FGFR-Specific TKIs Versus Multikinase Inhibitors

Sumanta Pal, MD:I definitely think that the more we can home in on a) the right population of patients and b) the right drug to hit relevant genomic targets, the more successful we’re going to be in treating bladder cancer. When we think about agents like dovitinib, for instance, the issue in the context of those trials might have been the affinity of the drug for a multitude of different receptors. Although dovitinib certainly has affinity for fibroblast growth factor receptor, or the FGFR family of proteins, it also has affinity for multiple other kinases. And I think that may potentially lead to some diminution of its activity and some increase in its toxicity. So I think that’s probably why agents like dovitinib probably faltered. I will say that beyond dovitinib, now we’re of course very fortunate to have agents like infigratinib, erdafitinib, that really home in on FGFR3. So, beyond our ability to select patients with FGFR alterations, we’re now really able to treat those patients with a much more potent specific inhibitor, increase efficacy, limit toxicity.

With the multikinase inhibitors that are supposedly abrogating signaling through fibroblast growth factor receptor, I think you run into a lot of off-target effects. For instance, with dovitinib, I think some of the issues that we ran into pertain to diarrhea, pertain to perhaps hand-foot syndrome, some of the things that I would expect from VEGF receptor antagonism. On the other hand, when it comes to the more specific kinase inhibitors, we might see a little bit more in the way of on-target toxicities, things like hyperphosphatemia and what have you. Those are by and large quite manageable. But we actually limit the extent of diarrhea and other toxicities that we see. So I think there’s some rationale for really homing in on the agents that target FGFR family proteins more specifically.

Richard Kim, MD:Dr Shroff, there are other TKIs [tyrosine kinase inhibitors] that have been studied. We talked about very selective FGFR inhibitors. But there are also nonselective TKIs that have seen studied. I think you’ve had some experience as well using a drug like pazopanib or ponatinib, and I personally have experience using regorafenib, and I’ll talk a little bit about that as well.

Regorafenib has been studied in a couple of settings in cholangiocarcinoma. And the biggest difference between the study that we did versus the one that’s using FGFRs, is that we did not enrich anybody for FGFR fusion. We allowed all-comers. And we had a study, it was a single-arm phase II, a 40-patient study. The results were modest. The response was less than 5%, and overall survival [OS] was anywhere from 8 to 9 months. There were some patients who did very well. However, in a single-arm study, it’s tough to tell what benefit the patient’s going to derive from it. However, at GI ASCO [the Gastrointestinal Cancers Symposium, American Society of Clinical Oncology] this year, there was a trial done in Europe which was a small randomized phase II study where they randomized to placebo versus regorafenib. In that study the primary endpoint was PFS [progression-free survival]. And they met that endpoint and basically doubled going from 1.5 to 3 months of PFS benefit. There was no difference in overall survival, but it was not powered to show OS benefit.

But with that enriching patient population, it’s tough to say whether this, what we call not selective TKI, will work as well in patients with FGFR fusion compared to those very selective TKIs.

In your experience, I know you've done studies with other TKIs as well, are there any comments about other TKIs?

Rachna Shroff, MD, MS:I agree. I think unfortunately we had a study with pazopanib and trametinib, for instance. And this was before the true understanding of how important these actionable alterations are and how much of a driver these FGFR fusions and such are. And so we saw a low amount of activity, but it was not a selective population, and I think that’s where we were remiss. But I do have to ask with these multikinase inhibitors, do you worry about additional adverse effects?

Richard Kim, MD:Yes. By blocking other pathways you’re going to get more adverse effects. We talked about adverse effects caused by pan-FGFR inhibitors. But by blocking VEGF, other receptors, you’re going to get hypertension, hand-foot skin reaction, more fatigue. And that’s been sort of the dose limiting stuff as you know with other…TKIs.

So yes, I think if you bought other pathways, if it’s not a clean TKI, I think we get more toxicities that you have to deal with other than your typical FGFR toxicities you see.

Transcript edited for clarity.