Urothelial Cancer: What’s New in 2023? [Slides] Targeted and Novel Therapies Nataliya Mar MD

Urothelial Cancer: What’s New in 2023? Targeted and Novel Therapies Nataliya Mar MD

By Nataliya Mar, MD

Good afternoon, everyone. It’s my pleasure to be the last speaker of the afternoon. So today, I thought, since we had so many wonderful speakers before me who went through so many clinical trials and the data, I thought that this would be a little bit different.

And we’re going to zoom out a little bit from the clinical trial world and focus a little bit more on how oncology as a field evolved in the past 20 years, let’s say and how we’re using really exciting drugs with novel mechanisms of action. That weren’t there 20 years ago, let’s say.

And think about it more from a maybe theoretical perspective rather than, us writing prescriptions in clinic and treating our patients. So the title of my talk is Updates and Targeted and Novel Cancer Therapies with a GU Bias.

Of course, we’re going to use GU malignancies as our example but generalized to other tumor types as well because I’m a GU medical oncologist, so it makes sense. So these are my disclosures. Okay, so this is gonna be a little interactive so nobody falls asleep. Okay. So does anyone know what this molecule is? Any trivia buffs, oncology trivia buff.

Nitrogen mustard. Oh my God, yes. Yes. Applause. So it’s nitrogen mustard. So this is our first chemotherapy drug. So the first experiment with it was done in the 1940s at Stanford. It was called Substance X. And they used it to treat a lympho sarcoma patient with very short response rate and then rapid disease progression.

But this is what kind of our old historic prototypical drug that has been there, and again, this is just to contrast how much we have evolved over time. So these are trends in oncology, drug approvals since the early 2000s, and you can see that the line vastly is going up. And we have had many more drug approvals recently to early 2000s, 20 years ago. However we know that development of drugs takes time, and it’s a lot of work as you can see in this little chart. So time from concept to kind of drug registration. Is long maybe 15 years or so, and we have to keep that in mind that developing novel agents is difficult, costly and a lot of them fail and never make it to registration.

So one concept that we’re gonna also mention in this talk is drug repurposing. So developing drugs for one indication and then trying them in for different in. So this is very busy , and these are all the drugs that got FDA approved since 2000. I took the liberty of highlighting the ones for GU cancers in red just to show how much progress we have had.

But on the left you can see that the drug approvals were very few. In the early 2000s you’re talking about less than 5 per year. And then if you kinda shift more you can see that the, it is just exploded. Just really lots of drugs, novel mechanisms, and this is not even an all-inclusive list, for every indication for each drug. So drug repurposing, right? And this is just a continuation in the more recent years. 

So we are gonna talk a little bit about exciting, interesting pathways. And use our GU cancers as a prototype. So continuing in the trivia buff theme. Does anybody know what these molecules are? I’m sure all of you have used them. All of you! Yes. There you go. Dr. Pal is like taking the lead. Okay, so on the left you have cisplatin, on the right you have carboplatin. And these before about 2015-2016, these are what we’ve had for urothelial carcinoma. And the field was very stagnant for a long time. We had this, and then we had second line, other chemo agents with no overall survival benefit.

So that’s all we had to give our patients. However, we found out that urothelial cancers are really diverse molecularly and multiple groups did this work with urothelial carcinoma. This is just one group’s classification, the TCGA classification of urothelial carcinoma, maybe in a sense similar to breast cancer, but basically it’s, it subdivides urothelial cancers into luminol and basal/squamous subtypes based on molecular signatures and then further subdivides them into other molecular subgroups. These cancers look different on immunohistochemistry. They have different gene expressions and consequently also respond to different agent. So for example, if you look towards the bottom of this chart that basal cancers tend to do better with cisplatin based chemotherapies, but luminal cancers tend to do better with other agents, for example, checkpoint inhibitors FGFR inhibitors and other targeted therapies.  We later figured out that, we need other drugs with newer, novel mechanisms of action for urothelial carcinoma. 

So does anybody know what these two lovely people won the Nobel Prize for in 2018? Check. Yes. There we go. We have a lot of oncology trivia buffs. I love it. So these two people Dr. Honjo, Dr. Allison basically their work led to the discovery of checkpoint inhibitors. So Dr. Allison worked on CTLA, Dr. Honjo worked on PD-L1, and now for urothelial carcinoma and many other diseases. We have checkpoint inhibitors that, have done wonders in subsets of urothelial carcinoma patients.

So I try to minimize the clinical portion of this talk, but these are the clinical trials that led to accelerated approval of PD-1, PD-L1 inhibitors for urothelial carcinoma in the metastatic space. And you could see the response rates and all of that, but very active drugs for subsets of urothelial cancer patients. So really big major breakthrough in this field with the first drug being approved in 2016. 

So now we’re gonna shift gears a little bit, but keeping in theme of urothelial carcinoma. So this is a very kind of novel, interesting class of drugs, which we’ve heard about a little bit from the other speakers. But these are antibody drug conjugates. And really we have two approved for the urothelial carcinoma patients in the metastatic space. But again, really interesting molecule where you can design the antibody portion to target whatever target you want. Then you have a linker component.

And then you have the payload component, which also you can design to be whatever you want. So one drug that received approval in the urothelial carcinoma space is in Enfortumab Vedotin (EV), where the target is a molecule that is overexpressed on the majority of metastatic urothelial cancer now. Called Nectin-4 and the payload is monomethyl auristatin E, which is a taxane like microtubule inhibitor drug. So this molecule binds to Nectin-4,  gets internalized, the linker gets cleaved off, and the active payload drug gets released directly into the cancer cell. So precise delivery model of a cancer drug into the cancer cell. And I listed the clinical trials that led to the approval for metastatic urothelial carcinoma, a little bit to the right, in a tiny.

A second similar concept molecule that was FDA approved for urothelial cancer is Sacituzumab Govitecan (SG). So similar concept except the target is different. And it’s called TRIO-2, and then the payload is also different, and it’s a pro-drug of Irinotecan called SN-38. And this drug now also is available for breast cancer patients. Again, repurposing of drugs, right? Using similar drugs for different indications, like we discussed. 

And then there are many more ADCs coming down the pipeline. In the urothelial cancer space, we have a her two targeted antibody that is coming down the pipeline, but you could essentially design this to target whatever molecule you want, in whichever types of bladder cancer you want.

So shifting gears a little bit. This is our kind of third model of cancer drug development that came about in the urothelial cancer space. And this is designing drugs targeted agents based on gene altering. And this is, it got cut off a little bit, but this is Erdafitinib that was FDA approved for metastatic urothelial carcinoma. This is a really busy pathway just to illustrate how complicated signaling inside cancer cells is, but in this particular example we’re focusing on the FGFR transmembrane protein, and there are actually four of them, FGFR 1-4 and they bind ligands FGF in this case. And then they dimerize, auto-phosphorylate and then set off this whole cascade of signaling that leads to proliferation of cancer cells. Cancer cells figured out how to have alterations in this FGFR, receptor to skew the signaling towards cancer growth. And this graphic kind of demonstrates the variety of FGFR alterations across different tumors. So you can see that, for example, in bladder cancer, you tend to have gene fusions at one location. In other cancers you may have gene fusions at other locations, you can have point mutations, you can have amplifications. So this is what cancers do to gain a median survival advantage. However, we know now that FGFR tends to be overexpressed in about 20% roughly, of urothelial cancer patients, and that we can target that with a drug. So this led to development and eventual approval of Erdafitinib, which is a inhibitor of all the FGFR 1-4, as well as, other proteins. And then you have  drugs and other malignancies that became FDA approved. So you have Pemigatinib for example, and Infigratinib for other indications, but really interesting concept. . 

Now moving on a little bit. So switching to clear cell renal cell carcinoma. So this is an example of figuring out a pathway and then trying to design drugs to target different components of a pathway. So this is the kind of complex pathway in clear, transitional cell carcinoma or RCC. And we have some more photographs here. So who knows who these lovely men won their Nobel Prize for?  I think we should have a Jeopardy show with Dr. Pal as a host. Yeah so their work, their combined work led to development of HIF alpha inhibitor Belzutifan that is currently approved for VHL disease associated tumors, including RCC. So I think the conclusion here is if you do GU cancers, you’re gonna win the Nobel Prize, I think, that’s the conclusion. But yeah, so Belzutifan is currently approved for VHL disease associated tumors, and I listed the clinical trials kind of on the side, but to cut long story short clear cell RCC is associated with alterations in the VHL gene, Von Hippel-Lindau gene which causes increased expression of HIF and then all the genes downstream from, including VEGF, and we know that kind of the cornerstone therapies for RCC target VEGF. So this is an example of kind of exploiting one part of a big pathway within the disease. And then if you think about it, you have your VEGF therapies which exploit the other part of this pathway.

Now we’re gonna kinda shift gears a little bit to prostate cancer which also has really blossomed recently in terms of availability of therapies. So anybody know what these molecules are? The last one is tricky. This is old school. You have to reach back. You have to think back. Oh, no. Mitoxantrone. That’s really good. . Yeah. So you got 5 out of 5. So you have Docetaxel on the left and Mitoxantrone on the right. So these are our kind of classic chemotherapy (adjuvant chemotherapy) drugs that we have used for prostate cancer. But we have learned that prostate cancers are also very diverse molecularly which I’m not talking about today. I’m not talking about molecular therapies because that’s a whole another long talk. We’re going to instead focus a little bit on the radiopharmaceuticals that have come about in the recent years. The first example of that would be Radium-223. So this is harnessing the radiation idea and delivering it maybe in a more precise format. So Radium-223 is a radioactive alpha particle that gets incorporated into a bone and causes double stranded DNA breaks, and therefore causes cell death in plastic boney lesions. So then came this drug, 117-Lu-PSMA, which only was approved last year. And this again plays on that idea a little bit except it’s a even more targeted delivery of radiation into the cancer cell. Because it’s it’s again, this kind of antibody drug conjugate idea in a sense where you have a target, in this case, PSMA, which is overexpressed in prostate cancer cells. And joining that to a radioactive beta particle and precisely delivering radiation into the cancer cell. And with it there is a diagnostic test that’s approved, which is the PSMA PET scan, which is our picture on the left. So I wanted to illustrate that 117-Lu-PSMA is not the only kid on the block, and there are many more molecules in development that are being studied with various different targets, maybe, different attachments or still using PSMA as a target, but different companion, different radioactive drug. And these, this is just a listing of some of the ongoing studies in this space. So this field will definitely explode over the years. And this is again, coming back to the idea of drug repurposing. So this was a very interesting kind of, study I looked at to look at expression of the gene that codes for PSMA, and you can see that this is actually expressed in a variety of cancers, prostate cancer is all the way on the right, the highest the peak column, but you can see that PSMA is also expressed in other tumor types as well. And so, potentially, again we can consider developing it in other cancers with high expression of this gene.

Wrapping up where is the future of this? We have a lot of combination clinical trials going on with some of the drugs that I mentioned and other agents some drugs I didn’t mention and other agent sometimes these drugs are synergistics, sometimes they’re additive. So repurposing of drugs, again, we come back to the same theme. But just wanted to highlight, we’re not gonna go through this in excessive detail, but I wanted to highlight CAR T-cells, which is again, a very novel drug. So CAR T-cells are now of widely used in the HIM space. Not so much in the solid tumor space, although they’re coming. And these are some of the trials that are going on with CAR T-cells in the solid tumor space, including GU malignancies. So really interesting, and then again, just a very brief mention about CRISPR and gene editing. And again, designing compounds to target theoretically, , whatever you want. So I think we have come a long way in conclusion, from nitrogen mustard to these really interesting kind of genomic therapies, designer therapies, and I’m really excited to see what the future holds.

10 Key Takeaways about the Treatment Options for Urothelial Cancer 

1. Urothelial cancer (Urothelial Carcinoma), also known as transitional cell carcinoma, is a type of cancer that develops in the lining of the bladder, ureter, or renal pelvis.

2. The standard treatment plan for urothelial cancer includes surgery, adjuvant chemotherapy, and radiation therapy (systemic therapy) and follow up.

3. The choice of treatment depends on the stage and location of the cancer, as well as the patient’s overall health and preferences.

4. In early-stage urothelial cancer, surgery is often the first-line treatment, with the goal of removing the cancerous tissue and preserving bladder function.

5. In more advanced cases, adjuvant chemotherapy and radiation therapy may be used to shrink the tumor before surgery or to treat cancer that has spread beyond the bladder.

6. Immunotherapy is a newer approach to treating urothelial cancer that works by stimulating the body’s immune system to recognize and attack cancer cells.

7. Immunotherapy drugs known as checkpoint inhibitors have shown promising results in clinical trials and are now approved for use in certain cases of advanced urothelial cancer.

8. Combinations of different types of treatments, such as surgery followed by adjuvant chemotherapy or immunotherapy, may be used to achieve the best possible outcomes.

9. Follow-up care after treatment for urothelial cancer typically involves regular check-ups, imaging tests, and urine tests to monitor for any signs of recurrence.

10. Patients with urothelial cancer may benefit from working with a multidisciplinary team of healthcare professionals, including urologists, oncologists, and other specialists, to develop a personalized treatment plan and optimize their care.

Nataliya Mar, MD – About The Author, Credentials, and Affiliations

Nataliya Mar, MD, is a distinguished physician and medical researcher currently working at the University of California, Irvine (UCI). She specializes in internal medicine and has a keen interest in the field of gastroenterology.

Dr. Mar obtained her medical degree from the University of California, San Francisco, and completed her residency training in internal medicine at Stanford University. She then went on to complete a fellowship in gastroenterology at the University of California, Los Angeles.

Throughout her career, Dr. Mar has contributed extensively to medical research, focusing particularly on the development of new treatments for gastrointestinal disorders. Her research has been published in numerous peer-reviewed journals, and she has presented her findings at conferences around the world.

In addition to her research, Dr. Mar is also committed to educating the next generation of medical professionals. She has been a mentor to many aspiring physicians and has been recognized for her outstanding contributions to medical education.

Dr. Mar is a member of several professional organizations, including the American Gastroenterological Association and the American College of Physicians. She is also actively involved in community outreach and volunteer work, and has received numerous awards for her service.

As a physician and researcher at UCI, Dr. Mar is dedicated to providing the highest level of care to her patients and advancing the field of gastroenterology through her innovative research.