Expert Explains Significance of Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma

In an interview with Targeted Oncology, Arlene Siefker-Radtke, MD, discussed the results from this trial that led to the approval of erdafitinib in patients with locally advanced or metastatic bladder cancer who have progressed on platinum-based chemotherapy. She also explained the impact of this approval in this patient population and next steps planned for this agent.

Arlene Siefker-Radtke, MD

A phase II trial demonstrated that the oral targeted therapy erdafitinib (Balversa), an FGFR inhibitor, improved responses in patients with metastatic bladder cancers. Findings show that this agent is well-tolerated and induced an objective response rate (ORR) of 40%, according to a report of data from the trial published inThe New England Journal of Medicine.

The standard of care for this patient population prior toerdafitinib, which was approved by the FDA in April 2019, included cisplatin-based chemotherapy and carboplatin-based regimens for patients who were not candidates for cisplatin. However, these regimens can be difficult to tolerate. Immune checkpoint inhibitors have also entered the treatment landscape, especially in the second-line setting, but only 15% to 20% of patients respond to these therapies.

Patients with locally advanced, unresectable, or metastatic urothelial carcinoma harboring anFGFRalteration were enrolled and randomized 1:1 to receive either an intermittent dose at 10 mg per day for 7 days on/7 days off of erdafitinib or a continuous dose of 6 mg per day in a dose-escalation phase. Based on an interim analysis, a continuous dose of 8 mg per day was selected for further treatment with up-titration to 9 mg per day.

Ninety-nine patients were treated with the continuous dose of erdafitinib. The primary endpoint was achieved with an ORR of 40% (95% CI, 31%-50%), per a confirmed investigator assessment. Additionally, 39% of patients had stable disease, of which 33% had stable disease for more than 6 months. Further, among 22 patients who had received prior immunotherapy, the response rate was 59%.

Secondary endpoints included progression-free survival (PFS), duration of response (DoR), and overall survival (OS). The median DoR was 5.6 months (95% CI, 4.2-7.2). Thirty percent of the patients maintained their response for over 12 months. The median PFS at a median follow-up of 11.2 months was 5.5 months (95% CI, 4.2-6.0). At 12 months, the rate of PFS was 19% (95% CI, 11%-29%) and the rate of OS was 55% (95% CI, 43%-66%).

Investigators also analyzed the safety of erdafitinib in these patients. Overall, 67% of patients experienced grade 3 or 4 adverse events (AEs) of any cause, while 46% of patients experienced treatment-related AEs of grade ≥3. The most common AEs of grade ≥3 included hyponatremia, stomatitis, and asthenia. Thirteen patients discontinued treatment due to toxicity, but disease progression was the most common reason for discontinuation.

These data led to the FDA’s approval of erdafitinib—the first targeted agent to receive approval in metastatic bladder cancer. The phase III THOR trial (NCT03390504) is currently accruing patients to further evaluate the efficacy of this agent compared with chemotherapy or immune checkpoint inhibition with pembrolizumab (Keytruda) in patients withFGFRalterations. This trial will help determine which approach is optimal for patients with these alterations and will act as confirmation for the accelerated approval of erdafitinib.

“There are several firsts with this trial,” said Arlene Siefker-Radtke, MD. “This is the first FGFR3-targeted agent that’s been FDA approved, it’s the first oral agent approved for bladder cancer, and it’s the first targeted agent for FGFR3 in this setting of bladder cancer as well.”

In an interview withTargeted Oncology, Siefker-Radtke, professor of genitourinary medical oncology at MD Anderson Cancer Center, discussed the results from this trial that led to the approval of erdafitinib in patients with locally advanced or metastatic bladder cancer who have progressed on platinum-based chemotherapy. She also explained the impact of this approval in this patient population and next steps planned for this agent.

TARGETED ONCOLOGY: How frequently doFGFR3mutations present in bladder/urothelial cancers?

Siefker-Radtke:In metastatic bladder cancer,FGFR3mutations are present in about 15% to 20% of patients. When you look at metastatic upper-tract urothelial cancer, there’s a higher frequency ofFRFR3mutations, and it’s estimated to be about 35% of patients. That’s in metastatic disease, but if you look at earlier stage disease, especially superficial bladder cancer, the rate ofFRFR3mutations is closer to 60% in intermediate- to low-risk superficial bladder cancer.

It does appear thatFRFR3alterations play a role in the development of bladder cancer, although perhaps only a small percent of those patients progress to invasive disease that is at risk for becoming metastatic.

TARGETED ONCOLOGY: What was the rationale for investigating erdafitinib in this population?

Siefker-Radtke:It’s basically the understanding thatFRFR3mutations are present in bladder cancer. There were early data in a phase I study where they saw evidence of clinical activity in patients withFGRFR3-mutated urothelial cancer.

There is also an ongoing question of whether patients withFRFR3receptor alterations respond better to immunotherapy or do they respond better to erdafitinib. When we looked at some early data on patients treated with erdafitinib who had received prior immunotherapy, we saw lower ORRs with the response to immunotherapy in around 1 out of 22 patients. While these are small numbers of patients, there are definitely limitations based on these small numbers.

Recently, other group have looked at other patients on trials including the immunotherapy agents atezolizumab (Tecentriq) and nivolumab (Opdivo), and there are some data suggesting that the response rate might be 20% to immune checkpoint inhibitors in the setting ofFGFR3alterations. That’s also limited by a very small number of patients withFGFR3alterations, the fact that there was enrichment for PD-L1—positive tumors, and there is a group ofFGFR3-mutant tumors that are more basal or appear to enrich with some immune markers, so perhaps the enriched group of patients may be more likely to benefit in the setting of anFGFR3mutation and immunotherapy.

We also don’t understand the presence of co-mutations that may be driving the tumor preferentially overFGFR3,like DNA repair mutations. I would argue there is still a lot we don’t know about thisFGFR3-altered bladder cancer that helps guide us more toward definitive treatment. However, if you look at the ORR which is 40% with erdafitinib, the response rate with immunotherapy appears to be lower. There is also a sense that immune checkpoint inhibitors don’t work as well in patients with visceral metastases, and in this group of patients treated with erdafitinib, we saw a very high frequency of visceral metastases—79% had visceral metastases.

I think the question still exists, will patients with anFGFR3-altered tumor respond better to immunotherapy or better to an FGFR3-targeting strategy? We don’t yet know the answer, but we hope to provide the answer to this question through the THOR trial, which is currently accruing patients. Patients who haven’t received immunotherapy are randomized to erdafitinib or to an immune checkpoint inhibitor, so I think that will provide us a definitive answer of whether there is preferential benefit when you treat anFGFR3-altered tumor with an FGFR-targeted therapy compared to immune checkpoint inhibition.

TARGETED ONCOLOGY: How was this trial designed?

Siefker-Radtke:This trial was designed at a time when the 2 prior FGFR-targeted therapies dovitinib (TKI258) and infigratinib (BGJ398) were given on an intermittent schedule because of toxicity. At the time that we designed this trial, we didn’t yet know whether we could safely give an FGFR-targeted agent continuously or whether we needed an intermittent schedule.

For the first part of the trial, we randomized patients to either a continuous dose of 6 mg of erdafitinib daily or an intermittent dose of 10 mg erdafitinib for 7 days on and 7 days off. There was an early analysis where we looked at the combination of toxicity and potential clinical activity. As a result of that, we found that we could give erdafitinib in a continuous fashion. With additional pharmacokinetics testing, we found that we could increase the dose to 8 mg a day to more appropriately targetFGFR3with up-titration to 9 mg a day if patients did not have a target phosphorous level of 5.5 at day 15 of their dosing schedule.

The continuous dose was selected for the phase II expansion cohort, and we actually increased the dose from the original 6 mg to 8 mg with up-titration to 9 mg daily based on target phosphorous levels and additional pharmacokinetics modeling. That was the dose taken forward for this phase II expansion cohort of 99 patients presented in theNew England Journal of Medicine.

TARGETED ONCOLOGY: What were the findings in this phase II study?

Siefker-Radtke:Keep in mind that the time this trial was designed, second-line therapy was taxanes and they yielded a very poor ORR and very poor survival. Typically, response rates were sometimes even in the single digits, and median survival was 6 to 8 months. Taxanes performed very poorly. This trial was designed to look for an ORR in the setting of preselectedFGFR3mutations or fusions. We were looking for that ORR of around 40%, and the trial did meet its primary objective with 40% of patients responding to erdafitinib. This was investigator-reported response, and it did require confirmation with repeat CT imaging confirming the response approximately 4 to 6 weeks later. These were confirmed investigator-reported responses.

[The trial] did meet its primary endpoint with an ORR of 40%. We also looked at the median OS, which was 13.8 months. This also appears very promising compared to other therapies that have been studied to date.

On the basis of this phase II trial with the response and clinical activity observed, it was granted an accelerated approval by the FDA in April 2019.

TARGETED ONCOLOGY: What does the toxicity profile look like with erdafitinib?

Siefker-Radtke:As you’d expect with other targeted agents that work throughFGFR3, we did see hyperphosphatemia, and keep in mind, we actually increased the dose looking for hyperphosphatemia as a signal that we were targeting theFGFR3appropriately with appropriate dosing. We use that as a surrogate marker of appropriate dosing in the hopes of improving the outcomes for patients.

When we look at the toxicity profile, we did see grade 3 hyperphosphatemia in only 2% of patients. We also see other [adverse]effects that have typically been associated with these types of agents like tyrosine kinase inhibitors. We saw some stomatitis or mucositis, gastrointestinal effects like diarrhea. We also some hand-foot syndrome, and because it can impact the nails, we saw paronychia or nail dystrophy occurring as well.

There is a special toxicity of interest that is associated with other inhibitors of the MAP kinase pathway, and that’s central serous retinopathy. My ophthalmology colleagues tell me this is more central serous-like retinopathy; there are differences in serous retinopathy that occur in diabetes, but we look for this type of retinopathy by doing Amsler grid testing at every clinic visit. The rate of discontinuation for this was fairly uncommon. For most patients who would develop this, we would hold treatment, the retinopathy would improve, and they could then resume their therapy. This does appear to be manageable and is similar to what’s been observed with other inhibitors of the MAP kinase pathway.

TARGETED ONCOLOGY: With its accelerated approval in mind, how will erdafitinib impact this patient population?

Siefker-Radtke:When you look at the treatment of metastatic bladder cancer, the options are still very limited. We have platinum-based chemotherapy, which is typically cisplatin, providing the best clinical outcomes and most survival benefit, but there is a large number of patients who are not candidates for cisplatin. Those patients often receive a carboplatin-based regimen, but cisplatin and carboplatin regimens can still be difficult for this patient population to tolerate because they are often elderly, frail, with multiple comorbid conditions due to their age.

As far as second-line treatments go, we have immune checkpoint inhibitors coming in to play. With 5 checkpoint inhibitors approved, this ultimately results in just 1 treatment; we haven’t seen a substantial benefit by giving different immune checkpoint inhibitors when 1 doesn’t work.

We really have 2 good lines of therapy with either platinums or immune checkpoint inhibition. Presumably, third-line are the single-agent taxanes or vinflunine. There is a clear large unmet need for patients with bladder cancer due to very limited treatment options that have been approved to date.

TARGETED ONCOLOGY: Are there any next steps planned now that may help incorporate use of this drug into the clinic?

Siefker-Radtke:The approval is an accelerated approval based on phase II data. We have a phase III confirmatory trial called THOR. Janssen likes their Norse gods; erdafitinib is named for the goddess Erda, which is the goddess of the Earth. It kind of seemed like an appropriate name when you consider thatFGFRis implicated not only in tumor tissue but also potentially in targeting stromal cells. When you think of seed and soil, having something that targets soil as well through the goddess of the Earth, I thought it was a very appropriate name.

The THOR trial takes patients who failed prior treatment. If they’ve had no prior immunotherapy, they are randomized to either treatment of erdafitinib or treatment with an immune checkpoint inhibitor. The goal of this study is to really answer the question of whether there a differential response rate in an overall benefit in theFGFR3-altered patient population treated with erdafitinib as compared with immunotherapy.

If patients have received prior immunotherapy, there is a second cohort where patients are randomized to either erdafitinib or to single-agent taxane or vinflunine. There are also additional studies trying to see if the combination of erdafitinib with immunotherapy improves the immune response in patients withFGFR3-altered tumors. There is also a phase I/II trial that is currently accruing patients with the combination of erdafitinib plus immune checkpoint inhibition (NCT03473743).


Loriot Y, Necchi A, Park SH, et al; BLC2001 Study Group. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma.N Engl J Med. 2019;381(4):338-348. doi: 10.1056/NEJMoa1817323.