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Dr. Matin discusses early work with FGFR inhibition in localized UTUC


"And [3 out of 5] of those patients who were initially deemed to go on to nephroureterectomy were able to be converted to endoscopic management," says Surena F. Matin, MD.

Surena F. Matin, MD

Surena F. Matin, MD

In this interview, Surena F. Matin, MD, discusses the study, “Phase 1b trial evaluating tolerability and activity of targeted fibroblast growth factor receptor inhibition in localized upper tract urothelial carcinoma,” for which he served as the lead author.1 The phase 1b study (NCT04228042) evaluated the use of infigratinib, a fibroblast growth factor receptor (FGFR) inhibitor, in patients with upper tract urothelial carcinoma (UTUC) with or without FGFR3 alterations.

Matin is a professor of urology and surgery at MD Anderson Cancer Center in Houston, Texas.

This interview was edited for clarity.

Could you describe the background for this work?

The study was based on some of the initial work that we did, along with folks at Memorial Sloan Kettering, that identified FGFR3 mutations as being enriched in patients with upper tract urothelial cancer, particularly those with low-grade disease. That prompted us to start thinking about whether this was a targetable molecule, particularly in patients who don't have metastatic disease. At the time that we had published this, shortly thereafter, erdafitnib [Balversa] became the first drug approved in the market for targeting FGFR3 alterations for metastatic platinum refractory disease. That prompted us further to look at the potential for this target as a way to address some of the clinical deficiencies we have with upper tract urothelial carcinoma. So, that's what prompted this phase 1b trial.

What were the key findings?

This trial was set up as a phase 1b trial because we've never tested these compounds in the non-metastatic setting. One thing we've learned in our group from many years of doing neoadjuvant and adjuvant therapy is that patients with localized disease are a very different population than those with metastatic disease. Their tolerability for drugs that are used in the metastatic setting is not going to be the same; you can't make the same assumptions. First of all, we wanted to see the tolerability and the safety, because these drugs do have a side effect profile. Which, in someone whose life is immediately threatened by their condition, they may put up with, but in someone who has a longer lifespan and not a life-threatening disease, they may not tolerate. So, that's why this was set up as a tolerability trial primarily. As a close secondary end point, we wanted to, of course, look at tumor responses.

The way this trial was set up was a window of opportunity trial, basically like a preoperative trial. We offered this to patients who were going to have surgical treatment with either endoscopy or surgical removal of the kidney and ureter. It was treatment for about 7 weeks, and then surgery would be performed. Patients did have to have a residual tumor, and we performed a tumor map after any biopsies or lasering that may have been done at the time of endoscopy. Then, at the surgical treatment, after the drug trial treatment, we did a second tumor map. The difference between those findings is what provided the response data that we have. This essentially mimicked the way things were done for the registration trial for the mitomycin hydrogel compound. That set up a standard for what is acceptable by the FDA, and that is how we modeled this trial also.

What we find here was that of the patients who had FGFR3 alterations, 67% of them had tumors that responded. The average [tumor size reduction] was 67% also. So, two-thirds of the patients with the mutation had a response, and the responses were pretty dramatic considering this was a very short duration of treatment. [It was] 6 to 7 weeks of treatment. With the particular compound that we used, it was essentially 2 cycles, [conducted as] 3 weeks on, 1 week off, and then 3 more weeks, and then that was it. So, [we saw] pretty dramatic responses. And [3 out of 5] of those patients who were initially deemed to go on to nephroureterectomy were able to be converted to endoscopic management. They had so much volume disease or so much multifocality, that once there was so much size reduction, they became eligible for endoscopic management. For us, that gave us a perspective in terms of how this intervention could be used in a future trial, and potentially in clinical care.

The one thing I didn't touch on was the tolerability aspect, our primary end point. That was better than we expected. We did have a continuous monitoring plan, a Bayesian statistical plan, that would continuously monitor patients. The trial did end early because the drug supporter pulled the drug from the oncology market and trials that were going on. There were multiple trials affected by this internationally. The good news for us is that we had enrolled 14 out of 20 patients. Out of those 14, only 2 didn't tolerate the full 2 cycles of the drug. That was well below our safety threshold, meaning, even if all the next 5 patients didn't tolerate it, we would still have met the tolerability criteria. I think part of that speaks to the fact that it is a very short duration treatment.

You mentioned that the trial was terminated early. How should we interpret these findings in the context of a larger trial design?

It is very promising. I think the signal is very good in terms of tolerability, safety, and efficacy. It would have been nice to have more patients, because we would have had more efficacy data. For this particular disease, you can look at it 2 ways. If you put it in the context of all the other conditions that we treat, let's say prostate cancer and kidney cancer, the enrollment is small. On the other hand, if you look at it in the context of a rare cancer, the enrollment was pretty tremendous. So, it's all very relative. Again, going back to the 1 standard we have, the mitomycin hydrogel, that was an international trial with dozens of institutions, and 71 patients were enrolled over the course of 24 months or so. In our case, we enrolled 14 patients in 18 months within a single institution. In many ways, the absolute numbers are somewhat limited, so we do have to take some of this with a grain of salt. We do need more data, and I'll touch on that. But on the other hand, for this rare condition and a prospective trial, we're pretty gratified with that overall.

In terms of future directions, we are definitely looking at going into a phase 2 trial so that we can get more efficacy and safety data. Now that we have a little bit more of a perspective for how this fits, the idea here would be to try to focus on renal preservation. [We’ll focus on] patients who come in and who have the mutation that we can identify upfront and who are going to be managed endoscopically or we want to convert them to endoscopic management and preserve their kidney. The hope here is that we can intervene with a very short time period of drug treatment, and then potentially have a de-escalated surgical intervention, either fewer procedures or being able to convert them from kidney and ureter removal to kidney preservation and being able to treat them endoscopically.

How do you plan to design the follow-up phase 2 trial?

That's still in progress. There are now, thankfully, a couple of different companies out there with similar products, and we are in conversations with these companies. Of course, it will be a bit of a team effort. In general, it will likely not be randomized. It'll be a single-arm trial. Based on the initial numbers we have, we do expect to be able to set a threshold of what a minimum response should be for the trial to be considered positive. Then, same thing from a safety and tolerability perspective; we should have a threshold for that in terms of what is going to be our maximum allowable adverse event profile and things like that.

The other interesting aspect of this that is unexplored is whether this type of intervention may have a preventative role. I do have an interest in opportunistically looking at that possibility. Without getting into the weeds, I think there is going to be a way for us to design this strategically so that in patients who don't have any residual tumors but are at risk for recurrence, we are able to potentially intervene with a very short treatment, but long enough to be able to then determine whether it has a preventative benefit or not.

What are some key areas for future research in the area of targeted therapy for UTUC?

I think there's great interest in looking at targeted therapy in the earlier stages. It's true for the FGFR inhibition, particularly for low-grade disease and upper tract cancer, because it is so enriched–possibly up to 90% of these tumors are. Less so for bladder, but there may be a role there. Another targeted therapy that is very relevant for this disease is immunotherapy, particularly for those with Lynch syndrome. We do see roughly about 5% to 7% of patients who have Lynch syndrome and have upper tract urothelial cancer. There is interest in exploring that as primary therapy, and not even trying to manage them endoscopically or with surgery. There is great interest in looking at all these targeted interventions in the earlier stages to lower the burden of care that patients go through and to some degree that urologists and other health care professionals in this in this realm go through. Ultimately, we want to benefit patients. Everything we do has a risk effect profile, and so do these drugs. We need to carefully evaluate them as we go earlier in the earlier stages, particularly where patients may have a lot more to lose with a serious adverse event. It just has to be done carefully.

The one thing I will say about this particular intervention that is potentially attractive for urologists is that it is an oral compound. Urologists do have a long history of adopting oral therapies and interventions. We witnessed this with anti-androgens, probably one of the first experiences that urologists had with medical therapy. [This is also true for] lots of other things that we do in terms of overactive bladder, stone disease, you name it. There may be some comfort level, eventually, once people are more familiar with it and if this intervention becomes established, for adoption by urologists. The other possible benefit is that it may work for high-grade disease as well. Maybe not the more aggressive high-grade tumors, but in the few ones that do have the FGFR3 alterations, those may not be as bad players. So, there's a potential role for that to be of benefit. The one thing I would point out that it's interesting about this intervention compared to the 1 standard that's out there, the mitomycin hydrogel, is [that with] that 1, you do have to have low-grade disease, and there has to be some minimum amount of disease for it to be effective. With this drug, it doesn't matter. It could be very multifocal. It could be very high volume. As long as we know the tumor has the mutation, you could intervene with it, and potentially may be able to convert a lot of these patients who don’t have many other options other than removal of their organs to kidney preservation. Those are very unique aspects of this particular type of intervention.


1. Matin SF, Adibi M, Shah AY, et al. Phase 1b trial evaluating tolerability and activity of targeted fibroblast growth factor receptor inhibition in localized upper tract urothelial carcinoma. J Urol. Published online April 10, 2024. Accessed April 25, 2024. doi:10.1097/JU.0000000000003928

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