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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a medical oncologist at North Western University. I am thrilled to have here with me today a friend and colleague Dr. Petros Grivas who's an associate professor of oncology at the University of Washington where he practices in the Seattle Cancer Care Alliance, and the Fred Hutchinson Institute. Thank you so much for being here with me today Petros.

Petros Grivas: Thank you so much for having me and having this nice discussion. 

Alicia Morgans: Of course. 

So we're starting this new concept, these quick takes to really in rapid fashion, high efficiency, get across some key points that I think that can really impact clinical care. The quick take that I wanted to talk with you about right now, is a focus on Erdafitinib, a medication that was just approved a few months ago for the treatment of certain urothelial cancers, certain metastatic urothelial cancers, and I just want to understand from your perspective, who are the patients who can get this medication? How do you find them? And then, how do we follow these patients, what do we think about in terms of side effects? So why don't we start with, who are the patients who can potentially benefit from Erdafitinib?

Petros Grivas: Great questions Alicia. 

Erdafitinib, as you mentioned was approved by the FDA on April 12th, 2019 for the treatment of metastatic bladder cancer, tumors who exhibit mutations or fusions. The activated receptor, specifically the isoforms FGF receptor 2 or FGF receptor 3. There is a companion diagnostic that was also included in the FDA approval, which is a kit by Qiagen, a RT-PCR test, that specifically tests for FGF receptor 2 and 3 mutations and fusions. Having said that, the approval specifies the approval for the indication, I would say, for patients who already have received platinum-based chemotherapy. So those patients have been pretreated with platinum-based chemotherapy and they exhibit this genomic alteration from the tumor tissue. This approval was based on the phase two clinical trial that was presented at the ASCO 2018 annual meeting by Dr. Siefker-Radtke, and her team, that showed really promising data with an overall response rate with Erdafitinib approaching 40% in patients again with previous treatment with platinum-based chemotherapy, which is, I would say, very impressive in that particular pretreated setting. 

If you think about the comparative landscape, based on historical data checkpoint inhibitors have an overall response rate between 15-20% in that platinum-refractory setting and Docetaxel chemotherapy has a comparable response rate in that range. So definitely promising. Again, this was a single out-patient study, so definitely no randomization. The randomization phase 3 trial is ongoing, comparing Erdafitinib with chemotherapy or checkpoint inhibitor, two different, I would say, models in that phase 3 trial. The phase 3 results are pending but the approval of the FDA was accelerated and not regular with the contingency of waiting for the phase 3 trials. Who are the patients and how do we find them? As I mentioned, there's a companion assay and there is the opportunity to do genomic sequencing in the two academically available platforms or commercial available assay's outpatient platforms. I don't need to mention specific names but there are a number of vendors out there who actually have the kinds of test. 

The tumor tissue for particular genomic alterations, PD-L1, MSI, and other biomarkers, and through that testing the report may come back and they may mention the presence of a FGF receptor mutation or fusion. The tricky part is which mutation profusions are relevant to this treatment. I think the key part there is to look at the report carefully and see if there is any language or comment regarding the activating nature of the mutation or fusion, because, what you really want to know is whether this is a variant in genomic alteration but impacts and increases the function of the protein. The FGF inhibitor 2 or 3 and the use of language in the report and also the publicly available data suggest which mutations or fusions can be activating. 

After this finding is present either to the companion diagnostic assay or another commercially available or academic available platform then the only way to order a definitive, assuming that the genomic alterations are present, is to order the medication so that the US Bioservices would serve the only particular mechanism. The only mechanism through which the agent, the drug, can be ordered and there is a form through the US Bioservices that is a publicly available and providers can fill out the form with specific information about the agent and there is a question about the form, whether the patient has the particular genomic alteration of interest. But answers us here that the FGF inhibitor amplification is not part of that. There was no test in the clinical trial and there is a separate clinical trial testing the value of this agent in amplified tumors in the basket trial [inaudible 00:05:47]. We don't have yet a conclusive data about amplifications. After this form is being filled out, is being sent over as a prescription to US Bioservices and their particular boxes and information will be filled out in that form and then that data is actually evaluating insurance authorization and potential copay for the patient and the provider, and their team is being notified relatively quickly with a short turn around time. 

Then the medication, after the steps are being taken, can be sent to the patient. It is very important to discuss a little bit about how to monitor this medication. How to evaluate for side effects and also the dose. The medication could potentially cause some visual changes, particularly blurry vision, dry eyes and about 10% of patients or so may get what we call Central Serous Retinopathy, CSR, which is usually mild, grade 1 or grade 2, and usually goes away if the drug has been helped. User does not result in any permanent visual loss or anything like that. But, of course, can create anxiety and distress from the base and for the medical team. So a baseline eye exam is maybe a good idea but is not mandatory for baseline. However, I think the label mandates eye exams monthly for the first four months on treatment with Erdafitinib just to monitor for those potential findings in the eye. 

That the ophthalmologist or optometrist with the necessary equipment that can [inaudible 00:07:40] exam that can look at the pupil and also in the retina, with also a test called OCT, which is an optical tomography. It is important to evaluate for the potential emergence of these eye findings. Specifically Central Serous Retinopathy or any other eye events. Otherwise, another relevant factor is the high phosphate level and that is relevant because it has potential toxic implications with either high phosphorous can precipitate calcium and can cause calcifications or can have implications in other organs, however, beyond the toxicity aspect of it, it also the dose titration factor based on phosphate level. The starting dose of Erdafitinib is eight milligrams daily, and about two weeks on treatments there is a second phosphate level with blood work and this phosphate level can guide dose. 

If phosphate level is less than 5.5 and there is no eye toxicity, visual toxicity and no grade 2 or more other toxicities. And again the phosphate level is less than 5.5 the dose can be titrated up to nine milligrams daily. So eight milligrams goes up by one milligram to nine milligrams daily. This can have logistical implications for the team, the different strengths of pills may be utilized, like four milligrams plus five milligrams equals nine. Then the patient is being monitored, so there are some dosing indications there. Beyond that, eight is usually well tolerated but can cause potential side effects like stomatitis, mouth sores, some skin changes, rashes, sometimes nail changes as well as less commonly, diarrhea, no or low appetite, or less commonly other events. Definitely watch monitoring close to the patients, both for response and toxicity and cause of mentioned phosphate levels can be relevant. If the phosphate level goals above seven, their phosphate binders that can be used in that sense. 

And of course, low phosphorous diet, which can be hard, and like I said earlier, if there is some significant increase of phosphate level on treatment usually people start on a regular diet, you may utilize a low phosphorous diet and potential later on it being on the level phosphorous binders if need be for this particular side effect. Overall, a very promising agent. Important for patients with this particular alteration, which are present in about 20% or so of medical subjects with urothelial cancer, but definitely important for the education that will provide us and the team and the patients about the logistics of ordering the [inaudible 00:10:48] phosphate level from treatment as well as the toxicity management.

Alicia Morgans: Wonderful. So just to recap very briefly, either the companion diagnostic or an approved next-gen sequencing can be used to identify these fusions and FGF mutations. We're going to put up a link that can illustrate some of the FGF-R3 gene mutations and the fusions, FGF-R3 and R2 gene fusions that were included in the clinical trial. The phase 2 that you mentioned so that practitioners can actually look at that list, but, as you mentioned before we really want to identify patients with activating mutations. Sometimes if you're not sure, certainly a call to whoever is doing the test can be useful. If you're using a particular company to do your sequencing you can call that company and say, is this an activating mutation or maybe in the body of the report not just in the list of the mutations. 

We are also going to put a link up to some information about patient co-pays assistance. As this is an oral agent, co-pay assistance can be necessary for our patients to get some of these therapies. We should just also mention that there are multiple other FGF targeting treatments that are currently in development. We may see that this landscape also becomes more crowded over time. Engaging early on with an ophthalmologist and watching phosphate levels is very very important. The toxicities that we see are reversible but we have to keep track of them and this ophthalmologic change is not something we as oncologists are used to. Being aware of it on the front end and engaging early and having someone for the patient to see, on a regular basis, is going to be critical. Thank you so much for your time today, Petros. As always we appreciate your expertise.

Petros Grivas: Thank you very much for having me.