Update on First Biomarker-Directed Trial of Non-Muscle-Invasive Bladder Cancer

Erdafitinib (balversa), an oral pan-fibroblast growth factor receptor (FGFR) 1-4 inhibitor, is being used in one of the first biomarker-directed trials of high-risk non-muscle-invasive bladder cancer (NMIBC). The Thor-2 trial (NCT04172675) targets tumors with driver mutations in the FGFR3 gene. This gene is altered in 40% to 70% of early-stage bladder cancers and may be a rare driver mutation in bladder cancer. If successful, Erdafitinib would the first precision therapy for early stage bladder cancer.

In this podcast episode, lead investigator Joshua J. Meeks, MD, PhD, the Edward M. Schaeffer, MD, PhD Professor of Urology and associate professor of Urology and of Biochemistry and Molecular Genetics at Northwestern Medicine, explains the Thor-2 trial and how it could be a new paradigm in bladder oncology.

Disclosure Statement:
Joshua J. Meeks, MD, PhD has received consulting-related fees from Janssen.
Update on First Biomarker-Directed Trial of Non-Muscle-Invasive Bladder Cancer
Featured Speaker:
Joshua J. Meeks, MD, PhD
Dr. Meeks is an Urologic Oncologist and Assistant Professor of Urology at the Northwestern University Feinberg School of Medicine, He is a urologic surgeon with expertise in the diagnosis, treatment and management of bladder cancer. His research interests focus on both the epigenetics and genetic mutations associated with cancer biology. Specifically, he is studying how chromatin remodeling genes play a role in bladder cancer. In addition, he is investigating the “driver mutations found in bladder cancer. In the future, he hopes to develop novel systemic and intravesical therapies to improve survival of patients with bladder cancer.
His research laboratory is focused on the molecular pathways involved in the progression of urothelial carcinoma (bladder cancer). His research has two themes: 1) to investigate the epigenetic mechanisms of gene regulation in bladder cancer and 2) to identify the interaction of the immune response to tumor mutations.
Update on First Biomarker-Directed Trial of Non-Muscle-Invasive Bladder Cancer

Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. Today we're discussing the THOR Two trial, one of the first biomarker directed trials of non muscle invasive bladder cancer with lead investigator, Dr. Joshua Meeks. He is the Edward M Schaefer professor of urology. Associate professor of urology, biochemistry, and molecular genetics at Northwestern Medicine. His expertise is in the diagnosis, treatment and management of bladder cancer. And among his recent research, this includes this new study that uses the drug. Erdafitinib to target tumors with driver mutations in the fibroblast growth factor receptor three gene.

Dr. Meeks joins me today to talk about this study and how it could change the landscape of bladder cancer treatment. Dr. Meeks. Welcome to the show. I'm so glad you could join us today. As we get into this fascinating study, can you briefly explain the role of biomarkers and molecular subtyping in bladder cancer? How much time is your research dedicated to this field right now? And how has it led you to the THOR Two trial?

Dr. Joshua Meeks: Well, thank you very much. It's really great to be here. I would say that overall, honestly, all of my time is spent either caring for patients with bladder cancer or sort of researching the causes and better management of patients. So the. half of that's probably spent in the laboratory and then the other half is in the clinic and the operating room. So, it's really kind of the sole focus of what I do at Northwestern. This is a really interesting trial and trying to approach bladder cancer in a way that, that most people haven't done before.

We really haven't had any molecular targets that we can go after and say, if we are able to block this gene, then we could improve recurrence for our patients. And much of this work actually comes from the metastatic setting where they found that the mutation FGF receptor is not a very common finding. But when they give this drug to patients, it actually leads to a very significant response in their tumor. And this was. Really groundbreaking for metastatic bladder cancer. It led to an FDA approval for patients with this mutation.

And what makes this a unique approach is that we've really gone two steps backwards or actually two steps forward and are treating patients in early stage bladder cancer with an oral therapy, a pill. And then the reason that is so significant is that before this. All of our drugs really are directed into the bladder. And so patients have to come into the office. They have to have a catheter place. They have to have drug put in and. While that can be effective. And many people are okay with that.

This is a new approach where a pill could be an opportunity for a patient to really try to knock down the activity of their cancer. And one thing that we're finding out is whereas in the metastatic setting, maybe anywhere from 11 to 20% of patients have this mutation, we find. 40% of patients in the early stage have it. So it's at least twice as common. So that means a lot more people are gonna have a benefit. And now that we're seeing these people come into our clinic, we find that they're the tumors that really aren't responding to the normal standard of care.

And the patients are very frustrated because no matter what we do for them, they're really not getting a good response from what we're, how we normally approach them. And so this is a new way to go about trying to treat them and hopefully have their cancers go away and stay away for a long period of time.

Melanie Cole, MS (Host): Absolutely fascinating. You're really advancing the field of cancer medicine. So expand a little on the THOR Two trial that you're leading and tell us about your aim and your goals.

Dr. Joshua Meeks: Yeah. So I think what's kind of unique about this is that and patients are getting very smart and asking us, is there anything we can do to test my cancer to say, am I gonna respond to the treatment that I'm gonna go through? And really up until this point, we haven't been able to offer anything. I mean, again, there's a lot being done in more advanced cancers for looking at individual mutations to say, can we give you chemotherapy?

Are you gonna respond to immunotherapy? But we've just not had that strong of data in the early stage and realizing that 80% of patients are in that early stage. So up until now, we've really not had that biomarker. And so when we see a patient who comes in with an early stage bladder cancer, we're actually sending their tumor off to be sequenced for this FGF receptor three alteration. Because even though many of them are gonna undergo the start of care, If they don't respond, we wanna have an option for them afterwards.

And so THOR Two is actually a three arm trial. And two of the three arms are for patients who are not responding to the standard of care. And then, this is a secondary option for them. And so when I see patients who come in with early stage tumors, I'm actually sequencing their tumor right away. Because if we know their tumor has this alteration, we know that they're potentially a candidate for this trial if they have a recurrence. Now, we hope that they respond and many of them will respond to the standard of care.

But if they don't, we don't wanna have to have them wait for that sequencing. Cause cuz that can be several weeks. This at least, everyone comes in. We're trying to really know if they're a candidate for the trial and then If they don't respond to therapy, there potentially can go on this trial and give them treatment. So the three arms, the first arm is a randomized arm where they either get erdafitinib or intravesical chemotherapy. So they're out of there, get a pill. That's the trial component erdafitinib, or they would get therapy in their bladder.

And again, that's a two to one randomization. The second arm is actually they just go onto the drug. And it's kind of, we think it's a little more rare it's when their tumors have carcinoma in sight too. Again, we don't think it's gonna be very many of those tumors, but then the third arm is kind of a very interesting group of patients. Those are people who haven't gotten any kind of therapy. They're actually. Intermediate risk or there are tumors that are low grade, but keep coming back.

And we're paying much more attention to those, patients recently, because these are people who they've never really experienced therapy before, and they have these low grade cancers that just keep coming back. And that may sound like a less scary situation for a patient, because they're not likely gonna gonna die from these tumors, but they just keep coming back no matter what we do. And many folks get very frustrated by that. So, and we don't really have great therapies for them. So, this trial is actually a marker lesion trial.

So they have up to a one centimeter tumor. And instead of going to the operating room where we would remove that, we actually would just put them on erdafitinib and we watch their tumor and we see how they respond. And so far, the early responses have been very strong On this trial. I know it's a little bit for folks to sit back and say, so you're not gonna remove my tumor, but that's the purpose of a mark or lesion. And so most of these, the folks that we've been able to put on this trial, they're pretty frustrated by the fact that no matter what we do, the tumors, keep coming back.

So this marker, lesion's actually a pretty reasonable approach and we're excited to see where it goes. Because Again, the long term benefit for patients is that we have a treatment for them where they don't have to keep coming in and getting therapies and dealing with surgeries and tumor resections. They could potentially go on this pill, which hopefully will keep their cancer away.

Melanie Cole, MS (Host): So then how are you assessing clinical benefit in your study and how do you envision this research translating to patient care? You've mentioned convenience, which is certainly a factor and also the frustration of not going right into surgery. Tell us, give us the picture Dr. Meeks of the clinical benefit in this study for other providers.

Dr. Joshua Meeks: Yeah. So I mean the real clinical benefit is if this has good long term activity against these tumors, you could imagine There are many other solid tumor fields that are way ahead of bladder cancer, where the tumors are evaluated for a biomarker very early on and treatment kind of falls down sort of a course based on if the biomarker is present or not. So, you can imagine for breast cancer estrogen receptor positive or negative, the same is true with lung cancers, ALK positive or negative.

If this becomes a truly predictive biomarker that you can treat based on sort of a precision of care, then you can imagine how if a patient has this, they don't have to go through one and two lines of therapy, which may or may not work. These therapies, overall are relatively successful, but they're not precise. And we honestly don't know why they work or don't work. But if you have a drug, which is perfectly targeting one molecule and a patient has that biomarker, then in a lot of cases, it just makes sense to begin with that.

And erdafitinib is an oral drug going after that biomarker. There may be, you know, in the future therapies that go right into the bladder and are a little more targeted to the bladder. We think those are potentially coming down the road. So, that's one of the reasons we're so excited about erdafitinib and targeting the FGF receptor three is that it's probably the best biomarker we have right now in bladder cancer.

Melanie Cole, MS (Host): Wow. And as we wrap up Dr. Meeks, when do you envision this trial will be more advanced and really reiterate how this could change the landscape of bladder oncology. As you've already said, there are far reaching initiatives for this. It can really go further than just bladder cancer, but I'd like you to tell other providers what you would like to take away from this podcast to be how you feel this research impacts patients as you get into this and other clinical trials and what you would like other providers to know?

Dr. Joshua Meeks: Yeah. I mean, I think, our next generation of oncology treatments, in addition to adding more therapies, It's gonna potentially be moving towards more precision. So, we're hoping to introduce that in this trial to early stage bladder cancer. I would say that this trial is an international trial. There's a lot of sites that are open. We obviously have a site open here at Northwestern. I have folks that were testing their tumors from across the country, they're sending us samples that we can see if they'd be potential candidates to go on this trial.

And again, that they may be that they come to Northwestern for their care. It may be that they go to another site locally where the trial is open. But my sense is in the next 18 to 24 months, as this trial comes to a close and we're able to look at the results of it, that this is really gonna be hopefully the next generation of treatments for bladder.

Melanie Cole, MS (Host): Well, I hope you'll join us again and update us as things continue. It's really exciting, Dr. Meeks, thank you so much for joining us. And to refer your patient or for more information, please visit our website at Breakthroughs For Physicians.nm.org/urology. That concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians for more updates on the latest medical advancements, just like you heard here, breakthroughs and research, follow us on your social channels. I'm Melanie Cole.