Dr. Guerrero-Ramos on the evolving treatment landscape in NMIBC

In this interview, Félix Guerrero-Ramos, MD, PhD, FEBU, provides an overview of the latest breakthroughs in non–muscle-invasive bladder cancer (NMIBC) and anticipates what may be on the horizon. This was highlighted in the recent publication, “Novel Delivery Systems and Pharmacotherapeutic Approaches for the Treatment of Non-muscle-invasive Bladder Cancer,” for which Guerrero-Ramos served as the lead author. Guerrero-Ramos is the coordinator of the urologic oncology unit and the bladder cancer unit at Hospital Universitario 12 de Octubre, in Madrid, Spain.

This transcription has been edited for clarity.

Félix Guerrero-Ramos, MD, PhD, FEBU

Could you describe the background for this work?

In the NMIBC setting, we've been using BCG and mitomycin for over 30 to 40 years. No new alternatives have been released. In the last decade, we've observed a high number of new alternatives within clinical trials, especially with intravesical delivery. We have some approvals from the FDA for BGC-unresponsive NMIBC, both systemic and intravesical. We have been learning that intravesical has similar or even increased efficacy with much less toxicity than systemic therapies. So, that's why we decided to give an overview of all the new alternatives with either final, preliminary, or still no results, so that readers can be up to date on what's going on and what's coming through in this field across all stages of NMIBC and with intravesical therapies.

You mentioned that there have been a few new recently approved therapies. Could you highlight those?

There are currently 3 approvals by the FDA. There was [an approval], some years ago, [for] intravenous pembrolizumab (Keytruda). It is important to highlight that these approvals are for carcinoma in situ (CIS) with or without papillary disease, but the patient must have CIS, which is BCG-unresponsive, as per the definition of the FDA or the EU or the [American Urological Association] guidelines. Pembrolizumab was the first approved agent with a 41% complete response rate at 3 months. Then the curve goes a little bit down for the response rate. I think it was at 18% at 3 years, which is the last [data that] was reported at the [European Association of Urology] Congress in Paris last April.

After that we had nadofaragene firadenovec (Adstiladrin) with a 3-month response rate of around 50% in these patients. [Nadofaragene firadenovec] is an intravesical virus that we put into the bladder.

The most recent approval has been Anktiva. Anktiva is a combination of BCG plus N-803, which is an interleukin 15 super agonist with a 71% complete response rate at any time, which is significantly higher than the former approvals and with a very favorable toxicity profile. So, these are the 3 agents that are currently approved by the FDA for the use in the United States for CIS with or without papillary disease that is unresponsive to BCG.

What are some things to consider when choosing between these therapies?

There are some limitations for these. Number 1 is that only the US FDA has approved these agents. No European or Asian agencies have approved these agents. So, I am based in Spain in Madrid, so I cannot use any of them outside of a clinical trial.

Another issue for the drugs is the cost. Pembrolizumab is not an expensive drug. [With] nadofaragene and especially Anktiva, there is an estimation of around $750,000 per treatment, which is quite a high cost for these drugs as compared to radical cystectomy, which is estimated to be at $150,000 at the first year. So, this is the main drawback I think for these therapies. However, in the near future, if they expand and are available for more people, I suppose that with higher manufacturing, the costs may decrease.

Could you highlight the therapies that are currently in development?

For the BCG unresponsive scenario, we have promising therapies. One of them is TAR-200, which is an intravesical releasing system that you put into the patient's bladder every 3 weeks. It's a sustained delivery of gemcitabine. The preliminary results that were reported at the 2024 American Urological Association Annual Meeting in San Antonio in May reported around an 83% complete response rate, which is higher even than Anktiva. This is one of the most promising drugs. They already have an FDA fast track designation as a breakthrough therapy. So, I suppose in the near future, we will have a new approval.

Then there are 2 studies with a CG-0070, cretostimogene grenadenorepvec. One of them is the CORE-001, in which cretostimogene is combined with intravenous pembrolizumab. They reached response rates of around 88%. The BOND-003, which is [evaluating] just CG-0070, avoiding all the systemic toxicity of pembrolizumab, [and which achieved] around a 70% to 80% complete response rate. So, for me, this is another very promising agent.

If we focus still on the BCG-unresponsive scenario, we have also TAR-210, which is a similar design of TAR-200, but instead of gemcitabine, there's erdafitinib inside the device. This is for patients who only have papillary disease, because erdafitinib is a targeted agent for FGFR mutations or fusions, and we know that CIS does not present in mutations or fusions of FGFR. So, that's a reason why this is only for papillary disease. They are using this device in an in-person human trial with 2 cohorts. There's 1 cohort for BCG-unresponsive papillary disease, where they reached very nice disease-free survival rates of 80% to 90%. This is a future option that may be available for those patients with papillary only disease for whom there is currently no approvals.

If we move to the intermediate-risk scenario, they are trying this device, [TAR-210,] in the intermediate-risk population as an ablative approach. There is a molecular screening prior to the inclusion in the clinical trial. If there are mutations or fusion for FGFR either in during orientation, the patient is a candidate for the therapy, and you can put the device into the bladder. There's over 90% of complete response rates in these patients. In both of the cohorts, the toxicity is negligible.

What do you think the future holds for the NMIBC space?

There are 3 clear scenarios in non–muscle-invasive bladder cancer. One is the intermediate risk. There are mainly ablative approaches trying to avoid to TURBTs, but also some new trials with adjuvant therapies being compared with mitomycin. In the future, I believe those higher recurrent patients might be candidates for ablative therapies so that we avoid TURBTs and the cost of a TURBT: the inpatient, the hospital bed, and everything. We have, in fact, a nice figure in our paper showing the proposed future algorithm in case we have any approvals for intermediate risk.

If we go to the high-risk BCG-naïve scenario, we have clinical trials mainly assessing the efficacy of systemic immune checkpoint inhibitors with BCG maintenance or with BCG induction only. We have no data on these; we only have preliminary data of the BladderGATE trial (NCT04134000), which is a trial conducted in our center. It's a [phase 1b/2], 1 arm trial where patients receive both atezolizumab plus BCG with promising complete response rates, but with a limitation of being a small phase 1 trial. In the future, we are awaiting the results of the CREST (NCT04165317), POTOMAC (NCT03528694), and big phase 3 trials to see what happens with these. In this population as well, there's another trial with a slightly different design, which is the SunRISe-3 trial (NCT05714202), where there is an arm with no systemic therapy. We have the control arm with BCG, we have an interventional arm with TAR-200, and another interventional arm with TAR-200 plus intravenous cetrelimab. So, we will wait for the results of these, because if there's efficacy with TAR-200 alone, you can avoid systemic therapy for these patients.

Then finally, for the BCG-unresponsive scenario, several alternatives have been approved, as we previously said. But what we are learning––and this is my personal opinion, but it's a shared by many of my colleagues––is that the way to go is the intravesical therapy, because you do avoid toxicity. It's an easy route of administration for both urologists and nurses. Maybe those systemic therapies would be reserved for those patients who go to second- or third-line therapies who do not respond to the first-line intravesical therapy.