Case 3: Experience With FGFR-Targeted Therapies in Bladder Cancer

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Arlene O. Siefker-Radtke, MD:I’d like to ask a few more questions. Have any of used erdafitinib, or any of the other FGF receptor inhibitors?

Tian Zhang, MD:Yes, we’ve had other FGFR inhibitors on trial. And then also I’ve used erdafitinib as part of the expanded access protocol early on, and then now as standard of care. So I have a handful of patients. We’ve been dealing with the nail bed changes, with the rashes. And as you say, taking some time off, and then going back to our small molecule inhibitor types of dosing schedules, we take a 2-weeks-on, 1-week-off approach for some of these patients who have really significant toxicities despite dose reduction. And then also paying really close attention to baseline ophthalmology scans and then periodic follow-ups.

I’ve also noticed some dry mouth, stomatitis, mouth ulcers that also occur. Taste changes. My patients will say, “You know, food just tastes off, and may have a metallic taste, or taste very different than I’m used to.” So we’re dealing with getting dietitians into the clinic at their consult visits, and making sure that we’re keeping up with their nutrition as well.

Arlene O. Siefker-Radtke, MD:Great. And I know some of the trials that are ongoing, some of them rely on the presence of mutation, but some are using other strategies, including amplification or overexpression ofFGF. Betsy, what are your thoughts about the use in non-FGFmutated, but overamplified states?

Elizabeth R. Plimack, MD:I think it’s a pretty rare condition. We had the AstraZeneca FGFR inhibitor years ago in phase I, and I think we screened 62 patients to treat 2, and this was across tumor type. So prevalence I think will be an issue if looking at that. I think scientifically it makes sense, if you’re overexpressing the target, to then hit the target. But I’m not sure it will be clinically relevant until we can really find enough of those patients.

Arlene O. Siefker-Radtke, MD:How about you Tian?

Tian Zhang, MD:Well you know at ESMO [the European Society for Medical Oncology 2019 annual meeting], the BISCAY data came out as well, and specifically regarding the population withFGFR-positive mutations treated with this AZD4547 drug that targets FGFR—there were 20% objective responses; I think it’s pretty comparable to other FGFR agents we’ve seen. I don’t like to useFGFamplification on its own. Mostly from other data I’ve seen that the amplification patients don’t necessary respond quite as well as the patients who have the true driver mutations, or translocations that are driving tumor proliferation.

Arlene O. Siefker-Radtke, MD:We saw in the BISCAY data a response rate probably about half what was achieved with erdafitinib. What do you think about any of the other FGF receptor inhibitors? Are there any others that are promising?

Elizabeth R. Plimack, MD:I think erdafitinib is the one to use right now. It’s FDA approved. It’s one we can use in the clinic, we have the most data on it. There are more trials cooking that will inform us better. And I think the prevalence of the mutation in the population that we’re using it in right now, metastatic, has been defined. So I think until we see something significantly better than erdafitinib, it’s something worth investigating in clinical trials. But I would agree with you. I don’t think the AZD4757 has sort of met that bar that’s been set by erdafitinib.

Arlene O. Siefker-Radtke, MD:So perhaps a lower bar with some of the previous or early inhibitors that were given whether it’s intermittent scheduling or just inhibitory concentrations that weren’t quite as optimized, may make a difference. So not all FGF receptor inhibitors are created equal at the moment.

And any thoughts about the ideas of combining it with an immune checkpoint inhibitor?

Tian Zhang, MD:We also saw data from the BISCAY trial combining the AZD4547 FGFR inhibitor with durvalumab. Certainly we saw more disease stability in patients who were treated with the combinations than with the FGFR inhibitor alone. Some more durable effects. The progression-free survival, for example, was 19% at 6 months, and then also for 1-year overall survival, that rate was 47%.

So I think it’s promising in combination, and certainly active therapies in an active population where it’s a target, hopefully will improve overall efficacy. We’re looking at this in a less controlled population where it’s still hypothesis generating and doesn’t change my current standard of care, which is an FGFR inhibition alone. I also think that when we’re talking about these combinations, we also need to be careful of any overlapping toxicities, and trying to tease out which drug is responsible for the adverse effects that we’re seeing.

Elizabeth R. Plimack, MD:I think the caveat we talked about with the IMvigor130 data holds true here. I would rather give these in sequence to achieve the same results than give them together with overlapping toxicity to achieve the same results. So until we have a sense that we’re helping people live longer or really denting the disease to a greater extent with combination versus sequential, it’s nice to have multiple options for patients along the way, especially as their disease evolves both clinically and molecularly, as we talked about.

Arlene O. Siefker-Radtke, MD:It sounds like we really need for that combination to meet the scientific rationale that it’s, you can take an immunologically cold tumor and really warm it up to the immune system and knock it out of the park with a good survival benefit or dramatic response before we’d be willing to move this forward in all patients in the clinic.

Elizabeth R. Plimack, MD:I would agree, and I don’t think we’re quite seeing that with the BISCAY data. The numbers are small, but I didn’t quite see it in those data.

Arlene O. Siefker-Radtke, MD:OK, so the first data not looking quite as good, although Tom Powles, MD, sort of indicated at his presentation that maybe the AstraZeneca compound wasn’t quite as good at hitting the target compared to….

Elizabeth R. Plimack, MD:I think the single-agent data support that hypothesis.

Arlene O. Siefker-Radtke, MD:Some of the other agents. We’ll be looking forward to additional trials coming down the road showing, does it make sense to give it in both an amplified and nonmutant state? And does it make sense to combine it in a thoughtful fashion, or is it even a thoughtful fashion, to combine it with immunotherapy? So please, I would again ask the listeners, if you have a patient with anFGF-altered tumor, we have lots of great trials for them. So always consider clinical trials in this space.

Transcript edited for clarity.