FGFR-Altered NMIBC Treatment Advances With TAR-210 Findings

Antoni Vilaseca Cabo, MD

Data from a first-in-human, phase 1 trial (NCT05316155) showed that the erdafitinib (Balversa) intravesical delivery system TAR-210 led to early clinical activity in patients with FGFR-altered high- and intermediate-risk non–muscle invasive bladder cancer (NMIBC).¹

Patients with NMIBC harboring FGFR alterations were enrolled in the study. In cohort 1, those enrolled had recurrent high-risk disease that was high-grade Ta/T1, papillary only, with no carcinoma in situ. These patients had also received Bacillus Calmette-Guérin, did not undergo radical cystectomy, and underwent transurethral resection of bladder tumor (TURBT) with complete resection of all visible disease before treatment. Those enrolled in cohort 3 had recurrent disease that was intermediate-risk and low-grade Ta/T1, and target lesions before treatment.

In cohorts 1 and 3, patients were given TAR-210 at a dose of approximately 2 mg/day or approximately 4 mg/day during the dose-escalation phase with placement of the device occurring every 3 months. Both dose levels were expanded in part 2, the dose-expansion phase of the trial, and response was evaluated every 3 months. Treatment continued for up to 1 year if patients were recurrence-free in cohort 1 or experienced a complete response (CR) in cohort 3.

The primary end point of the study was safety and secondary end points were recurrence-free survival (RFS), duration of CR, and pathological CR rate, among others.²

Findings showed that the estimated 12-month RFS rate at a median follow-up of 8.9 months was 90% among patients with high-risk NMIBC and FGFR alterations (cohort 1; n = 21). The median RFS was not estimable. Two patients had recurrence and no difference in RFS was seen between TAR-210 dose levels.

In cohort 3, which included 31 response-evaluable patients with intermediate-risk NMIBC and FGFR alterations, the 12-week CR rate was 90%, with all patients achieving a clinical response. The CR rate remained consistent across all dose levels, and 86% of CRs were ongoing at the time of data cutoff. Durable response rates were 100% (95% CI, 100%-100%) at 6 months and 89% (95% CI, 43%-98%) at 9 months.

In an interview with Targeted Oncology^TM, Antoni Vilaseca Cabo, MD, adjunct physician of the Urology Service at Hospital Clínic de Barcelona in Spain, discussed the clinical activity of TAR-210 in patients with NMIBC.

Bladder cancer stages: © pikovit - stock.adobe.com

Targeted Oncology: Can you explain the rationale behind the phase 1 study evaluating the safety and efficacy of TAR-210 in patients with NMIBC?

Vilaseca Cabo: We know that even with some available treatments, recurrence rates for patients with NMIBC remain high, highlighting the need for more effective therapies. Activating FGFR alterations are present in about 50% to 80% of patients with advanced bladder cancer, and these are known to be potential oncogenic drivers.

We also have a drug, erdafitinib, a selective pan-FGFR tyrosine kinase inhibitor, which has shown good results in metastatic and advanced urothelial carcinoma. It is already approved in the US and other countries for patients following first-line systemic treatment.

In a previous study, called THOR-2 [NCT04172675], we observed some activity with systemic use of erdafitinib in NMIBC. However, systemic [adverse] effects were likely too high for this patient population. To address this, a new intravesical drug delivery system has been designed to evaluate the use of erdafitinib locally, aiming to reduce systemic toxicities while maintaining its efficacy.

Who was included in the study and what were the methods and design utilized?

This study has different cohorts and we presented data from cohorts 1 and 3. Cohort 1 included patients with high-risk NMIBC. These were patients with recurrent high-grade TA or T1 papillary tumors, without carcinoma in situ, and all had previously been treated with BCG. Cohort 3 included patients with intermediate-risk NMIBC. These patients had a history of recurrent low-grade TA or T1 disease. All patients in this cohort had visible tumors in the bladder before starting treatment. The study used an accumulation design, and all patients in both cohorts had FGFR alterations identified either in tissue samples or through cell-free DNA from urine.

Can you discuss this trial's findings?

The [data] are very encouraging. In cohort 1, there were patients with high-risk NMIBC, [and] we estimated a 12-month recurrence-free rate of 90%. The median follow-up at that point is 8.9 months, and only 2 patients out of the 21 patients treated have recurred. In cohort 3, the chemoablation design study of this intermediate-risk NMIBC, 31 patients have been treated until now and assessed for results. And we have a CR rate of 90% at week 12. Just to let you know, all the patients, 100% of the patients, had at least nonprogressive disease. So if they did not have a CR, they had a non-complete response but non-progressive disease, and 86% of the patients that had a CR in the first assessment at 12 months are still recurrence-free at the time of the clinical cutoff.

How do these results shape the potential of erdafitinib?

These results are encouraging because oncologically, erdafitinib intravesical delivery is very useful. It has a high rate of responses on our patients, and the most important thing, probably, of this study is that there are no systemic [adverse] effects. Actually, what we also see in the study is that we get sustained release of erdafitinib within the bladder with very high concentrations of erdafitinib in the urine, and with very low concentrations of the drug in the blood, so there are no systemic [adverse] effects in our patients. The thing is that we can have some [adverse] effects locally because we are using this pretzel-shaped device, putting it into the bladder, and you can get some grade 1/2 low urinary tract symptoms, mainly some infections because of the of the manipulation, but there are no systemic toxicities, which is probably the most important thing that we can see in this study.

What are the next steps for this research?

The next step for this research is already ongoing. At the [2024 American Urological Association Annual Meeting there was a trial-in-progress discussion of] the MoonRISe-1 study [NCT06319820], which is a phase 3 study in patients with FGFR alterations and intermediate-risk NMIBC. Patients will be randomized to receive either the device with erdafitinib or the standard of care, which will be gemcitabine or mitomycin C, also for patients with FGFR mutations.

REFERENCE:

1. Vilaseca A, Jayram G, Raventos C, et al. First safety and efficacy results of the TAR-210 erdafitinib intravesical delivery system in patients with non–muscle-invasive bladder cancer with select FGFR alterations. J Urol. Published online May 1, 2024. doi:10.1097/01.JU.0001008712.53259.7d.02

2. Study of erdafitinib intravesical delivery system for localized bladder cancer. ClinicalTrials.gov. Updated October 9, 2024. Accessed November 19, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05316155