New Therapeutic Targets and Investigational Drugs in the Pipeline for Advanced Bladder Cancer - Joaquim Bellmunt

December 28, 2022

Alicia Morgans speaks with Joaquim Bellmunt about advances in urothelial carcinoma. Dr. Bellmunt outlines the progress and challenges in targeted therapies, such as PARP inhibitors, antibody drug conjugates, and immunotherapy checkpoint inhibitors. Despite some negative trials, there are exciting prospects on the horizon. He discusses promising therapies like antibody drug conjugates targeting HER2, CD138, and transcription factors like PPARγ. Further, intratumoral therapies, bispecifics, and novel techniques like "fake libraries" and "bicycles" are also in the pipeline. Bladder cancer treatment is also set to benefit from RNA-based enhancers of checkpoint inhibitors developed by Moderna and a new CAR-T cell approach using NK cells. Dr. Bellmunt expresses excitement about these ongoing developments and the globally concerted efforts in bladder cancer research.


Joaquim Bellmunt, MD, PhD, Medical Oncologist, Director, Bladder Cancer Center, Dana Barber Cancer Institute, Boston, MA

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here at SOGUG 2022, where I have the opportunity to speak with Professor Joaquim Bellmunt who is joining us from Dana-Farber Cancer Institute. Thank you so much for being here with me today.

Joaquim Bellmunt: Yeah, it's a pleasure to join and be able to share what has been presented during this meeting.

Alicia Morgans: It's wonderful to have you here, and so exciting to see you, being from Barcelona, but also practicing in the US, and being so transcontinental in your opinions and your perspective. It's just very exciting and so worldly, and very helpful as we put these things into our algorithms.

Now, you spoke about really, advances in urothelial carcinoma, and I think I'd love to have you start off with some of the things that are a little closer to what we are already using, before we get into the new advances that are beyond what we could imagine even at some point. So really, PARP inhibitor advances, antibody drug conjugates, immunotherapy checkpoint inhibitors. Tell us a little bit about where we are, and where we go in the very near future with these approaches.

Joaquim Bellmunt: Yeah, no, no. I think that we know that for bladder cancer, we have only one targeted therapy approved that is against the EFGR pathway, right. And we have tried to build on that and looking for other targets. And also, we have the antibody drug conjugates, and in the US we have enfortumab vedotin and sacituzumab govitecan. But we are building on the concept of ADC with new approaches. And also, the same for checkpoint inhibitors. We have the anti-PD-1, anti-PD-L1, the CTLA-4 inhibitors, but we are getting more that start being studied in advanced bladder cancer.

Alicia Morgans: So tell me, are there any that you see on the nearer horizon, studies that you want to highlight or bring up?

Joaquim Bellmunt: Yeah, so I think in terms of targeted therapies, still FGFR3, erdafitinib, is the only drug that is going to be approved. Several others have failed, because it's like FGFR alterations are seen in only 12% of bladder cancer patients. And then, you see responses in only 40%, like with erdafitinib, and the responses are not long-lasting. So recently, for example, the development of infigratinib, that is an FGFR inhibitor, has been discontinued, that it was exploring the use of adjuvant infigratinib in the upper tract. The lack of accrual decided the company to shut down the project of this compound in bladder cancer.

And we have tried other new targeted therapies. A recent paper has published about the role of cabozantinib. We know that cabozantinib is highly useful in kidney cancer. But in bladder cancer, in second-line, only 16% responses. And even the same group that is Andrea Apolo from NCI, they have published a paper combining cabozantinib and nivolumab, also working well for kidney cancer. But in fact, in bladder cancer, even this was tested in patients that fail the immunotherapy, and then maybe there's a small role, but only 16% of patients responded.

So that mean at this point, we are a bit stuck, in terms of targeted therapies, and others that we have been looked for in prostate cancer are the PARP inhibitors. PARP inhibitors, we have three studies. The study of ATLAS with rucaparib, completely negative, no responses in unselected patient population. Then also, rucaparib has been studied in as maintenance, also no good results.

And most recently, there is the BAYOU study, that is in unfit patients with bladder cancer combined with atezolizumab, some data, but only in patients with HCR alterations. Likely, there might be a role, but it's not like in prostate cancer. So yeah, more studies need to be done in that sense.

About new checkpoint inhibitors, we have the anti-TIGIT and anti-LAG, and those are now, interestingly, being explored, the anti-TIGIT, as maintenance with atezolizumab in bladder cancer. And the anti-LAG is going to be added to nivolumab, based on studies that have been seen in melanoma, as an adjuvant therapy, and also, including the cell-free DNA in that space.

So we have also new checkpoint inhibitors. We have enhancers of the checkpoint inhibitors. There is a drug named mitazalimab, that is an antibody agonist of CD40, that in patients that might have failed immunotherapy, continuing the immunotherapy and adding this agonistic antibody, maybe we will be able to reverse. And there is a planned study in bladder cancer.

Alicia Morgans: Wow. So lots of activity. Thank you for walking us through all of that, and giving us the context in detail. Because it's so important as we think about where we're going, to understand where we've been in the last few years, with multiple negative trials, but really giving the opportunity to these new approaches. So can you tell us, what's on the horizon? What are the new approaches that you're excited about?

Joaquim Bellmunt: Yeah. So in fact also, there is new horizons with the antibody drug conjugates. Classically, we know the EV, enfortumab vedotin, SG, sacituzumab govitecan, were targeting the nectin-4 and the Trop-2. Now there is a new ADC targeting the HER2, that can be used in patients with low HER2 expression in bladder cancer. There is data presented at ASCO, 26% of responses in low expressors.

And then, there are other ADCs in the future. One is, for example, targeting the CD138, that is a marker of multiple myeloma, but it has been seen that is highly expressed in bladder cancer. And there is data of these ADC using the CD138 to treat bladder cancer patients.

New ways to approach targets. We are now in the pipeline, drugs that are going to target transcription factors. There is a drug that is going to target the PPARγ that is a marker of luminal. Meaning, patients, that is more around 50% of patients, having this genomic alteration in the PPARγ. This new agent that is going to block the transcription factor of PPARγ is going to be tested in advanced bladder cancer patient. And this is going to be open at the end of our presentation this trial.

Alicia Morgans: So this has been a lot, but I know that there are more things that you're excited about. What about intratumoral therapies, cellular therapies, bispecifics? I know these are of interest as well in urothelial carcinoma.

Joaquim Bellmunt: Yes, correct. So there is now a new perspectives on that. So there is a trial that's going to be also open at the Farber, where we are going to use the Moderna vaccine. In fact, the behind this project there is Moderna company, using RNA-based enhancers of checkpoint inhibitors. There is this compound that is given intralesionally inside the bladder. So the urologists need to place this mRNA there, and those contain IL-15, IL-18, and those are supposed to be enhancers of checkpoint inhibitors. That is like agents like the durvalumab. So a trial is going to be open soon, a Phase I trial is going to be.

So in terms of bispecifics, so there are also trials using bispecifics that are what is called conditional bispecifics antibodies. For example, there is a trial where PSMA, that is used in prostate cancer, is targeting tumors that can express PSMA. We didn't know that PSMA can be expressed in bladder cancer patients. And this bispecific is using PSMA as a target linked to the CD137. That is not the 138 that I mentioned before. This is 4-1BB, meaning that it's going to enhance the immune response, and this Phase I trial in patients who are PSMA positive.

And then, there are new ways to build antibody drug conjugate type of agents. We have the new technology that is using, this was described by Greg Winter who was a Nobel Prize in 2018, using the fake libraries to build ADC type of compounds, using peptides that are going to be targeting antigens like nectin-4 or efrin-A, and then link to monomethyl auristatin as a payload.

And the last thing is that, so agents named the bicycles, and these bicycles are made also based on peptide technology, and also using, they're going to use a payload and also targeting antigens like also efrin. And there is one that is also is a bicycle targeting CD8, CD137, and also nectin-4. And there is some preliminary data that is so exciting in bladder cancer.

Alicia Morgans: Well goodness, we are in for a lot. And what I think is so fascinating, and so important in bladder cancer research, is that after a period of years, and years, and years, where we could not get enough patients to actually accrue and complete a trial, we are in a new era, where we're finding all of these new therapies, and we're ensuring that patients get on these trials. Our patients are motivated. Our doctors are motivated. Our researchers are motivated. And what an exciting time it is. So any closing thoughts or final things that you want to share with the listeners, as we wrap this up? And very exciting.

Joaquim Bellmunt: Yeah. I forgot to mention there is, everybody is using the CAR-T cells, right? But CAR-T cells are not working in solid tumors, because of the axis of the lymphocytes that are modified with the chimeric antigen receptor. But there is also a project in bladder cancer using a type of, let's say CAR-T cells, but are NK cells, with the same subject, that are make with memory and being immortalized. And then, those are being expanded ex vivo, and then infused to the patients. You need to do lymphodepletion, like the same as with autologous bone marrow. And then, this is given with immunotherapy. So this is a project that is going to happen in patients with kidney cancer and bladder cancer. The lead is Dr. Choueiri, and I will be involved, and also Vincent from Dana-Farber. So this is a project that is so exciting, coming from the research that is being done at Dana-Farber.

Alicia Morgans: Wow. Well fantastic work. And so, as I said, exciting for patients, and exciting for all of us. I sincerely appreciate the time that you took to share this with us, and the continued work that you and the team, and the global community, are really continuing in this effort. So thank you so much for your time today.

Joaquim Bellmunt: Thanks for the opportunity.