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Felix Guerrero-Ramos: Hello, everybody. My name is Felix Guerrero-Ramos and I'm a urologist at Hospital Universitario 12 de Octubre. I'm the coordinator of the Bladder Cancer Unit. Thanks, everybody, for watching and thank you UroToday for the invitation to make our comment seen on the recently published paper at European Urology Oncology, Novel Delivery Systems and Pharmacotherapeutic Approaches for the Treatment of Non-muscle-invasive Bladder Cancer. This is the paper. I first want to thank all my co-authors who made a very good job and we got a very nice paper. Dr. Boormans, Dr. Daneshmand, Gontero, Dr. Kamat, Roupret, Antoni Vilaseca and Dr. Shariat.

This is why we decided to perform this review this paper because in the last decade we have experienced great improvements for both locally advanced and metastatic disease with many new approvals and lately a big change in the algorithm of treatment, especially with the publication of the data of enfortumab vedotin plus pembrolizumab. But we have been nearly four decades using only BCG and/or chemotherapy, intravesical chemotherapy, for those non-muscle-invasive bladder cancers with scarce advancements in this stage of the disease. So there are several medical needs across the stages of non-muscle-invasive bladder cancer. For those intermediate risk patients, the objective is to avoid or delay recurrence and avoid TURBTs, especially in those highly recurrent patients. For those high risk patients, we want to avoid recurrence but also progression to muscle-invasive bladder cancer, so we need alternatives to BCG. And for those BCG unresponsive patients, our objective or the main aim of the trials is to avoid a radical cystectomy without impacting in the cancer specific survival of the patient.

So we wanted with this article to provide a comprehensive overview of the new therapies that are under investigation for non-muscle-invasive bladder cancer. So if we start with the most advanced setting of non-muscle-invasive bladder cancer, here we include a table just to remind and refresh all the definitions of the different responsive to BCG, from the BCG naive to the BCG unresponsive patient, but including the new category defined as BCG exposed, which is those patients with a high grade recurrence during the first 24 months after finishing BCG but who do not accomplish the BCG unresponsive criteria.

So if we look at the most recent data that we have of new drugs for BCG unresponsive patients, we see that there are three approvals by the FDA. There's pembrolizumab, which you can see here with a 41% complete response rate of three months for CIS with or without papillary disease. It is important to highlight that the FDA approvals are only for those patients with BCG unresponsive CIS with or without papillary disease and not for papillary disease only. We have also although nadofaragene firadenovec with a 53.4% complete response rate at three months and ANKTIVA, which is BCG plus super agonist of interleukin-15, which is N-803 with 71% complete response rate at any time. If we look at the safety profile, we see that those intravesical alternatives have similar or better efficacy than intravenous or systemic therapies with a decreased grade three or higher adverse event toxicity rate. So we have many other drugs with promising results, as you can see here, with low rates of significant toxicity and still we don't have any more FDA approval. So we suppose in the near future we will have new approvals by the FDA.

If we look at the papillary only disease here, the main objectives are recurrence-free survival rates given that we do not assess a complete response rate as for CIS and data are even better than for the CIS patient, but still no approvals in this setting. Moving to the BCG naive high risk non-muscle-invasive bladder cancer, the main aim is to avoid progression to muscle-invasive bladder cancer, and this is the common design for the systemic immune checkpoint inhibitors trial. There's usually a control arm with BCG induction plus maintenance and then there is another arm with BCG induction plus maintenance with systemic immune checkpoint inhibitors, and a BCG saving arm with BCG only induction plus immune checkpoint inhibitors. The primary and secondary outcomes are similar and the follow-up of these patients is according to high risk patients seeing both EAU or AUA guidelines.

Looking more closely to all the phase three trials currently running in the high risk BCG naive disease, we have here the four trials with... On the left we have the four trials with systemic immune checkpoint inhibitors. There are several differences between them, which are not a lot, but for example, as you can see, the ALBAN trial from the French group there is only two arms, BCG induction plus maintenance versus atezolizumab plus BCG induction plus maintenance. In the case of the CREST trial, the systemic therapy, which is sasanlimab, is administered subcutaneously and not intravenously. And for example, there are also differences in the duration of the BCG maintenance, which ranges from one year in the ALBAN trial to two years in both the POTOMAC and CREST trial. Also, the sample size of the different trials slightly differs. Of course due to one less arm of study, the ALBAN trial is the one with the less number of patients.

And there are a couple of two phase three trials assessing the efficacy of new treatment regimens. We have the SunRISe-3 trial where BCG induction plus maintenance, as for any trial, is the control arm, but we have an arm with intravesical TAR-200, which is a device with a sustained release of gemcitabine, and there's another arm where TAR-200 is associated with intravenous cetrelimab which is another immune checkpoint inhibitor. So this is one of the trials where there is an arm without systemic immunotherapy. And if we look at the BRIDGE trial, given the promising results shown by sequential gemcitabine docetaxel intravesical in BCG unresponsive patients, this trial is randomized in patients to receive either BCG induction plus maintenance versus sequential gemcitabine docetaxel. So again, no systemic therapy. Both of these trials are awaiting results. The estimated completion date is around 2030. So we have to wait a little bit.

Finally, if we move to the intermediate risk scenario, we have in these boxes with the thick line all the current algorithm. It is true that this algorithm includes something very important, which is the sub-classification of the intermediate risk patients proposed by the IBCG, the International Bladder Cancer Group. And depending on the additional risk factors of these intermediate risk patients in the standard of care, we would recommend one or another therapy. But if we look at all the new approaches we have, we can have patients who after TURBT and their postoperative chemotherapy will receive adjuvant CG0070 as an adjuvant therapy if there would be good efficacy outcomes and then being followed up.

But maybe the most novel approach in this intermediate risk population is the ablative approach where we are trying to avoid TURBT for patients, especially for those highly recurrent patients who need more than TURBT per year, and there are two main options here. We have UGN-102, which is a mitomycin gel where we administer this gel to the patient and we try to avoid the TURBT and eliminate the tumor. So in this case, a patient with a complete response would just undergo follow-up as any other patient. If there is no complete response, we will have to look for other alternatives, either the standard one or looking for other ablative approaches. In this sense, ablative approaches with personalized medicine, molecular screening for FGFR mutations or fusions, either in urine or in tissue, will allow us to use the TAR-210 device, which contains erdafitinib and has reported over 90% of complete response rates.

So those patients being positive for those selected alterations will be candidates for TAR-200 and in case of complete response, which is with a probability higher than 90%, those will be follow-up. We still have to know data on the duration of the response of these new alternatives, but of course, as you can see, the intermediary setting could have a big change in the near future.

So just to sum up and after the conclusions and the discussion of our paper, we can see that in the intermediate risk scenario where there's a trend for more ablative rather than adjuvant approaches. In the high risk scenario, we want to minimize the use of BCG or even substitute it like trials with SunRISe-3 trial or BRIDGE trial. In the BCG unresponsive scenario, we have a high number of alternatives currently being investigated, but we want to avoid or significantly delay a radical cystectomy. There are only three approvals and only by the FDA which are based on single arm trials, and this is one of the limitations. There is a big heterogeneity in the intermediate risk group, which sometimes limits the results of the trials. And in all these cases, in all these settings of the disease, the intravesical route seems much better. So thank you very much for your attention. You can see here how to contact me by email, by Twitter. Thanks for watching. I hope you like this video. Have a great day. Bye-bye.