FGFR Inhibition: A Novel Therapeutic Strategy - Episode 7

FGFR Inhibitor Toxicity Profile

June 21, 2019

Sumanta Pal, MD:I have to tell you that in my experience with infigratinib and with other FGFR [fibroblast growth factor receptor]-directed compounds, it seems to be a very well tolerated class of drugs in general. The one thing to bear in mind, and this is really based on a rather complex mechanism, is that FGFR inhibition can potentially lead to hyperphosphatemia. Now, as medical oncologists, that’s not something that we deal with day to day in the clinic, so it does require a little bit of nuance in terms of management. But having said that, we do think that hyperphosphatemia really reflects an on-target effect, it may actually be as a consequence of FGFR1, not 3 in this case, and its ability to affect phosphate transport. With that in mind, beyond that, we did have some concerns early on about potential corneal or ocular toxicities with FGFR-directed therapies. I have to tell you, I really haven’t seen that to any significant extent. So with agents like infigratinib, I’m not particularly worried about that.

I definitely think that there’s some rationale for increasing specificity for FGFR, if possible. And we do that with infigratinib. Again, we’re hitting FGFR1 through 3 at these nanomolar concentrations. We’re not getting FGFR4 to the same extent. And importantly, we’re really avoiding other potential targets like VEGF receptor, etcetera, that may not be so important to the biology of urothelial cancer. So I think by virtue of that, we really do potentially spare patients toxicities like diarrhea, etcetera. We certainly do see it with some incidence, but not at the same extent that I would expect, for instance, with agents like sunitinib or pazopanib, your classic VEGF inhibitors.

In terms of a side-by-side comparison of all these agents, obviously it’s very challenging to do with the data that have emerged so far, I do ultimately feel like the specificity that infigratinib has for FGFR3 and the fact that it really hits that particular moiety instead of other off-target receptors and so forth, is going to lend itself to further clinical development of a compound. I definitely think that the inhibition that FGFR3 demonstrates with infigratinib exceeds that with the other compounds. So, when it comes to on-target effects like hyperphosphatemia, when it comes to potential ocular toxicities, I don’t expect too much of a difference. But I do think we’ll see more limited diarrhea and other off-target effects than we’re seeing with other entities.

Richard Kim, MD:Thank you. You’ve had a lot of experience with this drug in the trial basis and in the clinic as well. This is a new class of drug that also comes with new adverse effects. And you’ve treated some patients with those drugs. Can you tell us sort of a general adverse effect that you see with an FGFR inhibitor that is different than the other TKIs [tyrosine kinase inhibitors]?

Rachna Shroff, MD, MS:One of the things that everyone talks about is the hyperphosphatemia. And that we know is an on-target effect and this is a class effect, we see it across the inhibitors. That is something that now that we know it, we know how to manage it. With early intervention in terms of low phosphate diets and use of phosphate binders and things like that, the clinical implication of that is actually relatively low. But it is an important adverse effect that we talk about, and having the awareness to manage that early on is important.

The other things I think are day-to-day things. There’s dry eyes, dry mouth, dry mucous membranes, that obviously is not the most pleasant thing for our patients. There are ophthalmologic changes. A lot of these studies require regular and early ophthalmologic evaluation. The more dramatic things, such as corneal or retina effects, are obviously what they’re looking for.

But there are things like trichosis, that basically eyelashes are growing to the point that they’re irritating and scratching the cornea, and that can affect vision. You were mentioning something about the importance of a multidisciplinary approach. How do you approach these patients when you put them on these drugs?

Richard Kim, MD:I think hyperphosphatemia is something that we now know. So this is where we get our dietitian involved at the forefront, to educate the patient about a low phosphorous diet. And this is where eye issues are possible, as you mentioned, but even the retinal detachment, those are not very common. If you see one, it’s a very serious condition where you need a treatment, you need help from ophthalmology as well. So I think this is where everybody has to be on board to manage those kind of adverse effects. Other adverse effects that you mentioned are the skin changes, the nail bed changes, which you may need to get involvement of the dermatologist as well.

The kind of adverse effects we see are dependent upon which receptors you hit. For example, hyperphosphatemia is more FGFR1 driven, it’s not FGFR2. And FGFR4 is a receptor that causes GI [gastrointestinal] toxicity such as diarrhea because we know that FGFR4 is responsible for bile acid secretion. So if there are drugs targeting FGFR4, then the FGFR2 or 3, you may get more diarrhea toxicity as well. Depending on which FGFR inhibitors you use, if it’s hitting the FGFR4, you may have to sort of take care of the diarrhea issue.

Rachna Shroff, MD, MS:Do you find that the diarrhea, if it’s more of a pan-FGFR inhibitor, is still relatively easily managed with anti-diarrheals, loperamide and that sort of thing, or does this seem to be a different or bigger problem than that?

Richard Kim, MD:I’ve done studies with pure FGFR4 inhibitors, and we know that that’s a dose-limiting toxicity, GI toxicity. So if you have a pan-FGFR inhibitor and if it’s able to spare FGFR4 to some degree, obviously that’s preferred. Because even the grade 2 diarrheas, you’re still going to the bathroom a couple of times a day. If you could avoid that, it will be very beneficial. Once again the target is FGFR2, not FGFR4. So if you could avoid any of those other receptors if possible, I think that would be very helpful and I’m sure the patient would appreciate that as well.

Transcript edited for clarity.