and we’re going to submit it. Because the problem with this molecular testing and saying, ‘Well, we put GATA3 and FOXA1 and so on and then if it’s expressed it’s a luminal type,’ it’s not so simple. It’s not validated very often; some retrospective studies, we have enormous data but we do not have validated prospective data. Our recommendation in this paper will be against doing immunohistochemistry to do this kind of molecular testing. We do not think this is really very useful, unluckily.
AN: Great. So back to the data that have been generated on the FGFR targeting in bladder cancer. We know that erdafitinib received accelerated approval by the FDA in the United States, based on the data that have been generated in the BLC2001 study in which erdafitinib was tested in a single arm, single group, study on FGFR mutated or rearrangement tumours, including FGFR 2 alterations, 2 and 3 alterations. So based on the data from the BLC2001 study which was an open label, single group, phase II study with erdafitinib that included patients with FGFR 2 and 3 mutated or rearranged tumours to receive erdafitinib as single agent, the study actually provided a response rate of 40% in heavily pre-treated patients and actually established a new standard of care.
Interestingly, there have been so many data generated as a translation counterpart of this study or retrospective data, retrospective analysis, post-hoc analysis from this study looking at many aspects, part of which have been updated and presented at the last ASCO GU meeting, One of the most intriguing data that have been presented to me, and that I would like to discuss then with Eva, related to the fact that we have provided a landscape of surrounding genomic alterations that involve EGFR alteration, CCND1 alteration, BRAF alteration, that could be overall leading to a different prognosis or potentially to a different sensitivity to erdafitinib. So which is your point of view regarding the developments of targeted therapy in this disease? Shall we look at the overall landscape of genomic alterations surrounding FGFR3 or is everything the matter of FGFR alterations?
EC: No, I don’t think so. I think the surrounding is very important. Something which we really underestimate very often is the transition between the lamina propria and the urothelium. This is something which is, in my opinion, completely underexplored because as a pathologist I can see it, for example. You have different vascularisation and so on; you have different stroma; you have more or less inflammation and so on. So there are many things which are unexplored.
On the other hand, when I look at all the literature we have now so much data, we now have so much knowledge, and I have the impression that the further you go the more you really lose actually how to treat the patient because it is getting so complex with the tumour heterogeneity and all these different pathways. I’m really a little bit afraid that maybe we should be more pragmatic, I don’t know. It’s complicated, it’s really very complicated.
AN: I fully agree. We also should realise that there is always a distinction and a discrepancy between liquid biopsy and tumour tissue biopsy. We have reported the interesting data, for example from the Foundation Medicine Database, when we look at the fraction of FGFR and then the potential matching of FGFR3 alterations from the tumour assessment and the liquid biopsy. We realised that, for example, a difference of 180 days between the biopsy, tumour biopsy, and the liquid biopsy was significant in finding out a significant difference in terms of frequency of assessment and the reporting of FGFR3 alteration. So the timing is crucial.
EC: And the timing is crucial but the second problem with all the liquid biopsies, in my opinion but I’m not a specialist of liquid biopsies, you know you have the tumour bulk – some things happen inside the tumour and some things outside the tumour. So the tumour is spreading but probably it’s just spreading what is outside of the tumour and you don’t really get what is inside. So this is one of the problems.
AN: And back again to the way of determining FGFR alterations in regards to the use of specific compounds, we know, for example, that we have a 40% response rate with erdafitinib. Unfortunately, this information and this data have not been replicated so far with other similar compounds. For example, rogaratinib was used based on a selected patient population that was selected according to the mRNA expression. So do you think that the way of selecting patients and the way of assessing FGFR, back again to the former question but with a specific aim of looking at the data, might have somehow biased or influenced the results in terms of drug activity?
EC: I don’t think so because I think people are aware that these were selected patients. On the other hand, I think it’s useful to select patients with treatments which are extremely expensive and you don’t really know how they will be supported also by the patient. So it is a very good idea to do first a test and then the treatment.
AN: A further point which is highly important in clinical practice is based on the paradigm that FGFR altered tumours are less responsive to immunotherapy or more immunotherapy resistant in principle. Actually, when looking at the data from the BLC2001 study and potentially other data from a retrospective series, it’s pretty unclear whether actually these tumour types are less responsive, potentially, to immunotherapy, at least to single agent immunotherapy. What is your impression, your view, based on the data?
EC: I had the impression, but maybe I’m completely wrong, that these are more or less immune desert tumours. So this is probably the reason why they do not respond very well. From a really practical point of view, when you look at these tumours we do not recognise all of them. But there are some tumours which are really extremely papillary and we recognise them even without any molecular help. These tumours are never very infiltrated by lymphocytes. There was a paper where I was co-author recently where we talked about these large nested urothelial carcinomas which are really, by definition, extremely papillary and they have, really, over-expression of these FGFR3 alterations. It’s a small group of tumours but, nevertheless, these really extensive papillary tumours have a very particular aspect and, for me, they are really more or less immune deserts so that’s why they don’t react very well to immunotherapies.
AN: And I think that also we should wait for more data, robust data, on the combination therapy studies in, for example, combining lorlatinib and tarextumab The first, preliminary data have been presented at ASCO GU this year with an important response rate of 60% in the phase I part of the study. So the potential of shifting the microenvironment from cold to hot by combining the two drugs or by proceeding, for example, as was demonstrated with vofatamab, an antibody anti-FGFR3, in induction therapy with an anti-FGFR3 was able to convert or to shift the microenvironment from cold to hot and then leading to a response to combination therapy, or something like that.
EC: Yes, but really the problem actually is we have to look at several things. We have to look at the molecular classification; we have to look also at the alterations of FGFR3. We also have to look, for example, on the Nectin-4 things which are pretty new and pretty non-well-explored. We do not have very much data on that and also this is something which is really very promising. I think you should, as I’m a pathologist, of course, not let completely out of sight the really histological point of view. For example, we know that FGFR3 is never expressed in carcinoma in situ, which is really something which is pretty important.
AN: Yes, so you raised the anticipated and very important point that I would like to discuss with you in the last five minutes regarding sequencing. We know, for example, that data that have been just presented a few days ago demonstrated that, for example, luminal type tumours have a high expression of the Nectin-4 genes, even at the immunohistochemistry level. So in principal, immunotherapy, erdafitinib, enfortumab vedotin for an FGFR altered tumour, based on the fact that the first line is still a matter of immunotherapy somehow because we don’t have robust data in first line for the use of erdafitinib. What about the post-immunotherapy space? So if a patient is known to have and to harbour an FGFR altered tumour would you privilege the use of erdafitinib in sequencing principle or would you still privilege the approach of all comers with enfortumab vedotin based on the data?
EC: That’s a very difficult question and I think there is not complete agreement. Probably I would go for the second, based on the data, but it is pretty tricky because we do not have any guidelines as pathologists on what we really should and shouldn’t do the testing. This is something which is completely open – is it the primary, is it the lymph node, is it the distant metastasis? So this is something which is… after having been treated, shall we do the primary which has been treated? Nobody knows.
AN: It’s also interesting to realise that there have been some preliminary data showing that FGFR3 altered tumours may be less responsive to enfortumab vedotin also. Very preliminary data presented at this year’s ASCO meeting, ASCO GU. So it would be great for us as clinicians because we would be happy to envision a more clear future of our sequencing therapy but I think and I fear that the future will not be so simple to envision. According to you, the expression and the reporting of Nectin-4, as well as of Trop-2 which is a target of sacituzumab govitecan, another ADC which is FDA approved, should be incorporated into the routine practice for pathologist reporting, for example of cystectomy or biopsies or not?
EC: If you go really towards the guidelines, the guidelines are always just true pathology without any immunohistochemistry and so on and so on. On the other hand, I think it can be useful and I think this should be a trial. It can be a European or international trial where everybody has to do the same. We know Nectin is a little bit complicated because it’s really overexpressed in many tumours; it’s expressed in more than 93% of tumours. You have to be aware that it’s extremely heterogeneously expressed in the bladder tumours. So it’s pretty difficult, at the moment, to give really an answer because I have the impression we’re really just starting a new chapter and we do not really know very well to go. But from a purely pathological point of view we will not do Nectin to guide you with anything. It’s a little bit like PD-L1 which is still not recommended, neither in the guidelines nor in pathology guidelines.
AN: Lastly, we should mention important trials that are running in the FGFR targeting space which are represented, for example, by the PROOF302 which is a trial in the perioperative setting of patients with localised bladder upper tract urothelial carcinoma harbouring FGFR alterations who may receive an adjuvant period of infigratinib therapy and pan-FGFR inhibitor therapy compared to placebo if they have a high risk pathology, for example pT3 or pT4 tumour, after neoadjuvant chemotherapy.
So, Ava, my last question to you in these final minutes is about the upper tract tumours. We know that they are enriched of luminal type tumours so potentially enriched of FGFR3 alterations. There are trials with FGFR inhibitors like infigratinib in the adjuvant period post-radical nephroureterectomy, for example. In this space we have the data from from POWER chemotherapy, so the level 1 evidence of the role of chemotherapy in the same clinical setting. So do you think that specifically in upper tract tumours we will have the possibility to use FGFR inhibitors rather than immunotherapy? Mainly in specific contexts like the peri-operative setting.
EC: I’m very hopeful that it will work, yes indeed. On the other hand I think we will have to make a… really distinguish between these luminal-papillary tumours which are mostly very exophytic and so on and I think there are other tumours which will not do so well which are these which are really invading deeply and ulcerated and so on. Probably the surgeons during the operation will see pretty well, as well with the imaging, but also because they’re in the space, they look at the samples, what is going on, and think interoperative treatment would be, for sure, something very interesting in the upcoming years.
AN: So we have touched very, very briefly on many aspects of the treatment and diagnosis of these specific alterations of bladder tumour types. So it has been a great pleasure to discuss in these twenty minutes with Eva, as usual. Very insightful comments as usual and much of the work should be done. We have to wait for mature data from big phase III studies like the THOR study with erdafitinib comparing with chemotherapy, or other randomised studies, to declare the success or not of these specific alterations. But they are, of course, indeed very, very promising in this space for the patients. So thank you very much for your attention. I would like to thank the readership, I would like to thank the audience and, of course, ecancer TV for this possibility. I thank again Eva for participating and commenting with me. Thank you.
EC: Thank you.