Erdafitinib Elicits Responses in High- and Intermediate-Risk NMIBC Harboring FGFR3/2 Alterations

Siamak Daneshmand, MD, shed light on the phase 2 THOR-2 study evaluating different cohorts of patients with recurrent NMIBC, key findings from cohorts 2 and 3, and how ongoing research seeks to move the needle forward with novel drug delivery methods.

Siamak Daneshmand, MD

Siamak Daneshmand, MD

Oral erdafitinib (Balversa) was found to have antitumor activity with an acceptable safety profile in patients with high- and intermediate-risk, recurrent non–muscle invasive bladder cancer (NMIBC) harboring FGFR3/2 alterations.1,2 Efforts are now focused on examining new ways to deliver agents like erdafitinib to further reduce toxicity, according to Siamak Daneshmand, MD.

Findings from the interim analysis of cohort 3 in the phase 2 THOR-2 trial (NCT04172675) were presented at the 2023 Genitourinary Cancers Symposium.1 At a median follow-up of 5.7 months, 7 of the 8 efficacy-evaluable patients had responded to treatment with erdafitinib. Six patients achieved complete responses (CRs), translating to a CR rate of 75.0% (95% CI, 34.9%-96.8%) and 1 patient had a partial response (PR). The median observed duration of response (DOR) observed with the agent was not yet reached. Notably, the safety data reported with the agent were consistent with its known toxicity profile.

Data from cohort 2 of the trial, which were concurrently presented at the meeting, indicated that in 9 evaluable patients with high-risk NMIBC, the CR rates achieved with erdafitinib were 100% and 75% at the time of the first and second evaluation, respectively.2 The median DOR in this group was 3.0 months.

“In the near future, we’re going to have an armamentarium that not [only includes more] drugs, but also [novel] methods of delivery for these patients,” said Daneshmand, who is a professor of Urology with Clinical Scholar designation, director of Clinical Research, and fellowship director of Urologic Oncology at the University of Southern California, Los Angeles, CA. “[It’s] not going to be a ‘one-size-fits-all’ [approach] anymore. We have been using Bacillus Calmette-Guérin [BCG] and intravesical chemotherapy for a long time and it is time to think outside of those routes of delivery.”

In an interview with OncLive®, Daneshmand shed light on the phase 2 THOR-2 study evaluating different cohorts of patients with recurrent NMIBC, key findings from cohorts 2 and 3, and how ongoing research seeks to move the needle forward with novel drug delivery methods.

OncLive®: To date, what has been learned about FGFR inhibitors like erdafitinib in NMIBC?

Daneshmand: [FGFR3/2 alterations] are highly targetable. If the tumor harbors that mutation, the response rates [with FGFR-targeted agents] are good in this recalcitrant population, particularly in [those with] metastatic disease. Naturally, we want to move these drugs into earlier disease stages. [That said,] we’re still learning what the response rate is [with erdafitinib] in [those with] early-stage disease.

Could you expand on the THOR-2 trial evaluating erdafitinib in patients with NMIBC?

[The cohort 3 data] presented [at the 2023 Genitourinary Cancers Symposium] are part of the larger THOR-2 study of erdafitinib in [patients with] NMIBC [who are] refractory or unresponsive to BCG. The study is ongoing and has 3 cohorts.

This particular cohort [included] patients with intermediate-risk and recurrent low-grade tumors; it’s an offshoot of the main study. [The drug administered] is oral erdafitinib, [which is] a different approach [than] most other studies [that are being done] in high-risk NMIBC. [Erdafitinib] is approved for the metastatic setting in patients who harbor the FGFR3 mutation.

What should be known about the patients included in cohort 3?

We looked at 20 patients with intermediate-risk disease [who had] recurrent, low-grade tumors. Currently, we don’t have [many treatment options for] those patients. Sometimes we use intravesical chemotherapy but are discouraging the use of BCG given the current shortage. [Overall, this is] a unique cohort for whom we have little to offer. We started sending those tissue [samples to test] for FGFR3/2 mutations [and found that these] mutations are seen in up to 80% of patients [with] low-grade tumors; [this was] much higher than [what is seen] in high-grade [tumors].

Please describe the methods utilized in this cohort.

We presented an interim analysis on 8 of those [20] patients. Eleven patients have been dosed, but we have data for 8. Of those 8 patients, 6 had a CR to a marker lesion that was left behind. To get into this study, [patients] had [to have] multiple low-grade tumors. We took biopsies and ascertained [whether] they were low-grade tumors in the intermediate-risk category. Then, we left a marker lesion behind, and [began treatment with] oral erdafitinib. [The drug] was started as a 6-mg daily dose [given] in a 28-day cycle. We reassessed with cystoscopy at 6 weeks and then did routine [check-ins] at 3, 6, and 9 months.

[I will note that] it was difficult to convince patients [to] leave a marker lesion behind, but [we] watched them closely, and [they had] a very low risk of progression so it was safe to do. Once we had the marker lesion, we took pictures and patients started erdafitinib. We [monitored the] toxicity profile for these patients and performed surveillance cystoscopy at 6 weeks [to] assess response within those lesions.

What was observed with erdafitinib in terms of efficacy?

We realized that at even at 6 weeks, we were seeing some CRs where the tumor [had] completely disappeared. At 3 months, we [also] had good responses. We heard about the other patients [receiving this agent] globally, and [there] seems to be a [similar] pattern.

Of the 8 [patients] for whom we had data available [at the time of] cutoff, 6 had CRs. [This] means [that] the tumor marker lesion that we left behind [had] completely disappeared. It is fascinating to see a tumor disappear in the bladder in such a short time with an oral drug.

The results speak for themselves here, as 6 of the 8 [patients] had CRs, with a PR in [1] other. We’re just presenting the first 8 patients in the cohort, [so there might] be more encouraging results later.

Were there any notable differences in the safety profile of erdafitinib observed in this analysis vs what has previously been reported?

We know [that] erdafitinib is an FDA-approved drug for the metastatic setting, and its safety [profile] is well established. I want to note that [we used] the 6-mg dose and not the 9-mg dose that is used in the metastatic setting, so the [severity of] AEs is going to be less, and you can titrate down the drug. We do see some hyperphosphatemia [associated with] this class of medications. We [also] see some nail changes, dysacusia, diarrhea, and hair texture changes. Most of [these AEs] are very tolerable, and most patients continued with the drug.

Early data from cohort 2 of the trial were also presented at the meeting. What was observed in that population?

There were 10 patients in that cohort, which included patients with BCG-unresponsive, high-risk NMIBC. At first [interim] analysis, which was at cycle 3 of the drug, we saw 100% response rates in the 9 evaluable patients. By cycle 6, [patients had a] 75% response rate, which is quite high [for] this resistant patient population. [We also evaluated the] safety profile, which is well known in this drug class.

What were some caveats seen with the use of oral erdafitinib, and what research efforts are being made to address them?

In the intermediate-risk cohort, the caveat is [that we’re still determining] how long to treat these patients. There are some systemic AEs [associated with prolonged treatment]. These patients are not very high risk; they have low-grade tumors. [However], the alternative is that they [may] go to the operating room to resect these tumors, and there are [AEs] associated with that. We must balance those AEs.

There’s a [phase 1] trial [NCT05316155] evaluating the TAR-210 product, in which erdafitinib is placed in an [intravesical delivery system], [which aims to place the drug] directly into the bladder [to avoid] systemic absorption. That trial is ongoing and is beginning to enroll globally. We’re very excited to see whether we can decrease systemic AEs and deliver the drug directly into the bladder. The preliminary picture we’re getting from [this technique] is highly encouraging, and we’re excited to start the trial here in the United States.

How might ongoing or future studies contribute to the expansion of treatment options in this space?

It’s time to think outside of [standard] delivery routes. We’re going to have oral [delivery], [new] devices, and [even] systemic immunotherapies for the patients [with the] highest risk. There are also some ongoing trials that target patients [who have] intermediate risk. [These patients] have had [few options] and recurrent tumors [that] are very difficult to manage. I’m excited for the near future, where we’re going to have a [larger] armamentarium of drugs to use for this [population].

Editor’s Note: Dr. Daneshmand reports serving as a consultant or in an advisory role for Ferring, Photocure, QED Therapeutics, and Taris. He received honoraria from Aduro Biotech, Allergan, Bristol-Myers Squibb, Ferrin, Janssen, Johnson & Johnson, Olympus, Pacific Edge, Photocure, and QED Therapeutics. He has stock and other ownership interests in Taris, and he received research funding from Photocure.


  1. Daneshmand S, Zaucha R, Gartrell BA, et al. Phase 2 study of the efficacy and safety of erdafitinib in patients (pts) with intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) with FGFR3/2 alterations (alt) in THOR-2: cohort 3 interim analysis.J Clin Oncol. 2023;41(suppl 6):504. doi:10.1200/JCO.2023.41.6_suppl.504
  2. Catto J, Tran B, Master VA, et al. Phase 2 study of the efficacy and safety of erdafitinib in patients (pts) with Bacillus Calmette-Guérin (BCG)-unresponsive, high-risk non–muscle-invasive bladder cancer (HR-NMIBC) with FGFR3/2 alterations (alt) in THOR-2: cohort 2 interim analysis results. J Clin Oncol. 2023;41(suppl 6):503. doi:10.1200/JCO.2023.41.6_suppl.503
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