RH: Good afternoon. Welcome to this ecancer expert to expert forum. My name is Robert Huddart, a Professor of Urological Cancer at the Institute for Cancer Research at the Royal Marsden Hospital in London. With me today is my colleague, Ignacio Durán, medical oncologist from Santander in Spain. The subject of this expert forum is the use of FGFR inhibitors in the management of advanced bladder cancer. Alongside the excitement of using immunotherapy agents one of the new breaking areas is the development of targeted therapies based around targeting the FGFR receptor which has been developing over the last two to three years. One of the lead compounds, and at this year’s ASCO there were a number of interesting abstracts which have given further information on the use of these agents. One of the first reported agents was the drug erdafitinib, an FGF2/3 inhibitor, which is based on an FGFR mutation screening tool. This single agent dose, the updated information was given on the response to this showing a 40% response rate in patients treated with this agent with a durable response and 30% of patients maintaining a response for a year and a significant number of patients living for two years following treatment, in fact almost 30% of patients alive two years later, confirming this agent has significant activity. Of course this has now been licensed by the FDA with a companion diagnostic for use, although not at the moment in Europe. There are some issues regarding toxicity with mucosal and eye toxicity needing to be managed but this looks like an interesting development in the management of patients.
The next area that’s likely to be in development is whether these drugs should be used in combination. One of the abstracts at the ASCO meeting reported on the early results of the FORT-2 study looking at a combination. So, Ignacio, what did you make of the use of these agents as a combination?
ID: Thank you Robert. As you mentioned, this is a very interesting area and there is no doubt that this is coming probably to stay around and is a new family of compounds that is going to make a change in the way we treat bladder cancer patients. One of the issues probably which is still ongoing and depending on where we live around the globe is how we test for these mutations. But, as you mentioned before, not only single agents have demonstrated activity but also there are some data recently presented about combining an FGFR inhibitor with an anti-PD1 or anti-PD-L1. We had previous experience combining FGFR inhibitors with anti-PD1 but the data presented in the FORT-2 study is a combination of rogaratinib, an FGFR inhibitor, with atezolizumab. This is a phase Ib/II study that checked two different dose levels, 800mg b.i.d. plus the usual dose of atezolizumab or 600mg b.i.d. of this compound rogaratinib combined with the usual dose of atezolizumab of 1200mg q three weeks. This second lower dose was deemed as the tolerated dose, they couldn’t really maintain patients at the dose of 800mg. The remarkable thing is that the overall response rate was about 44%. The results were an interesting thing about this drug rogaratinib is that the patients are not selected based on DNA mutations, they were selected based on mRNA alterations. I think this is a differential fact of this compound. It’s true that if you look at other studies in this setting such as the NORSE study that was a combination of erdafitinib plus anti-PD1, the overall response rate was very similar, it was about 44% as well. So you could have doubts about thinking whether these two compounds have synergy or are only additive activity. But I think it opens a scenario that is worth evaluating and now there is a phase II study which is recruiting with this combo.
RH: Do you think that these agents are likely to be synergistic or additive in their nature? I think that we’re expecting that the single agent FGFR inhibitors seem to be reporting round about 25%, the erdafitinib study in the BLC2001 study was probably the highest rate of response, round about 40%, what do you make of that?
ID: Even looking at the small numbers and initially we were fortunate to participate in the NORSE study and we saw some remarkable activity with this combination although not as long-lasting as we would have liked. I had my concerns because, as you mentioned, erdafitinib single agent is over 40% response rate in patients also pre-treated. So if I had to guess I would probably go with additivity rather than synergy because the synergy would have given probably better results.
RH: How do you think we are going to… Most of these drugs are being marketed at patients with abnormalities – for the erdafitinib it’s for mutations, for the rogaratinib it’s based on an RNA hybridisation screen. Which do you think is likely to be the one that we’ll be using going forward and how is that going to affect our practice? Or how do you think it’s affecting your practice nowadays?
ID: I think that’s a critical point because these compounds, and people need to be aware of this, are only useful in patients with certain FGFR alterations so it’s critical the way we get those results. Probably the answer is different, as I mentioned initially, depending on where you live. If you live in areas where erdafitinib is already approved you are going to look for FGFR alterations according to the kit, the companion diagnostic that was approved along with erdafitinib which is done in tissue. It’s actually an RT-PCR from paraffin embedded tissue. But there are other options that are coming up and probably are going to replace that, let’s say, more traditional approach and this is the liquid biopsy. So the way we’re doing it right now to screen for patients to be included in the studies with FGFR inhibitors is through a liquid biopsy. It’s faster and it’s probably more precise of the current situation. It’s probably going to give you better information than looking at a tissue that sometimes is archival tissue and that has some implications.
RH: I think my concern about relying on the archival approach is partly because there is a certain number of patients who fail the quality assurance process for that and secondly just the logistics of retrieving an archival block and sending it to a lab, getting a result back can often take several weeks. When only a small proportion of patients, usually most of the studies it’s round about 15% of patients, screen positive for these agents you can’t really wait for that result unless you know it and actually it also suggests that we should be doing this early on in the pathway so we can actually apply the drugs appropriately.
ID: Absolutely. I think there are two issues to this argument. One is the low frequency of these mutations – literature tends to tell us it’s about one out of five patients so it’s about 20% of the patients that we see in the clinic. In real life the number, at least in my experience, seem to be a little bit lower than that, sometimes it’s difficult to find these patients. If you look at the numbers of the erdafitinib study they tested over 2,000 patients to get about 210 that were eligible to be included in the different cohorts. So it’s a low frequency of these alterations so that’s the first challenge. The second challenge is if you are going to find it, find it quickly because patients cannot wait for too long. So this is where liquid biopsy comes into play and it really turns into a very valid option because we’re going to have the results, probably, in a much faster time. I think that’s very important.
RH: I guess the tendency is, and it’s already happening with these agents, is the thought of bringing these drugs in earlier, even into the neoadjuvant setting. I think there was also an abstract on infigratinib, if you…
ID: Yes, obviously what we normally do in oncology we start in the later stages of the disease and when we find there is some activity we move into earlier stages. Probably with this approach, which is based on a molecular alteration, it makes sense and we’ve seen some interesting results in lung cancer this year at ASCO, very relevant in the adjuvant setting with targeted therapies. So it could be the case also in bladder cancer. So in this regard some data was presented at this ASCO with infigratinib. Infigratinib is another one of these FGFR inhibitors and the interesting thing is that infigratinib seems to have a bit of a different profile or a different action, depending on whether you’re treating bladder cancer or upper urothelial tract cancers. It seems to have a higher activity in the upper tract tumours and we don’t know whether this is because of a different mutation profile and R248C mutations seem to be more common in upper tract urothelial cancer. So the data presented at this year’s ASCO was a retrospective review of the activity of infigratinib in different settings and it comes to demonstrate that it’s probably worth moving it to these earlier stages that you mentioned. Actually there is this study called PROOF 302 which is an adjuvant study after either cystectomy or nephroureterectomy for an upper tract urothelial cancer, a very promising strategy.
RH: And I think there are even plans for people looking at this in the neoadjuvant space as well. I think this would probably push us towards ensuring that we need to look at these patients very early on in the pathway. Okay, well thank you very much for discussing that with me Ignacio and thank you everyone for joining us today for this talk. We’re going to wind up now. Thank you very much for your attention and listening to this programme.
