Novel intravesical drug delivery systems explored in bladder cancer

At the 2023 AUA Annual Meeting, Siamak Daneshmand, MD, shared promising data from the phase 2b SUNRISE-1 study exploring the novel intravesical gemcitabine delivery system TAR-200 in patients with BCG-unresponsive, high-risk non–muscle-invasive bladder cancer (NMIBC).¹ In an interview during the meeting, Daneshmand, a professor of Urology and director of Clinical Research at Keck Medicine of USC, discussed the SUNRISE-1 data and several ongoing trials of TAR-200 in bladder cancer. He also highlighted a trial exploring TAR-210, an intravesical delivery system for erdafitinib (Balversa) in bladder cancer.

What are the current treatment options for patients with NMIBC?

Daneshmand: General treatment for non–muscle-invasive bladder cancer would be intravesical BCG. That's what we've been relying on for many years. But a significant portion of patients are refractory to BCG and end up having recurrences and more importantly, progression to higher-stage disease. There's a real need unmet need for these patients because we have a paucity of treatment options for these patients.

"Other trials are open in this space. The SUNRISE-2 [NCT04658862], SUNRISE-3 [NCT05714202], and SUNRISE-4 [NCT04919512] studies are looking at the efficacy of this treatment and sort of the spectrum of disease," according to Siamak Daneshmand, MD.

Currently, for patients with BCG-unresponsive or refractory disease, the guidelines encourage clinical trial enrollment. We do have doublet chemotherapy available to us, which shows some good responses in many patients, but the data is retrospective and we're trying to see what data will show in prospective studies. Also, in this BCG-unresponsive space, we do have pembrolizumab [Keytruda] that was approved a couple of years ago for BCG-refractory carcinoma in situ. Pembrolizumab is used in some settings with some success, but the success rates are at 1 year, and it’s only 19%. We do need other treatments in this space that are both more efficacious and have a better duration of response.

Also recently, nadofaragene firadenovec-vncg [Adstiladrin] was FDA-approved in this setting, but we still don’t have the drug commercially available to us. Again, our options are somewhat limited in the in the space right now.

Please provide some background on the novel intravesical chemotherapy delivery system TAR-200.

TAR-200 is a sort of a pretzel device. It's a novel drug delivery mechanism that's placed inside the bladder, for sustained release of gemcitabine. There are tablets within the little pretzel device that are placed in the bladder through a special catheter and stylet. They are very easily placed in the office setting. The urine creates an automatic pump, and the little tablets will then elude the chemotherapy through a sort of central pour over a sustained period, in this case, 3 weeks. The idea is that if you get the drug in the bladder for a prolonged period, it will be more efficacious. And that's been our experience.

We did have a phase 1 trial in this setting in 2016 and 2017 and saw some complete responses in the pre-cystectomy timeframe. Patients who were not eligible for neoadjuvant chemotherapy underwent this principal device placement 1 month prior to cystectomy. We saw an early signal that this is having a response in the tumor. That is what led to this SUNRISE-1 trial trial looking at TAR-200 plus cetrelimab, which is a PD-1 inhibitor.

Can you highlight the SUNRISE-1 data you shared during the 2023 AUA Annual Meeting?

We presented the first results, which were from cohort 2 and 3. These cohorts received TAR-200 alone or cetrelimab alone. This was monotherapy. We had 22 evaluable patients for the TAR-200 arm, and 21 patients in the cetrelimab-alone arm. What we found was that the primary objective was CR at any point, and we found a 73% of patients in our TAR-200 alone arm had complete response, which is a high response rate in this refractory patient population. With cetrelimab alone, it was about 36%, which is what we have seen with other PD-1 inhibitors. There's not much surprise there in terms of the efficacy. In terms of duration of response, we have not reached a median duration of response. Fifteen of the 16 responders continue to respond. There's only 1 patient who discontinued treatment, but of the responders, none of them have had a recurrence so far. Again, these are highly encouraging results, and the median follow-up so far is about 11 months, so we're waiting for additional follow-up.

What are the next steps?

First of all, we're continuing the trial. With further enrollment of patients within these cohorts, we want to see what the combination therapy shows whether there's an additive effect of the PD-1 inhibitor. I think this completely changes the paradigm on how we think about management of patients. This is, again, a sustained release, and that's what we need rather than these 1-hour installations that we're doing. The 1-hour installation are maybe not enough time to penetrate the layers of the bladder that is needed for eradication of disease. I think this is just the beginning.

We already have another trial open called TAR-210 [NCT05316155], which is placing erdafitinib [Balversa] within a pretzel, and that's for patients with FGFR3 alterations. Already, we've sort of moved on to the next step and we have some interesting preliminary results. I think this is going to be part of our armamentarium in the future treatment of non-invasive bladder cancer, and some select muscle invasive bladder cancer as well.

Other trials are open in this space. The SUNRISE-2 [NCT04658862], SUNRISE-3 [NCT05714202], and SUNRISE-4 [NCT04919512] studies are looking at the efficacy of this treatment and sort of the spectrum of disease. SUNRISE-2 is looking at patients who have muscle invasive bladder cancer who are not eligible for cystectomy, and they are randomized between cetrelimab plus TAR-200 vs standard of care in that setting. We're sort of looking at this in the muscle invasive disease patients are unfit or unwilling to undergo cystectomy. SUNRISE-3 should be opening soon, which goes head-to-head with BCG, in the BCG-naive patient population.

Reference

1. Daneshmand S, van der Heijden MS, Jacob JM, et al. First results from sunrise-1 in patients with BCG unresponsive high-risk non–muscle-invasive bladder cancer receiving TAR-200 in combination with cetrelimab, TAR-200, or cetrelimab alone. Presented at 2023 AUA Annual Meeting. April 27-May 1, 2023; Chicago, IL. Abstract LBA02-03. doi.org:10.1097/JU.0000000000003361.03