Webinar | Advances in Muscle Invasive and Metastatic Bladder Cancer: Past, Present, & Future Directions

July 9, 2024

Medical oncologist Tyler Stewart MD from the University of California San Diego Health highlights how bladder cancer treatments have changed in the past 10 years to create more promise and hope for those with localized and advanced bladder cancer.

Year: 2024

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Part 1. Past and Present Advances in Muscle Invasive and Metastatic Bladder Cancer

Transcript (PDF)

Part 2. Future Directions in Muscle Invasive and Metastatic Bladder Cancer

Transcript (PDF)

Part 3. Advances in Muscle Invasive and Metastatic Bladder Cancer: Past, Present, & Future Directions Q&A

Transcript (PDF)

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Full Transcript on Advances in Muscle Invasive and Metastatic Bladder Cancer: Past, Present, & Future Directions

Stephanie Chisolm:

Hello and welcome to Advances in Muscle Invasive and Metastatic Bladder Cancer: Past, Present and Future Directions. I begin today’s program by thanking the sponsors of our Patient Insight webinar series, Merck and UroGen. Today’s topic is about advances in muscle invasive and metastatic bladder cancer, and BCAN started in 2005 when Diane and John Quale were really amazed at how limited the treatment options were back then. So we are now 19 years old. And they really were kind of taken aback by the inadequate research funding to find new ways to treat bladder cancer.

And I’m really happy to say that in the past 10 years or so, the landscape for bladder cancer patients has significantly changed, and I’m really delighted to welcome Dr. Tyler Stewart, a medical oncologist from the University of California San Diego Health, to share an overview of the treatment and research landscape since we started almost 20 years ago.

Dr. Stewart is a genitourinary medical oncologist and researcher. As an assistant professor of medicine at the University of California San Diego, his research focuses on clinical trials, translational studies, and urologic malignancies, with a special focus on bladder and upper tract cancer. He serves as a principal investigator for trials investigating novel therapeutics for advanced and locally advanced urothelial carcinoma, and he also serves as a principal investigator for studies investigating novel biomarkers in plasma and urine to detect minimal residual disease for genitourinary malignancies.

Dr. Stewart has published extensively on urinary malignancies and is an active member of the Alliance for Clinical Trials in Oncology cooperative group. And in addition to that, he currently sits on the NCCN, the National Comprehensive Cancer Network guidelines panel for bladder and penile cancer. I’m now going to turn your attention to Dr. Stewart for his presentation about advances in bladder cancer. So Dr. Stewart, if you’d like to share your slides, welcome. It’s a pleasure to have you here.

Dr. Tyler Stewart:

So thanks so much for having me and thanks for the whole BCAN community for coming out to this webinar. Really an honor to be here. As you know, BCAN has been such a great network for patients, and family members, and loved ones of patients with bladder cancer that I really feel honored to be part of this program series. Today I’m going to talk about advances in muscle invasive and metastatic bladder cancer.

Here are a couple of disclosures. So a little bit about me.

So I am a medical oncologist here at UC San Diego, and I do general urinary malignancies, which means that I treat mostly patients with prostate cancer, kidney cancer, really my specialty and area focus is bladder cancer.

My research is, as you said, Stephanie, in novel treatments for urothelial carcinoma and then biomarkers really for early cancer detection, minimal residual disease and predictors, and early detectors of response for therapy.

Today, we’re going to talk about two major topics. We’re going to talk about advances in advanced urothelial carcinoma and how the treatment has evolved, especially over that year of 2005 since BCAN’s inception. And then really the treatment and standard treatment therapy is currently available for patients with muscle invasive bladder cancer, and really where the horizon is going for both of these fields.

The first thing that you should know is that bladder cancer diseases, we treat these based on the disease state. So for many patients with bladder cancer, these may be very superficial, just really in the lining of the bladder, and nowhere else. And oftentimes, those might be treated with just surgery alone.

Once the disease gets into that muscle layer, it has an ability to then spread through the bloodstream. And so patients who have muscle invasive bladder cancer are at higher risk of the cancer spreading. And we certainly have to think about how we treat those patients a little bit differently than just resecting the tumor. In patients who have metastatic bladder cancer, what this means is the cancer started within the bladder or the upper tract, its upper tract disease, and then unfortunately is spread to another organ. And how we treat all of these is very different.

As a medical oncologist, my major role is to talk to patients about the systemic therapy options. So major providers that cancer bladder cancer include the urologists who do a lot of surgery, and oftentimes in the United States will do the intravesicular therapy. There are radiation doctors who may use radiation to treat bladder cancer, both for localized and metastatic disease.

I, as a medical oncologist, specialize in treating patient patients with systemic therapies, which sound like chemotherapy, immunotherapy. And we’re going to talk about a lot of these today.

Today, I’m excited to talk about where we were and mostly where we are going with advanced urothelial carcinoma. So what you can see here is that we have had chemotherapies throughout the years. And up until really the late 2000 teens, really the only treatments that we had for advanced urothelial carcinoma, meaning cancer that had started in the bladder and spread, was really just chemotherapy. So in the 1970s, we had cisplatin. Then we started combining chemotherapy agents together to treat patients with advanced disease.

When we started out, what we started to do was combine chemotherapies together with really the backbone of using this medicine called cisplatin. And what we found out is that when we combine cisplatin with other agents, patients generally did better than the single agent.

In this study, they looked at two combinations of gemcitabine and cisplatin versus another regimen called MVAC, which is four chemotherapies. The important take-home point of this is that although many patients who have advanced cancer might respond around 50% of patients, oftentimes patients would only respond for the course of seven, eight months. And unfortunately, the vast majority of patients would progress, and ultimately that cancer could be fatal.

When those patients progress on chemotherapy, oftentimes we would think about using a second line chemotherapy agent. So many chemotherapies were studied. Unfortunately, chemotherapy after you’ve already had chemotherapy doesn’t often work very well, with response rates only around 10 to 15%. Some patients may respond quite well to these for a limited amount of time. But what this really told the field is that we need to do better. We need to find other treatment options other than just standard chemotherapy.

Dr. Tyler Stewart:

Enter the age of immunotherapy.

So in the 2000s and early 2010s, scientists started learning more about your immune system and how your immune system can attack and kill cancer, but then how cancer can put up camouflage signals called checkpoints, so immune checkpoints.

And so researchers started to say to ourselves, “Well, what happens if you get rid of those checkpoints, if you found a way to inhibit the inhibition of the immune system?”

The major focus was on this target of anti-PD-1 and anti-PD-L1. This is a signal that stops the immune system from attacking cancer. And so early in the 2000s and 2010s, studies started to come out in multiple cancers looking at these checkpoint inhibitors.

One of these checkpoint inhibitors, it’s called pembrolizumab. And when this therapy was looked at for patients who have urothelial carcinoma, it looked like in patients who were treated with pembrolizumab, around 20, 25% of patients can respond to this. And unlike chemotherapy, when you had a response to this, it could last for a long time. In fact, there have been patients who have been treated with checkpoint inhibitors that are alive many years now without any evidence of disease.

We then did studies looking at these checkpoint inhibitors comparing them to chemotherapy as second-line agents. And trial after trial showed that patients who were treated with checkpoint inhibitors had a response rate around 15, 20 to 25%, and when they responded, could do very well.

This work led to the two pioneers in this field of winning the Nobel Prize back in 2018 really revolutionizing cancer care. And for patients with bladder cancer, although not everyone responds to this, those who do sometimes can enjoy a very long time on treatment without their cancer progressing.

So during this time, at least five different checkpoint inhibitors were actually approved for advanced urothelial carcinoma. Some of those have actually been taken out for other reasons, but this was really the dawn of a new era for urothelial carcinoma.

The next big leap for urothelial carcinoma was looking at genomic vulnerabilities. As the field of cancer research has evolved, we are oftentimes looking for how cancers are different than normal cells, and can we find something that’s abnormal in a cancer cell where we can find a therapy for that?

And what we know is that patients with bladder cancer and upper tract urothelial carcinoma, they have alterations in something called FGFR. This is the FGFR receptor, oftentimes FGFR2 and 3, really FGFR3 is a major component.

This is very prevalent in patients who have localized disease, but we see mutations in FGFR around 15% of the time in patients with advanced disease. So then the thought was, “Well, in patients who have these alterations in FGFR, which make this receptor constitutively active, kind of always on, can we turn off the switch by adding some therapy that is an FGFR inhibitor?”

The first of these that really came through in the clinic was a drug called erdafitinib. This is a therapy that blocks FGFR and can work on patients who have FGFR alterations.

In studies and early studies, about 40% of patients who were treated with this, who had an FGFR alteration. Again, that’s only around 15% of patients who have one of these. But of those patients who were treated, about 40% saw significant shrinkage.

And for some of the patients who were treated with this therapy, which is an oral pill that you take once a day, this is a therapy that sometimes can work for a long time, many months.

Dr. Tyler Stewart:

More recently, a trial underwent to compare that therapy versus getting that second line chemotherapy. And really, we saw significantly higher response rates, and patients overall did better, lived longer on this therapy. So like immunotherapy, really moving the field forward from just that second agent chemotherapy. Bringing new therapies, new weapons into our clinic.

The next big breakthrough that we’ve had in advanced urothelial carcinoma is really these antibody-drug conjugates. And these are the newest kid on the block, and we are still in the age of antibody-drug conjugates. Antibody-drug conjugates are this amalgam of ideas that have come together to create a very cool weapon against cancer.

This is how I think about them. So antibody-drug conjugates are just an antibody that recognizes a specific target on cancer cells. It then has a little linker to chemotherapy.

So the idea is that this medicine gets into your system usually by an IV infusion, goes throughout the body. And if it finds an area that is abnormal that signals a cancer cell, it latches onto it, oftentimes will get absorbed into the cell, and then releases its chemotherapy, kind of boom goes the dynamite.

A heat-seeking missile for cancer therapy and antibody-drug conjugates have been studied in many cancers and bladder cancer is not unique. But let’s take a look at the data for what therapies have been investigated.

The first of these drugs that really hit the scene was something called enfortumab vedotin. So enfortumab vedotin is an antibody-drug conjugate that targets nectin-4, which is highly expressed on urothelial cancer cells.

The antibody has something called MMAE, which is a type of chemotherapy that’s linked onto it. And again, the idea here is the antibody finds this target, this nectin-4 and gets absorbed into the cell. The linker breaks off, and then boom, chemotherapy is released and the cancer cell dies. So it’s a great theory, but how did it work out in the clinic?

Well, it started to work out really well. When this drug first came on the scene in early phase studies, we saw response rates of around 40 to 50% of patients. Which compared to 10 to 15%, this was really a big breakthrough, and some patients really had these dramatic responses.

This drug was also compared against chemotherapy in large randomized studies. And what we found again was that 40 to 50% of patients had significant shrinkage. And compared to chemotherapy alone, patients who received enfortumab vedotin lived longer, happier, healthier lives, which is certainly a great tool to have in our toolkit when we’re thinking about treating patients who have advanced urothelial carcinoma.

Another antibody-drug conjugate that is on the scene, something called sacituzumab govitecan. So similar to enfortumab vedotin, this is an antibody-drug conjugate. But now the target is a little different. It’s called Trop-2, and the chemotherapy is a little bit different.

In early phase studies, this has an efficacy rate of shrinking the tumor significantly around 25 to 30% of the time, which looks pretty good in comparison to historic rates of how chemotherapy did. There are ongoing larger studies that are evaluating this versus standard of care.

The newest kid on the block is trastuzumab deruxtecan. So similar to the last two, here, our target is HER2 instead of nectin-4 or Trop-2. Now we’re targeting something called HER2, which is highly expressed on some urothelial carcinoma.

In this study that was done, which looked at this agent against multiple cancer types, in the patients who have bladder cancer, they looked at patients where their HER2 expression was very high, meaning they had this signal on a lot of their cancer cells. And in patients where the signal was the highest, that three plus range, 56% of the patients responded.

And based on that, just a couple of months ago, the FDA actually approved trastuzumab deruxtecan for many cancers that express HER2 at high rates, including bladder cancer. And now this is in our armamentarium. And now I’ve been able to treat some patients with this agent.

Dr. Tyler Stewart:

So this is where we were with just immunotherapy, and now we have even more therapies that are at our disposal.

When oncologists start seeing drugs that are working pretty well, we start asking ourselves, should we combine these? Can we get a better effect if I add a couple agents together, trying to get rid of all of that cancer? Which is our ultimate goal?

The first thing that we try to do is do something like chemotherapy plus immunotherapy. Well, chemotherapy works sometimes and immunotherapy works sometimes. Let’s put them together and see how we do.

So it turns out that when we started doing this in big studies called IMvigor and Keynote, it didn’t seem to work. Compared to chemotherapy, those who got chemotherapy plus immunotherapy didn’t seem to be doing especially better, which was a real shock and real disappointment to the field.So then we had a little bit of a different idea.

So in the JAVELIN Bladder study, we actually took patients who got chemotherapy, had a response, or at least their cancer didn’t seem to be getting worse. And then we randomized to just watching them and waiting until their cancer progressed and then giving them immunotherapy or giving them an immunotherapy right away. And this immunotherapy was called avelumab.

In this study, the patients who received avelumab right away instead of waiting until their cancer got worse, did significantly better. And up until last year, this was really the standard of care for how we treat patients with advanced urothelial carcinoma. So chemotherapy, get the cancer under control. And then right away, give them some immunotherapy while they’re waiting.

More recently, another study came out looking at combination of cisplatin, gemcitabine, and nivolumab, another checkpoint inhibitor, versus cisplatin and gemcitabine alone.

And unlike the first two trials where the combination of chemo plus immunotherapy didn’t seem to work, this one seemed to work. Some of us think it’s because the chemotherapy agents here were limited to cisplatin instead of another agent called carboplatin. But clearly, patients who were getting cisplatin and gemcitabine, if they got nivolumab as well, those patients seem to be doing much better and lived longer. And as of recently, this triplet combination is approved to treat patients with advanced urothelial carcinoma.

But what about those other drugs that we were talking about, those antibody-drug conjugates? What if we combine those with immune therapies? Could we be doing any better? So this was a really sought-after question that we were all interested in.

So in early studies, what we did is we combined that in drug called enfortumab vedotin and pembrolizumab. And in the original study that was done with 45 patients, what we saw is that when patients got enfortumab vedotin and pembrolizumab, 73% of patients had significant shrinkage, with 18% of patients showing their scans after their treatment showed no evidence of cancer. Now, that doesn’t mean that all those patients were cured of cancer, but this is a huge, huge number. When we saw this, we, who treat patients with bladder cancer, very excited and said, “We have got to study this in bigger numbers.”

Last year, a major study was released that really changed the landscape for advanced urothelial carcinoma. And this study was called EV-302, where patients were randomized to get chemotherapy or enfortumab vedotin (EV) plus pembrolizumab, the combination that we just looked at. And in this study, the combination of EV plus pembrolizumab, the patients who received this did significantly better, really setting the standard as this is the new frontline treatment for advanced urothelial carcinoma. And as of December of last year, this is now FDA approved, and really my standard treatment for patients who come in and have advanced disease.

I will say as a medical oncologist who treats patients with advanced urothelial carcinoma, I am so happy to see this field move forward. But we are just not done yet. We have so much to do here. So this is a huge leap forward, but we still have a lot of work to do trying to increase the length of survival and really aiming towards cures.

This is where the landscape is now for advanced urothelial carcinoma. So right now, the two treatment options that I really think about is enfortumab vedotin plus pembrolizumab, and then maybe sometimes thinking about that combination of cisplatin, gemcitabine, and nevolumab.

I want everyone to know that there are new drugs and new therapies that we are investigating every single day. So all of us at academic centers and many non-academic centers as well, do clinical trials where we are investigating new drugs and new ADCs that are coming down the pipe.

I do think that the therapies that we have now have made huge gains, but there are new therapies that hope to do even better. There are new immunotherapies. We talked a lot about those, these anti-PD-1 therapies, but there are other immunotherapies that are being studied, and there are new FGFR inhibitors and more. So we are hungry to see these new therapies and see how they do, and really trying to make people live longer, happier, healthier, and increase cure rates.

When I see a patient who has localized cancer, what I think about is, can I use any of the medicines that I know can help people who have advanced disease, and can I improve the outcomes for patients who have localized disease?

So as we discussed earlier, patients who have localized cancer, we treat them very different. So patients who have non-muscle invasive bladder cancer, again, sometimes that can just be scraped out, or sometimes we give something into the bladder to prevent it from coming back.

But for cancer that has gone into the muscle layer, that really represents a more locally advanced cancer, which can have the potential to escape. Oftentimes, what we’ll do for patients with muscle invasive bladder cancer, a standard treatment is to remove the bladder, trying to get all of that cancer out of the body before it spreads.

When we looked at outcomes for patients who have locally advanced bladder cancer, what we know is that surgery can be curative, but sometimes that cancer comes back.

In studies that were done now over 20 years ago, what we found was that when we gave chemotherapy for patients who have muscle invasive bladder cancer who are planning to go for a cystectomy, we asked ourselves, “Can we give them chemotherapy and get rid of any cancer that spread, and can that improve long-term outcomes?”

So a study was done here, where looked at giving chemotherapy before. And this study suggests that when you give chemotherapy before surgery, on average, you increase your chance of being cured. In a meta-analysis, the chemotherapy probably increases your chance of being alive at five years by around 5 to 10%. So there is a chance you can be cured by surgery alone, but chemotherapy probably increases that chance by around 5 to 10%.

Dr. Tyler Stewart:

And so for patients who are coming to see me today with muscle invasive disease, the major question is should we consider some chemotherapy before to increase those cure rates after surgery?

So when we look back at this, we know that when we give chemotherapy and then people have surgery that many patients can be cured. Some patients, that cancer comes back. And so after surgery, there are some patients who are at high risk of their cancer coming back.

Because of this, we did multiple studies looking at immunotherapies for patients after they receive a cystectomy. So patients after they have their out getting a checkpoint inhibitor. And there are three major studies that have been done. One was with a drug called pembrolizumab, one with nivolumab, and one with atezolizumab. And generally, all of these studies looked at, should we give immunotherapy right away or should we just watch it?

So the CheckMate 274 study was a study where half the patients after they had a cystectomy received immunotherapy, and half the patients did not. And the immunotherapy they received here was a drug called nivolumab.

And what this study showed was that in patients who got nivolumab, there was a lower rate of your cancer coming back. What we don’t know yet is whether or not this really improved overall survival. Really, do we have to give it right away, or can we wait until it comes back and then give it? Because if we give it to everyone, some of those patients are going to be cured with surgery alone, and may not ever require nivolumab.

So we do really want to see what this overall survival data looks like. But the early data suggests that if you receive nivolumab, it decreases the rates of your cancer coming back. And because of this, this drug is now FDA approved to give for patients after a cystectomy who are at high risk of their cancer coming back.

But one of my interests and one key interest that I hope everyone is thinking is that, does everyone need this neoadjuvant and adjuvant therapy?

So here’s how I think about localized cancer. Let’s just say you come in and you have a cancer in your bladder. Patients come in, they have a cancer in their bladder, and then they have their bladder removed. They have surgery and they hope that they’re cured. And then sometimes we give some immunotherapy or something on the backend, and some people their cancer comes back, and some people their cancer doesn’t. So how does that happen?

Well, it turns out that when cancer comes back, it’s really because that cancer has already spread and we just don’t see it. So although oftentimes we oncologists will get scans and say, “You’re clear of cancer,” sometimes that cancer is just too small for us to see. So after surgery, there are some patients where there is a small amount of cancer left, and there are many patients who are cured with surgery alone. And wouldn’t it be nice if we knew who had cancer still left and who actually needed more therapy, and which patients didn’t need it at all?

So how can we identify patients who have cancer still left? So this is a concept called minimal residual disease. A microscopic cancer that is left in the body, how can we see that?

Well, one of the technologies that we are working on is something called circulating tumor DNA. So it turns out that in your body, your cells oftentimes will die and give off some of that DNA into the blood, and it will spread throughout the body. And in patients who have cancer, a small fraction of that will be cancer DNA.

And as our technology has increased, we are able to find cancer DNA in the blood at very, very low levels. And so many of us in the field are now thinking about this as, well if you have surgery, maybe we can look afterwards and see if you still have any of that cancer DNA in the blood. And maybe that can direct us on who should get more, and maybe who should get less therapy on the backend.

What’s important to know about this cancer DNA is that it’s not just in plasma. Actually, we can find this in all sorts of body fluids. In urine studies, in plural fluids, actually in spinal fluids as well. If there’s cancer there, then sometimes we can find cancer DNA.

In a very, very important study that really helped push this field forward, a group looked at circulating tumor DNA in patients who had had cancer and had their bladder removed. And what they found is that after cystectomy, if your ctDNA was negative, rarely did those patients recur. Whereas if your ctDNA was positive, if we found that cancer DNA in your blood afterwards, nearly all of those patients had their cancer come back. Really suggesting that that cancer DNA was really a sign that there is still cancer left over, and if left unchecked can come back and hurt a patient.

Dr. Tyler Stewart:

We are now in the midst of using this technology to personalize patient care. So although right now we do not use these tests to decide who should and who should not, because the data is not there quite yet, there are ongoing studies evaluating this.

Here I’m highlighting something called the MODERN trial. This is a trial that I happen to be involved with, where we are taking patients who have had a cystectomy to try to cure them of cancer. And then after that cystectomy, we are trying to decide who needs immunotherapy based on that circulating tumor DNA. Whereas if it’s positive, well those are patients who we think are at very high risk of their cancer coming back. They probably have cancer left over. And we’re actually studying whether or not we should give them just one immunotherapy. Or maybe because they’re such high risk, we should actually give them two immunotherapies with nivolumab and something else called relatlimab, which is a LAG-3 inhibitor.

But in patients where that ctDNA is negative, they are being randomized to nivolumab, which we would consider a standard of care, or just watching their ctDNA status, and only giving that nivolumab if their ctDNA becomes positive.

I personally think that these type of therapies and these types of trials are revolutionizing cancer care. And I’m really trying to ask the question, who needs therapy and who does not? And escalating the therapy if needed for the patients who need it and de-escalating therapy for the patients who do not need it.

There are some ctDNA tests that are around already, but there are new ctDNA tests that are being investigated using different methodologies. So the way that we track if somebody has cancer left in the body right now is often through something called PCR, and there are different methodologies that are being investigated that can be even more sensitive, that can really discriminate who is most likely to have cancer and who does not. And we’re excited to be a part of some of those studies here at UC San Diego.

One of the things that I’m very interested is, can we use ctDNA anywhere else? And if you’re thinking about bladder cancer, you got to be thinking about something else, and that is urine. And can we use urine tumor DNA to follow patients with bladder cancer?

So right now, as many people on this call might know, in patients who have bladder cancer, oftentimes what we’ll do is especially if they have superficial bladder cancer, we might go in there, resect that cancer, and then sometimes give them BCG or just watch. And what we’ll have to do in order to investigate if their cancer comes back is we do these cystoscopies every three months to see if their cancer comes back. Those cystoscopies are invasive, and they’re not fun, and nobody likes to do them, and nobody likes to have done on them.

So wouldn’t it be cool if instead, we could just have you pee in a cup? And if that urine could really tell if there’s cancer or no cancer in there, maybe we get to avoid a cystoscopy or maybe it’s less cystoscopies for a year.

So our team is very excited. Many teams are very excited about this out there, and I think that these tests are in the future. I think five, 10 years from now, these are really going to be used all the time in clinic. These are still in investigation right now. We’re still running clinical trials. They’re not there yet, but we’re getting closer and closer.

Bladder preservation is a huge interest of many of us who treat bladder cancer. So especially patients who have muscle invasive disease, the standard or at least a standard of care is to treat patients by taking their bladder out. And what we might ask is, is there any way that we can treat the cancer, get rid of all the cancer, but preserve that bladder?

One of the ways that we do this currently is something called chemo radiation, where we use radiation and a small dose of chemotherapy that actually weakens the cancer and makes that radiation more effective.

And what we know is that chemo radiation is a very effective method for many patients who have muscle invasive bladder cancer. And what we know is that there are more and more radiation novelties and new techniques that are being developed that can make it more efficacious and less toxic. So less damage to the bladder and surrounding areas, but more likely to kill the cancer, and those are being investigated.

We are also doing studies right now, for instance, the SWOG 1806 study, which is chemo and radiation, versus seeing if the addition of immunotherapy can actually improve those long-term outcomes.

This study is actually all enrolled. It was a national study that we’re very excited about, and hopefully we’ll find out the answer of whether or not immunotherapy can increase those cure rates in the next couple of years.

The other thing that we can think about is as our systemic therapy gets so much better with these new drugs that we are talking about, could there be a case where we could just treat somebody with medicine, and not have radiation, and still try to cure somebody’s cancer? These types of studies are already being done.

Dr. Tyler Stewart:

This is just one study that was done by Matt Galsky and his team that looked at patients who had muscle invasive disease, treated them with chemotherapy and immunotherapy. And if all of that cancer was totally gone from the bladder, they were just watched, and many of those patients actually did very well for a long time.

This study is just novel and absolutely not primetime, not ready for clinical, to be done in the clinic, outside of a clinical trial just yet. We need more patients. We need to have further investigation for this. But it is very exciting to think about a day when we might be able to just give medicines, treat somebody who has locally advanced cancer, and maybe cure them without getting their bladder out or even radiation.

I want to end on this note. So we’ve made progress, but it’s not enough. So through efforts here through BCAN, we are working really hard to try to increase the therapies and the agents that are available to make people live longer, happier, healthier lives.

And ultimately, what we are looking to do is we are looking to cure patients, cure patients with advanced, locally advanced disease. Trying to keep their bladder and making therapies more precise, finding out who really needs it, and giving therapy to those who need it, and holding back therapy for those who would not benefit.

And then I do think that we need methods to monitor patients less invasively, improve quality of life. We want patients to not just live with bladder cancer. We want patients to thrive beyond bladder cancer. We want patients to have great qualities of life and leave that bladder cancer behind.

Stephanie Chisolm:

Thank you so much, Dr. Stewart. That was a phenomenal presentation absolutely. So you mentioned a number of different things. And I know it wasn’t just pulling alphabets together in different combinations, but FGFR, nectin-4, HER2, those are all genetic mutations and changes in the genes, right?

Dr. Tyler Stewart:

Well, oftentimes what these are, so some things are genomic mutations, and sometimes they are markers on a cancer cell that are just more frequently seen on that cancer cell than normal tissue. For instance, in FGFR, this is a mutation that happens within the genome of somebody with cancer. And so this is not a normal mutation that we see.

And what we know about it is that 50, 60% of patients who have localized cancers might have one of these. And the patients with advanced disease, probably 15% of patients do. And these therapies that block FGFR can be effective for those who have these genomic alterations.

Meanwhile, for the other ABC word salad stuff that I mentioned, this nectin-4, HER2, Trop-2, what these are, these are little proteins that sit on cancer cell surfaces that are more prevalent on cancer cell surfaces than on normal tissue, and can serve as targets for our targeted therapy. So we can make drugs that seek out these targets and then hook a chemotherapy onto that drug. As soon as it hits that target, releases that chemotherapy, kills some cancer.

Stephanie Chisolm:

So how do you know if you have all of these weird little bits that might be attached to your tumor? Is this something that is standardly done in all institutions? Do they take a look for these things, or is this something that has to be done separately? And maybe if you want to stop your screen share, your picture will show up a little bit bigger, unless you need your slides again.

Dr. Tyler Stewart:

No, I’m all set. Thank you so much.

Stephanie Chisolm:

Okay-

Dr. Tyler Stewart:

Great question-

Stephanie Chisolm:

Really find this out. Yeah.

Dr. Tyler Stewart:

So a couple of things. Some of these things you need to do special testing. Some of them are so ubiquitous that the therapies are likely to work no matter what. So let’s take FGFR for example. So for this study, we can actually take somebody’s tumor, send it off for analysis, and see if they have one of these genomic mutations.

The other way we can find that out is actually using that same circulating tumor DNA thing that I talked about where we can isolate that cancer DNA in the blood and see if they have one of these mutations present.

So for patients who come to us, we actually do genomic sequencing on all patients with advanced disease. This is not necessarily a mutation that you are born with. It’s something oftentimes that is acquired over time, although there are some cancers that are associated with that familial history and some mutations in bladder cancer. That’s a very low prevalence, fortunately.

But these are acquired over time. There’s nothing that you did, or you didn’t eat something that maybe… This is just bad luck that it happens. But when it happens and a cancer is formed, sometimes we can find a target.

For some of these other ones, that enfortumab vedotin and the Trop-2, actually the nectin-4 and Trop-2 are highly expressed on urothelial carcinoma, that we don’t actually even test for these. We just use these drugs, and there’s not a test that we do first to see if you’re more or less likely to respond, at least not right now.

That’s a little bit different than one of these tests. So one of these tests, that HER2 one that just came out, that’s a drug where we actually stain your cancer. So we take a slide of your tumor, we stain it for something called HER2 to see how much of it is around, because it seems like the more of that HER2 that’s around, the more likely that patient is to derive benefit from that drug.

Stephanie Chisolm:

So a lot of these different treatments like the immunotherapies and some of the antibody-drug conjugates, I mean they work really well when they work, but they also have what we call adverse events, or in common terms, they’re known as side effects. People know them as side effects. So what are some of the common things that people should be aware of? And why when you’re on some of these treatments, could maybe a touch of diarrhea be more than you think it is?

Dr. Tyler Stewart:

Yeah. So it’s a great, great point. Back in the day when we just had chemotherapy, I think people had a real clear idea about what chemotherapy might do. It might make you more at risk for infections, it might give you some nausea, vomiting, diarrhea. Might drop your blood counts, might make you more tired. That is absolutely true.

And the truth about chemotherapy is that those drugs from the… We still use those today, but so many of our supportive therapies are so much better than they were in the 1990s. In drugs that make people feel very, very nauseous, many patients actually do very, very well with the drugs and supportive therapy that we have now. Many patients who might get drugs that should make them very, very nauseous actually do very well on chemotherapy now just because of all the other medicines that we can use.

The new drugs that we have are very different. So first off, immunotherapy works totally different than chemotherapy and the side effects are totally different. So sometimes, what happens with immunotherapy is that your immune system gets revved up, and then it starts attacking parts of your body that you don’t want it to.

Now generally speaking, immunotherapy is a very well tolerated drug, and compared to chemotherapy, super well tolerated. But some patients who get immunotherapy can have significant side effects that really affects their quality of life and some can be severe. What I quote is around 20 30% of patients are going to have side effects that they’re going to notice. About 10% of patients are going to have something serious where I might have to stop the medicine, and gives you something to dampen down your immune system. About 1% of patients could get very, very sick from this stuff, have to go to the hospital, or something along those lines.

That being said, immunotherapies, if you get one of these, they can work for a long time and provide really Lazarus effects. So certainly it’s a great treatment option.

The antibody-drug conjugates are kind of like chemotherapy. They’re kind of a mix. And so usually, the side effects are all about what is the chemotherapy that’s linked, because a small amount of that drug is going to get released into the blood system and can cause some of those side effects. Sometimes those can make you feel tired, sometimes it can cause some numbness or tingling in your hands, sometimes can give you diarrhea, sometimes it can drop your blood counts.

So really, it’s a complicated conversation and certainly one that patients should chat with their doctor about, about really what to expect. But I do want to make it very clear that the side effects are very different. And just because you may have known somebody who’s gotten chemotherapy in the past, that doesn’t mean that the side effects that that person had is going to be the side effects that you have or that your loved one has when they’re receiving one of these new agents.

Stephanie Chisolm:

Yeah, I think there’s a whole lot of great big unknowns. And I think that communication, both from the doctor’s perspective to explain to patients what could be a possible side effect or adverse event, but also the patient reminding the doctor, “Hey yeah, I’ve experienced some of this,” because it might be nothing or it might be something, and the doctor can bring out a whole bunch of other tools to help take care of that. So I think it’s really important to make sure that that communication is there.

Dr. Tyler Stewart:

So I might just emphasize, so I tell all my patients that I’m pretty good at treating the side effects. I really am, but I treat zero side effects that I don’t know about. And so really it’s all about that good communication, patients talking to me and let me know what’s going on. There are those modifications. I mean, there are just a huge number of things that we can do as long as we know about it.

Stephanie Chisolm:

Absolutely. You have to tell your patients and they have to tell you, because you don’t know. So this is really important. There were a couple of good questions that were submitted. Are there trials examining dose de-escalation for patients seeing pathological complete response with treatment by enfortumab vedotin and pembrolizumab?

Dr. Tyler Stewart:

Oh man, I don’t know who to ask that. What an amazing question. We are absolutely looking into this. So what an amazing place that we can have a conversation about deescalating therapy for advanced urothelial carcinoma based on how good these drugs work.

But absolutely the answer is yes. We are currently in the works. I actually have a meeting tomorrow about this exact topic, about if somebody does very, very well on therapy, maybe we can drop the enfortumab vedotin and, just keep the immunotherapy going. We don’t know the right answer here, but we are actively creating clinical trials that we need to investigate these questions.

These drugs, they have side effects. And if patients do extremely well, do they need to bear more side effects from it? An absolutely wonderful question. The answer is yes.

Stephanie Chisolm:

So we’d love to see more patients being in clinical trials. One of the things that I think is really important since BCAN started in 2005, there have been numerous, as you just saw, numerous advances in the treatment of bladder cancer. And that didn’t come just because somebody smart was just thinking up stuff. They had to test it, they had to see if it worked or not, and you need people to do that.

So some people will do a clinical trial and some people will want to be in a clinical trial. And the thing about a clinical trial is it’s not just a science experiment, but it’s really looking at an investigational medicine and trying to understand how this new treatment is going to act in the real world. Right?

Dr. Tyler Stewart:

That’s absolutely right. And just a couple of things about clinical trials, and I think these points are really important, so I’m going to take a second and just emphasize.

So we run clinical trials to ask the question, can we improve on the standard of care right now? Is there something that we can do that is better than what we normally do for patients with a specific cancer? Whether that’s a novel treatment, or a change of dose of treatment, or supportive measures, or you name it. The reason to run a clinical trial is to say, “Can we do better and can we prove that one agent is really more effective than another agent?”

We would never open up a clinical trial that we don’t think is actually moving the field forward. We would never open up a clinical trial that we weren’t totally supportive, that family member, loved one if we were in the situation that we would feel totally comfortable being put on the study.

It’s also important to know that you don’t have to be involved in the clinical study. This is something that has to be the right thing for you. And you have to feel comfortable with your clinician, the environment, and the study.

And I tell all of my patients that these clinical trials are investigations. And if you don’t feel comfortable, don’t do it. I’m going to give you the absolute best standard of care therapy. But if your hope is to be part of something that might be the next version of it, then this is the process that we do.

Some people will have a clinical trial that’ll have to be randomized to either X or Y therapy. And the reason why I can’t give you the Y therapy is that I don’t know that that therapy is better. It actually might be more toxic, but the reason why we’re doing this study is that we think it might be. And so those are my 2 cents about clinical studies.

Stephanie Chisolm:

Sure. Thank you so much. And I encourage everybody to do that, because you get much closer observation and you have the opportunity to try that new treatment. And also, patients can decide that they don’t want to still be in a clinical trial at some point if it becomes too onerous for them. I think that’s important.

Dr. Tyler Stewart:

100%.

Stephanie Chisolm:

Okay. Is gemcitabine and docetaxel still effective and still being used?

Dr. Tyler Stewart:

Great. So actually we’re moving on to the part of the topic that I didn’t talk about too much. So Stephanie, you’re asking about patients with non-muscle invasive bladder cancer, where in patients who have BCG… So patients who have non-muscle invasive bladder cancer are usually put into risk categories. And particularly in patients who are high risk, oftentimes we’ll give a medicine called BCG into the bladder to prevent cancer from coming on back, because some of these patients have such a high risk of their cancer coming back.

Unfortunately, that BCG medicine may not work and that cancer may come back despite that BCG. One standard treatment approach at that point is actually to just take out that bladder, because that means that the cancer might come back.

There are many new therapies that are currently FDA approved or currently being studied in the space to get rid of that cancer and prevent that bladder from having to be removed.

One of the treatments that we use in the clinic right now is a combination of two chemotherapies, gemcitabine and docetaxel right inside the bladder. And early studies suggest that this can be quite effective. And at UCSD, we oftentimes will think about this for patients who have BCG unresponsive or cancer that comes back after BCG. It is being used. Actually, there’s a large study ongoing right now that is looking at whether or not the frontline therapy should either be BCG or Gem/Doce because we think it’s so effective. So that study’s going on right now, and we’re happy to be involved with it.

Particularly with the BCG shortage that is ongoing, if we find that Gem/Doce is maybe just as good or if not better, I think that would be a real boon to our whole society.

Stephanie Chisolm:

So are there any clinical trials that are not treatment related that you know of, but more looking at post-treatment and quality of life aspects?

Dr. Tyler Stewart:

Well actually, we have some of those ongoing as well right now. We have a lot of biomarker studies that we are particularly interested, as I kind of mentioned. So just talking about what we’re doing at UC San Diego, which we’re really excited.

So we’re looking at a lot of studies, seeing if that urine tumor DNA might be able to identify patients who are at high risk of their cancer coming back or may actually be clear of cancer.

So I certainly think that more studies need to be investigated, particularly patients who have non-muscle invasive disease, to see whether or not we can use these urine biomarkers instead of having somebody undergo, for instance, cystoscopy every three months. I think that is a huge quality of life improvement for the vast majority of patients who have non-muscle invasive disease. And quite frankly, some patients may not even come to the doctor because they don’t want to undergo such a procedure.

And so having a new method to surveil patients I think is just a huge thing. Also, if you can make the test cost-effective as well, probably saves healthcare dollars in general too.

Stephanie Chisolm:

Absolutely. So treatment is one thing. Can you just briefly touch on how some of these different medications, these different treatment options are also being used as maintenance therapy to make sure that that cancer doesn’t come back? Because I know some of these are also being applied in a maintenance sense, where you might not have actual visible disease. Can you talk about maintenance?

Dr. Tyler Stewart:

Yeah. So maintenance is used in a couple of different aspects, and there are a couple of times that we use treatments when somebody doesn’t have any clear evidence of disease.

So one time that we use maintenance therapy is in patients who have advanced disease. So let’s say you present and your cancer is spread to the liver, lung, bone.

When I give treatment for patients, oftentimes when I think about doing, for instance, chemotherapy. That chemotherapy might cause a significant reduction in the amount of cancer in their body, but at some point that cancer is likely to grow despite that chemotherapy. And oftentimes we’ll use immunotherapy as a maintenance drug to keep that cancer down and at bay.

And so early on, we would use a medicine called avelumab as maintenance therapy really to prevent that cancer from coming back. Unfortunately, for some patients, the cancer came back despite that. We would have to be used different treatments.

Now when we’re thinking about combination of enfortumab vedotin and pembrolizumab, some patients who get a combination of these two drugs, they might have tremendous responses, but then they might get toxicities that is specifically from that enfortumab, that antibody-drug conjugate, that chemotherapy.

And so even though their cancer might be all gone from the scans, what we might end up doing is stopping that enfortumab vedotin and continuing on that maintenance immunotherapy trying to prevent that cancer from coming on back.

So that’s one key aspect, and oftentimes we will do that. We always have to balance from maintenance therapy what we think the real benefit of maintenance therapy is with the risk of the cancer coming on back. And in patients with advanced disease, I think maintenance immunotherapy in all of these settings makes a lot of sense.

The other place where we use therapy despite the fact that we don’t know if somebody has cancer left is after somebody has had a curative intense surgery where somebody might be at high risk of the cancer coming back. That’s the time when we were talking a little bit about that adjuvant therapy and adjuvant immunotherapy.

This is a time where I think that we are giving immunotherapy to a lot of patients. Some of those patients really should be getting it, and probably there are some patients who may not need it.

And so this is where I think that role of ctDNA, that blood-based cancer marker to see if somebody’s cancer is still there. And I’m hoping that that cancer marker might discriminate which patients really do need that adjuvant therapy to prevent the cancer from coming back, versus those who don’t need it at all.

Stephanie Chisolm:

Well, one of the things… We’re coming up on time, and I think I’m reading the vibe from this Zoom room. But I think you’ll all agree with me that with clinicians like Dr. Stewart, who’s also a talented researcher, over the last 20 years since BCAN started, there has been a significant change. And the future is very bright for bladder cancer patients because there’s so many talented individuals like Dr. Stewart. And this has been a comprehensive, wonderful overview of the history of the treatments and how it can help. And I thank you so much.

I want to just end with one last question. What do you say would be the single most important message you want our listeners to take away from what you were talking about?

Dr. Tyler Stewart:

Yeah. I would say that bladder cancer has made great advances, particularly over the last 20 years, through a lot of hard work and effort. And I want everyone on this call to know that we are proud of some of the work that is being done, but we are not happy with where we’re at, and we are hungry to continue to move the field forward.

We are aiming to cure patients with bladder cancer, every single one. We are moving the field forward. It is not as fast as we want it to be. We want it to be faster. I want it to be faster. You want it to be faster. But we are working real hard. Through support like BCAN’s network and through patients and clinical trials, we hope to move the field forward. And I really do see a day coming when we do get to cure every single patient.