Alicia Morgans: Hi, my name is Alicia Morgans and I am an Associate Professor of Medicine at Northwestern University where I practice GU oncology. I am delighted to have here with me today, Dr. Arjun Balar, who's an Associate Professor of Medicine as well, and the Director of the GU Medical Oncology Program at the Perlmutter Cancer Center. Thanks so much for coming to talk with me today.

Arjun Balar: Thanks so much for having me.

Alicia Morgans: Great. So Arjun, you know there have been lots of things changing in the landscape of bladder cancer treatment and one of the most exciting has been a recent FDA approval of a new drug called erdafitinib and I'm just wondering if you can talk to us a little bit about the drug, how it works, you know it is a targeted agent and some of the studies that led to its approval in this setting.

Arjun Balar: Sure. So, erdafitnib, to jump into the target and how it was developed, it's important understanding just you know, the biology behind why this drug was developed in the first place. FGFR alterations and specifically ones involving the third and the second isotype of the receptor, FGFR3 and FGFR2, these alterations that are activating, are present in anywhere between 15 to 20%, possibly higher in patients with muscle invasive and metastatic bladder cancer.

We know that these are genetic drivers and that therapeutic targeting of this pathway can lead to responses. A number of agents have been tested. erdafitnib is clearly one that has demonstrated activity and the study that ultimately led to accelerated approval was a trial called VLC 2001 and it was actually a single arm open label, Phase I trial as part of a dose expansion study that looked at about 87 patients who are treated on this trial.

It's also important to know that the patients who were treated on this study, were centrally selected in terms of identifying FGFR alterations and specifically in FGFR2 and FGFR3, and they focused on recurring alterations that are known to be driver mutations and these patients were treated at a dose of eight milligrams once daily.

The data that was presented at ASCO 2018 last year, were actually quite promising about just over 40% of patients were achieving a response. So the major efficacy outcome for this particular study was an objective response by RECIST, and the toe objective response rate is 32%, suggesting that there's clearly activity for this drug in this population including 2.3% of patients achieving a complete response.

The average duration of response, and which is very typical for agents targeting with specific molecular targets, was about 4.5 months. But clearly there was benefit and it was this trial that actually led to accelerated approval for this drug in this patient population.

Alicia Morgans: Great. So, Arjun, I assume that you may have had some experience with this medication and we're really excited about the response rate, but I'd love to hear your experience with how patients ended up tolerating this targeted agent.

Arjun Balar: So I, I was not specifically involved in this trial, but I have treated patients on other trials. They’re FGFR3 inhibitors. There are class specific toxicities that are commonly observed, and I think are there important to highlight, especially as we start expanding the use of these agents and other agents start coming into to use, and also as we have identified the duct you for three mutations are present in higher proportion of patients with non-muscle invasive bladder cancer. These agents will be tested so it's important to know as a class effect and you know just how these drugs work.

And in general, the majority of patients, you know that the side effects that I've noticed, are certainly fatigue, some mucositis, kind of break down and peeling of the nails of the fingers and the toes, a little bit of a rash, also alopecia. Patients do experience some hair loss and there's also elevations in serum phosphate levels that can occur with this treatment. It's something that actually needs to be monitored during the course of treatment. And for some patients who actually don't develop hyperphosphatemia, the dose can actually be increased from eight milligrams a day, which was tested in this trial, up to nine milligrams a day.

The other thing that can happen is a condition called serous central retinopathy, which is essentially the deposition of serous pigments between the retinal layer and it can actually cause a focal area of visual field defects and actually, that was determined to be found about 25% of patients who were treated on this trial.

It is reversible, which means that once patients discontinue or hold treatment it will reverse. So it's rare to see any permanent vision damage, but this is something that many oncologists may not be familiar with is sending patients to ophthalmologists for baseline exams and also on treatment OCT exams just to make sure that they're not developing this and so that dose adjustments can be made as necessary.

Alicia Morgans: I agree. Thanks for highlighting those because like you said, I think that those are kind of unique side effects to this class of agents and I know when I had treated some patients with this medication, we used some phosphate binders to ensure that serum phosphate levels stayed in the appropriate range and we definitely partnered, certainly during the clinical trial, very closely with our ophthalmologists. I think, you know, from a medical oncologist standpoint, it is important or from a urologist standpoint should urologists encounter these medications, t's going to be important to have an ophthalmologist sort of on hand, just that you have someone that you can get your patients into relatively quickly because ophthalmologist offices are often sort of overflowing with many patients and it can be a challenge to get patients in, in a timely manner.

So I think kind of setting up those connections on the front end as, as in general as a practice will be an important part of using these medications.

So, moving on, can you tell me a little bit about how you select patients for these treatments? Because this is one of the only targeted agents that we really need to identify patients who have these FGF alterations and for bladder cancer that's kind of a new thing. And so how do you go about targeting these patients.

And I would say that there is a companion diagnostic that's been approved to be used with this medication. But you know, you and I just talked offline for a moment. There are other ways that we can identify patients that may be outside of that companion diagnostic. So how are you identifying these patients?

Arjun Balar: Yeah, absolutely. So you know, one of the things that's really exciting about having an FDA approval for a drug that's targeted drug in this setting is that it opens the way for us to have patients undergo biopsies even for metastatic disease, for tissue, for the purpose of sequencing. And it will open up, hopefully, you know, many more opportunities to study other molecularly targeted agents down the road.

But right now, the basis for this drugs accelerated approval was specifically on FGFR2 and FGFR3, activating genetic alterations. And these are clearly codified in the FDA label.

It is paired with a companion diagnostic as you mentioned that this is the manufacturer's QIAGEN, it's an RTPCR based assay. However, my understanding when I've spoken to Janssen and others within the company, is that that other CLIA approved assays such as a Foundation One and Caris that can also identify mutations in this pathway, will also be valid for the purposes of obtaining an approval for the drug, assuming that they again have a specific mutations in FGFR3 and FGFR2.

It is important to highlight that there are other drugs that are targeting the FGFR pathway that may have shown activity in patients with other FGFR or FGF ligand mutations or amplifications. But again, this particular drug is restricted to activating mutations in FGFR3 and FGFR2.

So there should be, hopefully, access to patients who have a central testing based on other CLIA approved assays and not necessarily have to be off the companion diagnostic.

Alicia Morgans: Great. Yeah, and I think, you know, we as a field in bladder cancer at least, have not necessarily been held to a particular target in the past in terms of approved agents.

So of course, we have things like PD1, PDL1 at levels that we can use to kind of identify who may be more likely to respond to certain things or even, you know, some assays or even giving us information about tumor mutational burden, et cetera. But none of those are required for use. I think it's going to be important for us to recognize that we, this is a targeted treatment, and we do need to identify those patients who are going to be, who are actually going to match with this drug.

So we do have to use those sequencing or the QIAGEN assay to identify these patients. And I love that you highlight that, you know, if we are able to increase the access of our patient population to sequencing generally, we may identify other targets that may allow patients, should they not respond to this agent or not be candidates for this agent, to potentially enroll in other clinical trials or to receive other treatments down the road. So, it's something I think that can improve access for our patients in that way.

So just one more comment and caveat on the indication. You know, this drug is really approved for patients who have locally advanced or metastatic urothelial carcinoma, what is actually progressed after platinum containing chemotherapy. But there's no requirement that patients have actually been exposed to checkpoint inhibitors. And, so I wonder, and this is purely opinion and very early days, so who knows what your answer may be in six months from now even. But if you have a patient who has one of these potentially susceptible FGFR3 or 2 activating mutations and also appears to have high tumor mutational burden and may respond to a checkpoint inhibitor, what would you choose? And then also, do you have any comments on how commonly those two co-occur in a single patient?

Arjun Balar: Yeah, so there's a lot of background to this that needs, that merits discussion, which is that initial trials, particularly single arm trials of checkpoint inhibitors had noticed that patients with so called luminal-1 tumors, which is based on gene expression profiling using the TCGA classification, tended to be enriched with FGFR3 mutations. But the luminal-1 tumors in general, seem to respond less well too, are less likely, to checkpoint inhibitors and because mutations and FGFR were enriched in that population, it was an association made A to B to C, that FGFR3 mutations where somehow intrinsically more likely to be resistant to checkpoint inhibitors.

It turns out that when you take a deeper dive into the data, the patients with FGFR3 mutations exclusively if you just look at that population, the percentage of patients who respond or don't respond to checkpoint inhibitors is very similar, if not identical to the overall population.

So there are probably other areas of shared biology between FGFR mutations and luminal-1 subtypes, which again are, it's very difficult to compare those two, but it appears that that really is irrelevant.

So you can coexist with a patient, meaning up, high T cell infiltrate tumor mutation burden and also have a FGFR3 mutation and that does raise a question, how are you going to choose between PD1 inhibitors versus an FGFR3 targeted drug but they're not mutually exclusive.

So then the next natural question is that if a patient is eligible for potentially both of those treatments, how do you choose, I think clinical judgment will have to significantly factor in until we have randomized data available. And what I mean by that is, that what we have also learned is that the patients who have high volume rapidly progressive cancer, even after platinum containing chemotherapy and certainly clinical judgment is a major factor here, is that these are the patients that are least likely to respond to immunotherapy as a whole and probably would benefit for something that is more cytotoxic and lead to more rapid response early on.

And that is what we are seeing with drugs like erdafitnib and then also antibody drug conjugates which are also going to be playing a heavy role in metastatic bladder cancer, is that when you need a response right away, you want to lean on those drugs that will get a response right away and then perhaps come in with IO later.

However, the flip side is a patient with slower growing, progressing disease and small volume disease, certainly, immunotherapy will be the standard and probably the most appropriate therapy, simply because again, we have randomized data showing that immunotherapy compared to previous taxane based therapy improves survival. We don't know yet that about any of the extra of our three targeted drugs and so you have to kind of lean on level one evidence in those scenarios.

But there will be certain patients that just need a response right away and those patients are probably better treated with erdafitnib, but obviously, the field is changing so fast and we'll need to see what these data look like in the next six to 12 months.

Alicia Morgans: Great. I, I really appreciate you thinking that through with us and I think that we're going to have to circle back with you in about 6 to 12 months and see how your thoughts may be similar or different. And like you said, we really do need to have some further data to help us understand how to best answer that question and things even as we get more information, sometimes become increasingly complicated. 

So more to come there. But I really appreciate your time and your thoughts on this and I look forward to having the opportunity to use this new FDA approved medication in the clinic, and I'm sure you do too. Any closing thoughts?

Arjun Balar: I think that you know, every time we have these conversations, Alicia, I feel like, you know, we're talking about the next drug and the next big leap forward. And I think this is a particular drug approval and its impact on bladder cancer, patient care, is much larger than simply the approval of the drug and access for patients.

It really opened the door for a whole other avenue in way of studying bladder cancer that we weren't doing before, which was from a molecularly driven approach to show that we can develop a drug to get it approved in the setting is really noteworthy and will likely improve our access and understanding of other genetic alterations in the future and access to more drugs.

Alicia Morgans: I absolutely agree, and the landscape continues to evolve in bladder cancer and we are excited to be part of that progress. So thank you again for your comments and your thoughts today, Arjun and I appreciate your time.

Arjun Balar: Thanks so much for having me.