FGFR Inhibitor MOA and Adverse Events

Rachna Shroff, MD: In terms of the safety of FGFR [fibroblast growth factor receptor] inhibitors as a whole, what we know is that the majority of the adverse events that were seeing in the FIGHT-202 study in the initial work within infigratinib, and that of course are of interest in say the PROOF trial, are what we call class effects. These are adverse effects that we know come from targeting the FGFR pathway. They are very different from the types of adverse effects that we see with standard chemotherapy like gemcitabine and cisplatin.

We are not as worried about cytopenias and knocking out people’s immune systems, but there are adverse effects that are really important in terms of quality of life for patients. I think we have learned well how to proactively manage these adverse effects, so that we can hopefully maintain quality of life for patients. Those include things like dry eyes, dry skin, dry mouth, dry mucus membranes, as well as some alopecia hair loss. There are some interesting nail changes that happen that can be quite painful for patients. Some of the FGFR inhibitors cause diarrhea, some more than others. Then of course there’s hyperphosphatemia, which are the elevated phosphorous levels in the blood, for which some patients require the use of phosphate binders and such to ensure that their levels do not get too high. There are some ophthalmologic concerns in terms of vision changes. Patients’ eyelashes grow a lot and they tend to grow inward and can cause abrasions, of the cornea. Then there’s more serious ocular concerns, which frankly have been rare so far in the FGFR story. These are all things that are going to be of great interest as we put more patients on these frontline types of studies.

With the myriad FGFR inhibitors that we have now, I would say that the majority of the adverse effects that we see are similar across the board. I have not seen dramatic differences, for instance, in terms of the rate of hyperphosphatemia. Interestingly, in the FIGHT-202 study, they had a fair amount of hypophosphatemia, but I think that the thought there was is that that’s because the patients lacked being aggressively followed and then their phosphorous levels were being aggressively managed, so they ended up with lower phosphorous levels. I don’t think that those things are dramatically different. I think that the mucus membrane and skin changes also have been relatively equal across the board in terms of the FGFR inhibitors. There’s perhaps an indication that there is slightly more diarrhea with pemigatinib, for instance, compared to the data that we have with infigratinib. There’s a lot of scientific thought going in to whether that’s because infigratinib is a little bit more of a specific FGFR inhibitor and does not hit the FGFR4 receptor as much as pemigatinib does. The numbers are small, and I think as we do larger studies and follow this a little bit more robustly, we’ll have a better sense of that. That I think has really been the only difference that has stood out, the diarrhea.

The FGFR1 through 3 receptors, across the different FGFR inhibitors, there seems to be a similar amount of specificity for those 3 receptors, and they seem to play a large role in the phosphorus excretion and homeostasis, as well as some of the changes that are seen, for instance, in the skin and mucus membranes. The FGFR4 is where, like I said, we see a little bit of a difference in terms of the FGFR inhibitor’s level of specificity for binding FGFR4 versus the others, and that perhaps may play a role in some of the differences that we’re seeing in toxicity. This is so far hypothetical. I think we need a little bit more robust data to know that for sure. When you look at how these drugs find each of these receptors, there are clear differences there between the FGFR4 versus the 1 through 3, for instance, in infigratinib versus say pemigatinib.

Transcript edited for clarity.