Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma - Arlene Siefker-Radtke

March 6, 2024

Sam Chang engages with Arlene Siefker-Radtke to explore the transformative impact of erdafitinib in treating advanced and metastatic urothelial cancer. Dr. Siefker-Radtke illuminates the targeted approach of erdafitinib, emphasizing its efficacy in hitting specific genetic alterations, particularly FGFR3/2 mutations, prevalent in 15-20% of metastatic bladder tumors. Highlighting the drug's journey from its early promise in phase 2 trials to its confirmed superiority over chemotherapy in phase 3 studies, she outlines its significant improvements in survival rates and response rates. The conversation also ventures into future applications, including potential benefits in superficial bladder cancer through localized drug delivery systems and earlier stages of the disease. This insightful discussion underlines the strides towards personalized cancer treatment, heralding erdafitinib as an advancement in urothelial carcinoma therapy.


Arlene Siefker-Radtke, MD, Oncologist, The University of Texas, MD Anderson Cancer Center, Houston, TX

Sam S. Chang, MD, MBA, Urologist, Vanderbilt University Medical Center, Nashville, TN

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Sam Chang: Hello everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and I work at Vanderbilt University Medical Center. We're quite fortunate to have Dr. Arlene Siefker-Radtke, who's a professor and leads a program in urethral carcinoma and bladder cancer at the MD Anderson Cancer Center in Texas. And we're actually going to have Arlene speak and focus on kind of a comparison and evaluation of erdafitinib versus chemotherapy in advanced and metastatic urothelial cancer. Arlene, first of all, thank you so much for joining us, and we look forward to going over, I think, a presentation you put together focusing on the role of erdafitinib and its positioning in the treatment of patients with advanced disease.

Arlene Siefker-Radtke: Great. Well, thank you so much, Sam. It really is a pleasure being here today to speak about erdafitinib and the role it has in treating our metastatic urothelial cancer patients.

When we think of treatment with erdafitinib, this is really a therapy that's designed to hit the target. This is targeted treatment for patients with metastatic surgically unresectable urothelial carcinoma. And as you can see, the bladder field is really hopping, with lots of clinical trials that I hope you will support. But when we think of targeted strategies, there's a lot of different targets that have been studied, and I've included several here. But what makes a truly good target is one that is easily reproducible, where anyone can determine the target is present. Of course, you need CLIA certification, and it does not fluctuate or change in the face of therapy. Even better if it predicts a response or benefit to a particular therapy, at which point you really need to see if that target is present.

When I think of bladder cancer, bladder cancer really isn't just one disease. It's actually composed of multiple diseases which differ in underlying biology. And we saw early evidence that different mutation patterns played a role in this biology, specifically the presence of FGFR3 alterations. We've known for more than 20 years there are at least two different paths where most bladder tumors develop. The majority of them have this low-stage, low-grade, very papillary appearance, very polyp-like, yet only a small percent of them transform from this papillary pathway to the invasive disease that might take a patient's life. There's also a group that transforms quite rapidly along a non-papillary pathway with early P53 and RB mutations and carcinoma in situ associated with it.

When we look at FGFR3 alterations, FGFR3 mutations are present in over 60% of low-grade, low-stage tumors, and those are the tumors that follow this papillary path. Yet when we get to muscle-invasive disease or metastatic disease, the disease that kills, the percentage of FGFR3 alterations is around 15 to 20% of urothelial tumors of the bladder, likely due to the contribution of these flat carcinoma in situ, RB, and P53 altered tumors.

So when I think of targeted therapy, one where you need to determine the target is present in order to give the treatment, the first treatment that comes to mind is erdafitinib, which is truly a biomarker-targeted therapy in urothelial cancer. And we've had several studies now published on the treatment of erdafitinib in urothelial cancer. As I mentioned, FGFR3 alterations are overexpressed in 15 to 20% of metastatic tumors of the bladder, and over 35% of metastatic tumors of the upper tract, which include the renal pelvis and ureter. Erdafitinib is a pan-selective FGFR inhibitor, which inhibits all four FGFRs, FGFR1 through 4, in the single-digit nanomolar range. And in early studies, the phase 2 clinical trial of erdafitinib in FGFR3-altered urothelial cancer, we saw early evidence of clinical activity with an objective response rate of around 40% and a median overall survival of around 13.8 months, which resulted in the accelerated approval of erdafitinib.

But the story doesn't end there. We had to do the metastatic randomized clinical trial, and this clinical trial of erdafitinib took patients who received prior chemotherapy and prior immune checkpoint inhibitor. This was mostly platinum-based chemotherapy, and patients were randomized between erdafitinib and the taxane of choice, which could either be docetaxel or vinflunine, which is approved in Europe. And the primary endpoint for this trial was overall survival.

This slide shows the variety of FGFR3 alterations that were enrolled. The majority or most frequent alteration is S249C, so that is the one we see most commonly. We also see Y373C mutations and R248C mutations of FGFR3. And then we also see some of these FGFR3 fusions and the FGFR3-TACC3 fusion is typically the most common one observed in urothelial cancer. The trial was designed to determine that improvement in overall survival and then secondary endpoints were to look at objective response rate and progression-free survival.

When we look at the patients enrolled, they were fairly balanced over both groups. We saw about 74% evidence of visceral metastasis, and I think that's in line with this being a post-frontline treatment strategy where we see higher rates of visceral metastasis. In addition, the ECOG performance score we can see was fairly decent, with one to two in over 50% of patients. So patients, again, having prior treatment. And also observed with FGFR3-altered tumors, we saw low CPS scores, PD-L1 expression levels that are low, and again, there has been this biology suggesting FGFR alterations may associate with a more immunologically cold phenotype.

When we compared erdafitinib versus chemotherapy, we did see a significant improvement in overall survival in our patient population, which met the primary endpoint with a hazard ratio of 0.64 and a highly significant P value. The median overall survival for erdafitinib was around 12.1 months compared to 7.8 months with systemic chemotherapy. The progression-free survival was also significantly improved with erdafitinib compared to chemotherapy, coming in at 5.6 months versus 2.7 months with a hazard ratio of 0.58. Erdafitinib was also associated with an improved response rate. In fact, we saw a 45% objective response rate with 6% complete responses with erdafitinib compared to only an 11.5% response rate in patients treated with single-agent chemotherapy.

The adverse event profile was very similar to what has been reported with erdafitinib and with taxane-based chemotherapy in the past. We see a lot of that hand-foot syndrome, which is a reason why patients may need to take a break from treatment. Usually, after two to three months of therapy, most patients do need a two to three-week break and then can resume treatments, sometimes at a lower dose, but can maintain their remissions at that lower dose. We also see central serous retinopathy, which can occur as well in patients who receive erdafitinib. That central serous retinopathy rate is around 20%.

We saw that the overall survival in patients receiving treatment with erdafitinib appeared consistent across various poor prognostic factors, including poor performance status, whether it was a translocation or a mutation that was present. And we also saw responses in visceral metastases, including similar rates of response in patients with liver metastases. I would argue this is a good form of cytoreduction, as many patients who are receiving erdafitinib experience improvement in their symptoms within the first two weeks of starting treatment; they'll notice evidence of interval improvement.

This, again, discusses some of the side effects of interest, including nail and skin disorders, which were Grade 3 in about 11% of patients, and then the central serous retinopathy, which occurred in about 20% of patients. This is typically reversible. We hold the dose and wait till the patient's optical coherence tomography images resolve, and then patients can resume treatment with erdafitinib at a lower dose level. As a result of this, we do recommend being friendly with your local ophthalmologist and referring patients for baseline scans and routine monitoring during the first four months of treatment. And if a patient does report blurred vision, I ask them to first blink their eyes to make sure it's not dry eyes, but if the blurred vision persists, they should be instructed to hold the dose and schedule a visit with the ophthalmologist immediately so that they can be evaluated for central serous retinopathy.

So, when we look at the cohort of patients treated with erdafitinib compared to chemotherapy in those who had prior chemotherapy and an immune checkpoint inhibitor, we saw that erdafitinib significantly improved overall survival, objective response rate, and progression-free survival with a similar toxicity profile as has been observed in other FGFR3 tumors. This phase 3 trial supports the use of erdafitinib in patients with metastatic urothelial carcinoma, and as a result, the FDA has now granted erdafitinib full approval for the treatment of our FGF-altered urothelial cancer patients who have received prior treatment. So clinically targeted therapy is here to stay, and I would argue we're getting closer to personalized treatment strategies based on our understanding of the biology of patients' urothelial cancers.

Sam Chang: Arlene, that was fantastic. So, with the first targeted therapy, where do we go next? Should we be doing this in the noninvasive population, in the pre-chemotherapy, pre-immunotherapy treated population, where do you think we'll go next?

Arlene Siefker-Radtke: So, it's very clear that erdafitinib has benefit in metastatic disease, and with the high predisposition of mutations in superficial bladder cancer, of course, it's very intriguing to study erdafitinib in that group of patients. In fact, there was data presented at ESMO suggesting that oral erdafitinib improved the control of superficial tumors of the bladder. So, early evidence of benefit, but the biggest challenge for superficial urothelial cancer is toxicity. These are patients who can avoid toxicity by having cystectomy. So, having that hand-foot syndrome and dry mouth and nail changes and risks for central serous retinopathy leads us to conclude that orally targeted therapy with FGF may not be as palatable for that patient population.

But there's still hope because now there are drug-eluting pretzels that are developed, including the Taris drug-eluting pretzel with erdafitinib inside. It's like a tube and it's inserted into the bladder via cystoscopy, and as it's pushed through the scope, it forms a curl. It looks like a little pretzel, and the curvature of this helps open the pores and release erdafitinib into the bladder, so into the urine, resulting in more consistent localized dosing. And this avoids the systemic complication rate completely. Patients are able to tolerate it, and I'm very hopeful we'll see that improved benefit without the toxicity profile through a localized drug administration strategy.

Sam Chang: Arlene, how about in the patient population pre-platinum, pre-IO, do you think that targeted therapies like erdafitinib, we've had obviously this combination of EV and pembro now looking like it may become the new standard. Where do you think FGFR3 or its type of alterations will fit in terms of therapeutic next steps?

Arlene Siefker-Radtke: At the moment, I think any patient with metastatic urothelial carcinoma should be tested immediately for an FGFR3 alteration. We are not curing these patients routinely. They are going to need additional treatment, and if you wait, there may not be enough time to get this mutation test returned. I do see a role for this in earlier stage disease, and maybe we will start testing even in superficial bladder cancers, especially if we get approval with a targeted drug-eluting stent.

Now, muscle-invasive bladder cancer and the frontline treatment before EV, one of the challenges is we do have to wait for mutation results, and those can take several weeks, even when we rely on tissue collection or even using a liquid biopsy where we send a tube of blood looking for the presence of the mutation in the circulation. We do have evidence showing that if you detect the FGFR3 alteration in the circulation, patients respond to erdafitinib. And in fact, in one look, it was around 55%. So that might help you select the patients who would benefit the most from erdafitinib. But we still saw objective response rates of around 30%, even when we couldn't detect the mutation in the circulation, but it was still detected in the patient's tumor tissue.

Sam Chang: Ultimately, just as you are saying, making the steps in progress towards precision and care based upon the individual characteristics of that patient's tumor and tumor type, I think will become increasingly commonplace, increasingly effective. And the impact that erdafitinib has as being really the first one to show its possible benefit, I think really has opened up the landscape to other advances in therapeutic options for patients then with advanced disease. Arlene, thank you so much for spending some time with us, and I really appreciate the summary and its positioning when looking at erdafitinib as an option in terms of treatment choices for these patients.

Arlene Siefker-Radtke: Well, thank you very much, Sam. I appreciate your time and getting the word out to the benefit of our urothelial cancer patients.