Understanding Bladder Cancer | Metastatic Bladder Cancer

With Dr. Alicia Morgans

You can read the entire transcript of Understanding Metastatic Bladder Cancer at the bottom of this page.

Year: 2021

Part 1: Understanding The Basics of Metastatic Bladder Cancer

Video (19 mins) | Transcript (PDF)

Part 2: Treating Advanced or Metastatic Bladder Cancer

Video (31 mins) | Transcript (PDF)

Part 3: Question and Answer

Video (8 mins) | Transcript (PDF)

Full Transcript

Stephanie Chisolm:

We’re really delighted to have our speaker today, Dr. Alicia Morgans who is here as the director of the survivorship program at the Dana-Farber Cancer Institute. She’s here to talk to us about metastatic and advanced disease. And we know that a bladder cancer diagnosis can be terrifying to a patient and their families. And we really want to help you understand what you need to know about this advanced or metastatic diagnosis and what are your treatment options?

Dr. Morgans is a clinical investigator. She does actual patient care, but she’s also a very prolific researcher, and she has a lot of experience in clinical trials, particularly focused on patient reported outcome measures and is very involved in an incorporating what patients really want and what they really need into the care of her patients. And I think that she’s going to give you some really wonderful information today. So Dr. Morgans, it’s a pleasure to have you here.

Dr. Morgans:

Thank you so much, Stephanie. And I really appreciate everyone for being here today. As you heard, I am a GU [genitourinary] medical oncologist. So I take care of people with bladder cancer and I partner with them as they move through the treatment over time and help them to try to make the best decisions for them, because these are very personalized decisions and, of course, impact every day of a person’s life if he or she is suffering from bladder cancer. And I’m also the medical director of the survivorship program at Dana-Farber, where I’m trying to work with the team to really elevate the needs of bladder cancer survivors and ensure that we are really asking patients what they need as they go through this process. So I appreciate the opportunity to speak with you today and certainly appreciate all the feedback that you have as you’re listening and as you have questions throughout this conversation.

As we focus on metastatic bladder cancer, I am going to just give a little bit of background and then talk about how we approach treatment for metastatic disease. And there are a few key approaches, including chemotherapy, immunotherapy and targeted therapies, which, of course, also include antibody drug conjugates, which are our newest treatments. And then we’ll summarize at the end and really ask questions of you to understand how you need things to be answered or what questions you might have that I can help with.

So urothelial cancer is broader than just bladder cancer. We always say bladder cancer, but we actually mean cancer that extends up those yellow ureters that you can see between the bladder, which is the red thing at the bottom and the kidneys, which are the two kidney bean shaped things up towards the top of the screen. So urothelial cancer, a bladder type cancer can extend from the bladder all the way up those ureters. And these types of cancers are very similar, because they come from the same origin cell type in the body and we treat them very, very similarly as we move forward. I will say bladder cancer in most contacts as I talk going forward, but know that if you have an upper track urothelial carcinoma or an upper track cancer, that means that you still have the same type of cancer, it’s just up through the ureters and sometimes up into the kidneys almost. And all of these are really treated very similarly, because again, they come from the same parent cell.

When we think about metastatic urothelial carcinoma or metastatic bladder cancer, I think we also need to define that. So metastatic just means spread from its origin. So in this case, it would have spread from the bladder or spread from those upper urothelial cells, those ureters, or even the area very close to the kidneys into other places. And commonly, in this type of cancer that can be in lymph nodes, in bone, in lung or in liver. And it can go in other places, sometimes unfortunately to the brain or in other places in other organs, but those are the most common places. So lymph nodes, bone, liver, lungs, those are the most common places.

Dr. Morgans:

So we also know that in this type of cancer, there are different stages like in any kind of cancer. And for most people, they are diagnosed with in-situ bladder cancer, which really means bladder cancer that’s not even digging really into the wall of the bladder. But for this talk, we’re going to focus on the smaller percentage of patients who actually have metastatic bladder cancer spread outside of the bladder into other areas. And these patients have a different expected outcome. Their history is going to be different and they are actually a group of people where we don’t currently have a cure for metastatic bladder cancer. For patients who have bladder cancer, that’s all still in the bladder, we do have curative treatment approaches. We do have ways that we hope to cure the cancer, but once it has spread outside of the bladder, that’s a much harder thing to do. And we try, and there are patients who have these miraculous responses, but we don’t really, at this point, have a clear way to cure cancer of the bladder that has spread far outside the bladder.

And that is really reflected in the survival information that we have. So when the disease is all still in the bladder and not even really digging into the bladder wall, the five year predicted survival is almost 100%. It’s 96%. When it becomes distant, and that’s another word for metastatic bladder cancer, into more distant lymph nodes and into things like bone or liver or lung, that survival at five years is all the way down to 6.4%. And this is the most updated information that we have from SEER, which is our cancer registry here in the United States. And I would say that this is something that I do think will change over time.

And I’m hopeful and I think all of our researchers and clinicians are hopeful, because we are making great strides. And in the next five years, I hope that this particular graph among all the others is something that we are able to shift. So that, that group of people who have distant disease will see higher rates of survival at five years. That is one of the goals that we have, of course, as a community that cares for people with bladder cancer. So let’s dig a tiny bit into treatment and there are lots of options for treatment, but these are options that actually have come about and been described pretty recently.

If we look at this timeline, I think it’s pretty striking. We can see that back in the 70s back when many of the people on this call may be have been very, very young or not even born potentially, back all the way in the 70s, we only had a drug called cisplatin. This is a chemotherapy agent, and importantly, it’s actually still the backbone of our chemotherapy drug armamentarium, but it was the only thing we had all the way back in 1978. And at that time, there were clinical trials that demonstrated that it could do really important work in urothelial or bladder cancer.

If we fast forward into the 2000s when I imagine everyone on this call was around, we can see that we finally got an indication for gemcitabine, which is another chemotherapy in 2008. So up into the 2000s, even to 2010, we’re really dealing with chemotherapies for urothelial or bladder cancer. And chemotherapies we know are agents that we call cytotoxic treatments. These are treatments that go into the system, into a body and they go into lots of different cells and they destroy those cells. And that’s a really positive thing when they’re destroying cancer cells, but they’re not targeted treatments. And so they do cause destruction and symptoms in cells that are normal cells. And that’s what leads to our side effects of things like chemotherapy.

So when you go into hair follicle cells, you has hair loss. And when you go into cells in the GI tract, so anything between the mouth and the anus, you’re going to have things like mouth sores or nausea, stomach upset or sometimes diarrhea. So these kinds of things happen with chemotherapy and they happen relatively often. And these are very important drugs in our treatment of urothelial carcinoma or bladder cancer, but it was a pretty sparse landscape for us for a long, long time.

Dr. Morgans:

And then we hit around 2015, 2016, and we started having clinical trials. And finally got our first approval in 2016 for atezolizumab, which is a PD-L1 targeted agent that really was transformative, the first in a slew of approvals of immunotherapies. Treatments that harness the immune system to attack the cancer cells and cause fewer side effects in most people, they certainly can cause really destructive side effects in a few people. So smaller group of people, but for most people, gentle treatments that simply train the immune system to attack the cancer cells and help people feel better and live longer.

Atezolizumab was followed closely by nivolumab, durvalumab, avelumab and pembrolizumab. Four approvals in one year. All of them being these immunotherapies, this was incredible. We in the bladder cancer world were rejoicing, because as I showed you, there’s nothing in decades. So really exciting times. And this was followed relatively closely by additional approvals in 2019 of erdafitinib is a targeted treatment for particular mutations in FGFR. And then enfortumab vedotin, avelumab in a different space, a different patient population, and sacituzumab govitecan. So lots of complex names, but really exciting stuff. And all of last things that I mentioned except avelumab, which I already told you as an immunotherapy, these are all targeted type treatments, erdafitinib targeting specific mutations and enfortumab vedotin and sacituzumab govitecan being antibody drug conjugates, and I’ll explain those in just a second, targeting certain proteins on the cells of cancer to deliver really potent chemos right on the cancer so that we hopefully don’t have as many side effects and symptoms associated with the non -discriminant or general effects of chemo that can happen on cells that are not cancer. And that’s what causes all the side effects.

So it’s extremely exciting in bladder cancer and urothelial cancer. And really, I’m grateful that we are all here to live in a time when we have these treatments and others in the pipeline going forward. When doctors are thinking about how do we treat metastatic bladder cancer or urothelial cancer, we have a lot of things to think about. And this is a schematic of a way that we try to categorize patients to understand how we can use the treatments that we have most effectively. And as doctors, we have to use the treatments that we have for certain patients with certain types of bladder cancer at certain points of the disease. And we really have to match the right treatment that’s all based on the right trial for the patient in front of us. And so this is just one of the ways that we think about this. This is the schematic for how I think about the first treatment that we use in metastatic bladder cancer.

So first, doctors are often thinking about patients, are they going to be chemo eligible or not? And that’s what this word platinum eligible or two words platinum eligible or platinum ineligible means, because the chemos that we have are platinum type chemos, these type chemos are pretty effective, really effective we think in bladder cancer. Cisplatin, like I mentioned, is the first one that was approved. This was in the 1970s. We have not changed since then. So are you eligible for a chemo in that family, the cisplatin family or not? And if you’re eligible, then we think about whether you can get that really potent cisplatin, very effective chemotherapy or not. And if you can get cisplatin, then can give you an immunotherapy on the back of that to try to be even more effective. And we’ll go through how we get to that and what the data is.

And if you can’t get Cisplatin, what chemo can we give you? Can we give you some immunotherapy on the back end? Can we try to make things better that way? And if you can’t do that, can we do immunotherapies? And that gets us back into the people who really can’t get chemo, because there are people like that, there are a lot of people in my clinic that can’t get chemo. What immunotherapies can we use? What clinical trials can we think about? What other treatments can we use to try to make the days that a person has feel better, because we can do those kinds of things, those supportive care things. Whether you’re getting chemo, whether you’re getting immunotherapy, whether you’re getting a targeted therapy, we always need to be thinking about those things that make the day to day life better.

Dr. Morgans:

And so I encourage everyone in the audience to think about that as you’re going into see your doctor, what else can I do to make my day to day better? What can I do to improve my pain? What can I do to improve my mood? What can I do to improve my appetite? And just keep asking those questions, because there might be things that can be added. On top of the treatment that’s really focused at your bladder cancer or your urothelial cancer, there are things that we can add, there’s counseling we can use, there are nutritionist, there are exercise folks, there are physical therapists who can help make the day to day better even if they’re not directly attacking the cancer themselves, because you have to have a strong mind and a strong body to go through all the things that we go through. And that’s actually true for patients, but it’s true also for caregivers. So remembering to get support for the people around the patient, the loved ones, the family members, because they need to recharge too and need to think about how to keep themselves mind and body healthy as well.

So this is how we as a doctor community think about that first treatment for bladder cancer or urothelial cancer. And this is just step one, and it gets pretty complex as we move through the line. And one thing I want to be really clear about too is that systemic therapy, that includes chemo therapy, immunotherapy and all the other treatments that we’ll talk about, is something that as we go through treatment after treatment for a given person, a given patient, the likelihood that, that person is going to get the next treatment goes down each step of the way. And that can be for a host of reasons. That can be because the person has become too ill or if the person has decided not to do more treatment or the person has passed away.

But if we aren’t able to keep a person strong, mind and body, each step of the way, we’re going to lose people over time. And if we don’t treat them, then we won’t be able to make a difference in their cancer. That’s not to say that people don’t need to make those choices to focus on quality of life or to not move forward with further cancer directed treatment. But we as a community who treat patients with bladder cancer, recognize that we need to do better in supporting people from one line of therapy to the next so that we can try to get each patient as many opportunities to get each life prolonging and quality of life improving treatment along the way as we possibly can.

And what this figure demonstrates is that if we go from all people, 100% of people at the beginning, with each line of treatment that we go after that, after each treatment fails that patient, about half of the population, about half of the patients drop off and don’t get the next treatment opportunity. And so we need to think as a community, how do we help support people, get them the treatments that they need, and of course, help improve their quality of life, whether they’re getting treatment or not. So that’s just something that we think about.

So as we move on to our treatment portion of this conversation, I want to help everyone make sure that they understand how we look at survival curves. This looks really stressful I assume. As a non medical person, I can imagine looking at these blue and red lines is very confusing and very stressful. And I’m trying to break it down, because your doctors are going to talk to you about this. And you might look at papers on websites or you might look at meeting information and I want you to be able to have some confidence as you try to work through what we call survival curves. And there are essentially ways that we as doctors, as scientists, as researchers think about how effective a treatment is.

Dr. Morgans:

We usually, just to start, have two treatments. In this case, in this survival curve, we’ve got treatment A, we’ve got treatment B. And we represent each treatment with a color. In this particular diagram, we’ve got blue for treatment A, we’ve got red for treatment B. And we try to compare these treatments and see which one is going to be the most effective in taking care of our person, whether it’s person who’s being treated for bladder cancer or breast cancer, prostate cancer or lung cancer, we can compare the effectiveness of these treatments using these curves. And these curves are the data or the output that we get from clinical trials.

So the first step is knowing there are two treatments. One is in blue. In this diagram, it’s labeled treatment A. And one is in red, treatment B. The second thing to know is that time, the time on this clinical trial is going to go from left to right. And it’s represented on the bottom axis. That 0 to 1000, that’s in days. And you can see here, I made a little extra hour here time going from the beginning of the trial on the left to the end of the trial on the right. Now, the next thing to know is we’re looking at this is the number of people or the percent of people who are alive in this particular clinical trial are going to be represented on that up and down vertical access on the left. And this shows that the higher the curve is, the more people are alive over time.

So if we look at the very beginning, the upper left corner, so even I get confused, the upper left corner, where we see the blue and the red line are overlapping, 100% of people are alive and that’s time 0. That’s when everyone’s starting on this clinical trial, everybody’s alive. And over time as we move to the right, people are passing away and other people are surviving, and that the lines both move down, because the percentage of people is moving down. So if we go onto the final thing, the space between these curves is what’s going to tell us that there’s a difference between treatment A and treatment B. If there’s no difference, they’re on top of each other, if there’s a difference, they separate. And that shows us that one of these treatments is better than the other. Treatment A is better than treatment B here. Treatment A is further, it’s higher up, and so that blue line is better. Treatments are going to be better if they’re higher up on that graph. So treatment A is better.

So I will show you a couple curves in the following conversation, but I just wanted you to know this because your doctors will talk about improvements in survival, better survival. If you Google it and if you look at papers, you’re going to look at pictures like this and just know that the thing that’s on the top, regardless of the color, whatever it is, that’s better. The thing that’s on the bottom is a thing that’s not doing as well.

So chemotherapy. Let’s return to this. Let’s talk about some basic principles very briefly. And remember, these are things that have been used and have been unchanged essentially since the 70s. We have not found a better thing than cisplatin at this point in time, though, we have a lot of good candidates and we’re trying to replace it. But combinations of cisplatin, that’s that thing that was approved in the 1970s or its cousin carboplatin plus gemcitabine, that’s the other thing that was approved you saw on the timeline, are the most common first choice for treatment of metastatic, urothelial or bladder cancer. So cisplatin and gemcitabine or carboplatin and gemcitabine are the most common.

Cisplatin is the best chemotherapy we have against bladder cancer that has not changed since the 1970s, which is crazy, I guess, but is maybe opportune that we found a good chemo all the way back in the 70s and we just haven’t found something better to unseat it. I would say again, there are multiple candidates on the horizon. We might be able to get rid of this chemotherapy stuff at some point in time, but for now, cisplatin is the thing that is helping us through, it is the most effective thing that we have.

Dr. Morgans:

The choice of chemotherapy, whether it’s cisplatin or it’s cousin carboplatin really depends on a couple things, and they’re all related to the patient. How fit the patient is, how strong, how frail, how much vigor that person has versus how weak that person might be. That’s really important and is probably the way that we decide between chemotherapy at all or maybe a different pathway, that decision algorithm that I showed you earlier on the way doctors think about it. How well the patients kidneys work, is their creatinine number still at a low level, that helps us choose between cisplatin, which needs really high functioning kidneys that are healthy and happy or carboplatin, which can be given even if the kidneys are not so good, actually, even if the kidneys are not working at all and the patient has to be on dialysis. So that’s a decision point.

And whether the patient has other medical problems that might be really negatively affected by cisplatin chemotherapy, whether the person has heart failure or really bad neuropathy, maybe from diabetes, which would be numbness and tingling nerve damage in the fingers, in the toes or even in the ears, so hearing loss, because hearing is a nerve related function. So if there’s a lot of nerve damage preexisting, cisplatin could make that worse and we would not want to use that. So those are the main things that we think about when we’re trying to choose that chemotherapy. And usually if we can, we try to give someone cisplatin or carboplatin chemotherapy with gemcitabine if we can. For people who are strong enough, and of course, that’s not related to anything, that’s not a patient’s fault or a person’s fault, it’s just is there your body going to be strong enough to get this chemotherapy, which is tough, which we’ve already talked about, but is still the backbone of what we try to do for people with metastatic bladder cancer.

There are lots of effects of chemotherapy. Chemotherapy goes in through a vein. So it’s infused a catheter in the vein or sometimes through a port up here in the chest. And it goes through the blood, it goes everywhere the blood flows and it goes into cells of cancer cells and it just destroys them. And that’s our goal, that’s what we want to do. But it also goes into other cells, cells that are trying to survive by dividing and replicating themselves like blood cells that are just turning over and making new cells all the time or heart cells that can be damaged pretty easily or muscle cells that need to be in a healthy environment to stay well and to grow and to get strong.

So chemotherapy goes into all of those cells. It’s not really targeted, it doesn’t choose where it goes, it goes everywhere. And because it does that, it can cause low blood counts like white blood cells that protect our bodies from infection or red blood cells that carry oxygen to all of our organs and chemotherapy can damage those and make it harder for our bodies to do the normal things that they do with the blood that they normally have. It can also affect the cells in our mouths and the cells in the GI tract. So again, mouth to anus. And the reason that it can do that is because these cells in our mouths, in our esophagus, in our stomach, in our GI tract, these are all cells that replace themselves on a regular basis. They are only here around with us for a little bit of time and they replace themselves and get new ones, new versions of themselves very, very quickly in terms of a body’s life.

And any cell that’s going to turn itself over and make a new one in a short period of time is one that’s going to be affected by chemotherapy. So people get mouth sores and they get stomach upset, because those cells get irritated or they do get diarrhea, potentially. Cisplatin in particular can cause neuropathy that I mentioned. So damage the longest nerves in our body. The nerves that go down to the tips of our fingers or the tips of our toes are the ones that are damaged or affected by cisplatin chemotherapy. And so that can cause a numbness or a tingling. It’s very strange, I think to people at the beginning. They think, well, it just feels like my fingers fell asleep or my foot fell asleep. And hopefully, that as the body heals after chemotherapy, that should go away, but some degree of that can be more permanent, this numbness you could feel.

Dr. Morgans:

And hearing is also a nerve that helps you hear. And that can be affected by cisplatin chemotherapy and cause people to have ringing in the ears or even hearing loss over time. And the most sensitive organs to cisplatin chemotherapy are the kidneys. We get two. We’re lucky about that. But they can be really damaged by cisplatin. So really we have to recognize that cisplatin is not targeted, it’s the most effective treatment that we have, but it can cause some damage. It’s important to recognize that and acknowledge that as we try to keep people safe as we move through.

So anyone who can get chemotherapy, we try to give it to them first. If they can’t get chemotherapy, we use something like immunotherapy. And let’s go through that. And I have some immunotherapy basic principles. We usually try to use chemotherapy first if we can. But if we can’t because a person is not going to be able to get chemotherapy for whatever that reason is, we have the option to use multiple immunotherapies either first or after we’ve used chemotherapy and it’s no longer working for us. And sometimes we’re actually using them together, chemotherapy followed by immunotherapy. And I’ll show you that information in just a moment. That’s probably the most important advance that we’ve had or one of the most important advances that we’ve had in metastatic bladder cancer in the last year or so.

So the immunotherapies that we have are atezolizumab and pembrolizumab. You may have heard of Tecentriq or Keytruda. These are the other names for these drugs. And these are the drugs that we use for people who can’t get chemo right up front. Or after we’ve used chemo and the chemos no longer keeping the cancer at bay, we can use things like pembrolizumab, nivolumab or avelumab. And these are for people who have had cancer that’s growing this type of bladder or urothelial cancer after we’ve used chemotherapy.

So how does immunotherapy work? I think this is really interesting from a scientist and doctor perspective and was so exciting when we were seeing the development of these treatments back in 2015, 2016 or so. So let’s go through this just briefly. So T-cells are a type of white blood cell. These are cells that patrol your body all the time looking for invaders. And these invaders could be things like infections, they could be things like bacteria, something that’s not supposed to be there and that we need to get rid of or viruses that we need to get rid of, anything that’s not supposed to be there, because it’s not part of you and it’s not something that is going through your digestive tract. This is something in your blood, then T-cells are supposed to recognize it.

There’s something else that can be in a person that’s not supposed to be there, and it’s not an infectious disease, it’s cancer. Cancer cells start off as your own normal cells, but they go through mutations that make them go rogue and they are no longer part of you. And now they are trying to grow and spread and do whatever they want, but they’re not following directions by your body anymore. And that’s because they’ve gotten some mutations that essentially make these cells immortal, live forever, and make them have the ability to potentially spread and cause trouble.

So T-cells, these are the patrollers of our system, can recognize, hey, that cell used to be part of me, but now it’s not, now it’s doing something it’s not supposed to do. And it recognizes that, because it can see that these cells are putting proteins up on their surfaces. What’s in this diagram listed as an antigen, it’s just a protein that the cell is putting out there to allow it to do something it wasn’t supposed to do in the first place. A mutation allowed it to have that antigen or protein out there. And the T-cell can see that’s not supposed to be there. But the tumor cell is also putting out this PD-L1 protein, a different protein that is essentially a silence protein.

Dr. Morgans:

So when the T-cell comes in, it uses its T-cell receptor to recognize, hey, there’s a weird protein on there, this is not supposed to be here. But it has a second signal, a second protein called a PD-1 protein on that T-cell and the tumor engages with that with its PD-L1 silencer protein and turns the T-cell off. Binding between the PD-1 and the PD-L1 protein combinations block the T-cell, turn it off, put it to sleep, it doesn’t know what’s going on. So it recognized that, that tumor cell was weird, but it was silenced essentially, put in handcuffs before it could do its work and the tumor cell turned it off.

However, PD-1 and PD-L1 treatments, these immunotherapies can come in and stop that engagement between the T-cell and the tumor cell and let that T-cell do its job in getting that tumor cell out of the system. So the T-cell comes in, uses its T-cell receptor, it recognizes that the tumor cell is not supposed to be there, because it’s putting proteins, antigens up on its surface that are not right. It comes in, it engages and it’s ready to do its job, and before it is silenced by the tumor cells, PD-L1 that turns it off and makes it inactive, makes it go to sleep, the PD-L1 or the PD-1 treatment comes in, blocks that interaction, it stops that blockade of the tumor cell to put the T-cell to sleep. And it lets the immune system recognize that intruder and kill it.

So that was a whole lot of mess, a lot of stuff to think about, but essentially these treatments, these immunotherapies, let the T-cells be the police cells that they’re supposed to be, let them recognize the intruders, those cancer cells and let them get them out of there. So as they’re doing that, as they’re getting that immune system up and attacking those cancer cells, they can also cause side effects. And so that’s what I wanted to mention to make sure we were all aware of. They can cause inflammation. They can cause it anywhere. The most common places that they cause it are the thyroid. They can cause a little inflammation here. And sometimes people need to take thyroid medicine to replace thyroid hormone if the thyroid is irritated and it’s not doing its job because of the immunotherapy. They can cause inflammation in the lungs that can cause a person to have a bit of cough. And sometimes we need to monitor that or give some steroids to reduce the action of the immune system, turn it down so that people don’t feel that cough.

It can cause diarrhea, because it causes inflammation. Immune cells go into the colon and don’t allow the colon to absorb water the way it normally would. So extra water in your bowels means diarrhea. So that’s something certainly we’d need to be aware of and turn off the immune system so the colon can absorb water and do its job. Again, it can cause inflammation in the skin, immune reactions in the skin, and that causes an itchy rash, which no one likes. And we can use usually a steroid cream to a quiet down the immune system and help keep the treatment going and soothe the rash on the skin. And arthritis. Inflammation in the joints causes arthritis or pain, irritation and swelling in the joints, which is one of the more common things.

But in reality, the immune system is in the whole body and it can cause effects anywhere in the entire body. So it’s important anytime you’re on immunotherapy to tell your doctor if you’re not feeling well, if there’s anything going on, because the doctor can do a number of different tests or physical examination moves to understand what’s going on with you and make sure that the immunotherapy is not causing a problem.

What if we combined chemotherapy and immunotherapy? This is one of the big advances I wanted to tell you about tonight, because this study called the JAVELIN Bladder 100 trial came out in about the last year and a half, and I think was one of the most impressive treatments for metastatic urothelial or bladder cancer that we’ve had in a long time. So all of the patients in this trial got chemotherapy. And that’s one of the reasons that I, as a doctor, want to try to give chemotherapy to people. If there’s even a remote possibility, I want to try to help them get through that chemo, because I want to use this JAVELIN approach with my patients.

Dr. Morgans:

So they all got chemo. And as long as they had cancer, that had been stable, so no growth, no spread. Or if the tumor shrink, they could then get in this trial either avelumab, an immunotherapy every two weeks, or supportive care. So pain control and nutrition management and all the normal things that we do just to support people, but nothing directed against the cancer. And then the trial asked which group lives longer, which has a better survival? Here we have a survival curve. This is why I wanted to go through that with you to help make sure that everyone understood survival curves. And this survival curve is one of the most impressive that I’ve seen in metastatic bladder cancer in a long time. What it shows is a clear separation of those curves. And that means one treatment’s better than the other. And in this case, avelumab, given every two weeks to patients after their chemotherapy help them live on average seven months longer. But it’s not about the averages, it’s about the tail of the curve and the way that this whole disease trajectory shifts.

So because an individual person is not an average, an individual person could be the tail on the curve, could be the most impressive responder, so this caused a huge separation of curves. It showed that, that treatment with avelumab was really helpful for people after their chemotherapy. And it reduced the risk of death from urothelial cancer or bladder cancer by about 30%. So really, really impressive. 31% reduction in death, that’s huge in this type of cancer. And we can see that around that median time, that 50% time people are living for years, which is really, really impressive as compared to people who only got the chemotherapy, which also those people did pretty well too, but avelumab helped them do even better.

So let’s move on a little bit to talk about a couple targeted therapies. And then I want to have some time for discussion. So erdafitinib is a pill. And this is actually a slide that was made for the New England Journal of Medicine, which is one of our top medical journals. This slide was made when the phase two trial, so a clinical trial of a test of erdafitinib was done in patients with urothelial or bladder cancer. They were looking at these pills, this oral therapy, that was targeting FGFR mutations. So these are mutations that we can only find by testing the DNA or the genetic material of the cancer cells. And your doctor knows how to do this testing. And if we do this testing and we find these particular mutations, we can use erdafitinib as a targeted treatment.

Targeted treatments are nice, because they hopefully have most of their effect against the cancer cells that have this genetic mutation, because the person shouldn’t have the genetic mutation, only the cancer. Now, of course, they have their own side effects, but the majority of effect is supposed to be against the cancer. And the patients that I’ve treated with erdafitinib have done well, but we, of course, need to watch out for certain side effects. But this is a drug that was approved just in the last couple of years. It’s a targeted treatment for metastatic urothelial cancer only used if we can identify the mutation in cancer cells. So important to talk to your doctor, both doing genetic testing for erdafitinib.

So there are some quirky side effects. These are the main and major side effects. The most common side effects for erdafitinib also called Balversa, things like mouth sores or feeling tired and sometimes blood count effects. These are very common for many of the things that we do. But for this particular drug, we also have to remember that there can be specific eye effects that are reversible, but we do need to work with an ophthalmologist to make sure that it’s safe. And they monitor your vision and make sure that it’s safe for you to continue to get this drug. If you do have any vision to changes, we stop the medicine. Typically, those are all reversible, but important to be monitored for the eyes.

And the other thing that this particular drug can cause that’s a little unique is high phosphate levels. And that can be affected by diets. So you usually would do diet changes to lower phosphate. And then also sometimes we can use medicines to lower phosphate two. But these are two unique symptoms or side effects of Balversa or erdafitinib that we just need to be aware of as we move forward and use this targeted treatment, which is highly effective.

Dr. Morgans:

There’s a whole other class that I want to mention. It’s a targeted treatment that you need to be aware of if you’re thinking about metastatic bladder cancer. And this group of therapies is called antibody drug conjugates. Sounds very complex, but let me break it down. So the first part is the antibody part. That’s the Y part on this particular picture that you can see. And that why part binds to a very specific protein on a cancer cell, and is targeted to that cancer cell because of the Y, the way that the Y binds. And that is very specific and important. That’s one of the most important parts of this drug. Then the antibody drug conjugate has a linker, which is basically just a connector to what they call on this particular diagram a warhead, where it’s essentially the treatment, the thing that will kill the cancer cell. And it’s indicated by the red, that red warhead or that red floret on this picture.

So essentially what this drug approach is, is trying to use its very targeted antibody Y linked to a certain protein that’s hopefully mostly just on the cancer cell and deliver it’s very potent, either chemotherapy or targeted drug right there and dump all of that toxic stuff right on the cancer cell, kill the cancer cell and leave the rest of the body basically, hopefully untouched. So one of these is enfortumab vedotin, and this is the one that’s farther along in development, really effective treatment. And we’ll talk about that in just a moment. It’s target, it’s antibody Y is targeting a particular protein called nectin-4. And you can see in the diagram here, that’s an anti nectin-4 antibody. So the Y tries to get to this protein called nectin-4. And when it gets there, it’s dumping a really nasty chemo right on top of it called MMAE.

And that chemo is so potent that we would not want to give it to a person without that targeting, because it can really damage the cells. And it does. And it’s really importantly damaging those cancer cells and hopefully not the person. And I’ve treated many people with this particular treatment and it’s highly effective. And people even in their 80s and who have other medical problems, can get this treatment safely. But it’s important to be monitored, of course, with a doctor that it’s been in advance. I think that’s been very transformative in this field.

So this is a schematic of a trial that recently has been presented looking at enfortumab vedotin. This included, on the left, you can see people who have metastatic bladder cancer that’s growing after chemotherapy and immunotherapy. So the two other treatment approaches that I showed you earlier. And people got either enfortumab vedotin or another different chemotherapy. And the study asks which group lives longer, which group is going to do better. And here we have another survival curve. So we get another test of our ability to read these survival curves. And you could see separation of curves means that one group is doing better. And the group that’s doing better is the group that got the enfortumab vedotin by a lot. 30% reduction in death when they were treated with enfortumab vedotin versus a different chemotherapy.

And really this beautiful big separation of curves demonstrates that there’s actually nice and strong advantage to that treatment within enfortumab vedotin, that antibody drug conjugate as compared to the older chemotherapy options that we had. And this is, of course, in a group of people who had already had chemotherapy in the past. So it’s not the chemos that I’ve talked about, the cisplatin and a carboplatin, these are different second and third line chemos that we might use if the other chemos no longer are working. But this is really, really important, I think will be something that we think about as we move forward a lot.

Dr. Morgans:

So enfortumab vedotin is also called Padcev. And some of the most common side effects that, of course, we should review here, include things like skin rash, it can include some high blood sugar and some other complications. But generally these are very similar complications to regular chemotherapy. But the ones I want to mention, just so that we’re all aware are some more potent skin reactions that your doctor needs to watch for some pretty significant neuropathy that numbness and tingling in the longest nerves in the body, in the fingers in the toes, sometimes eye problems, though not as commonly as erdafitinib, high blood sugar, which is a unique thing about this and inflammation in the lungs, a little bit of cough. So important that a doctor is monitoring and watching, but generally quite a safe treatment under a doctor’s supervision.

And finally, we’ll talk about sacituzumab govitecan, another mouthful, but another antibody drug conjugate. This one is targeting against a protein on the cancer cell surface called trop-2. And it hones there and it binds the trop-2 and it dumps something called SN-38, which is something very similar to irinotecan, which is a chemo that we use in some other situations and other cancers. And when that irinotecan is targeted to the cancer and dumped there, it can help people live longer, it could help them feel better. But, of course, it has side effects that we’ll talk about in a second. This drug is also approved for patients with breast cancer. So not just used in urothelial carcinoma.

So it’s also called Trodelvy. And so these are the side effects that we can think about. Things like diarrhea are some of the more common effects. And that’s very common, because irinotecan, we know as a chemotherapy causes that. And so we use antidiarrhea medicines to help resolve that diarrhea. We can also cause blood count issues, some nausea, but generally people feel okay when they’re on this medicine. And again, it’s also used for people with breast cancer. So is something that has been tried in other cancer populations and can help people live longer, not just in urothelial carcinoma, but also in breast cancer.

There are multiple other trials that are going on, trials that are looking at things like enfortumab vedotin plus immunotherapy or sacituzumab govitecan plus immunotherapy or different immunotherapy drugs, nivolumab and ipilimumab used together, as well as multiple other approaches. These are just a couple. So it’s important, I think for all of us to recognize that even though this is not a disease that we can cure, it’s disease that we are attacking from every front and using every bit of technology and brainpower that we have to make a difference and really help people live longer.

So in summary, I know I’ve talked for a long time, metastatic bladder cancer is less common than non muscle invasive and muscle invasive bladder cancer. That’s the earlier stage bladder cancer, and it’s not curable, but it is highly treatable. And treatment advances are giving us more options and more hope every single day for patients. And I really appreciate the time that you spent here. And I am looking forward to answering some questions. So thank you. And it looks like Stephanie’s back to ask some of those questions.

Stephanie Chisolm:

This has been phenomenal, Dr. Morgans. I think that your explanations of everything have been absolutely on point and I hope in really plain language for people to really get it, because as you said, understanding those survival curves, it’s really scary from a patient’s perspective when they see that and they don’t know how to read it. So I thank you for doing that. We have a couple of questions that have come in and we’re not going to have time for a whole lot of questions. But when you’re doing a comparison between survival rates between local metastatic and then distant disease, how do you address that with a patient? What are some of the concerns that patients should know about?

Dr. Morgans:

Yeah. So anytime the cancer has spread, it’s usually something that it’s going to be more challenging and more challenging to cure. So I always with as much tenderness as possible, try to explain what our goals are of treatment are going to be, because sometimes even spreading into lymph nodes and more distant lymph nodes, we can’t always cure people. And we do need to make sure that people understand, I think what they’re facing when they’re making decisions for treatment, because some people will choose not to do things or choose to do things based on that. So that’s important, setting expectations and setting thoughts and saying, “Of course, we’re going to try whatever you’re willing to try, but I need you to understand where we stand.”

And then when we’re talking about more local disease where maybe the symptoms are not so bad versus more distant metastatic disease, perhaps there’s cancer growing in a bone that’s causing a lot of pain, we need to think not just about how we try to get that cancer back under control in general, which, of course, we’re trying to do, but what else do we need to do to deal with the symptom that’s coming from that? Do we need radiation to a bone to try to help that person feel better fast from that pain, because that radiation can be really, really effective in reducing pain control or improving pain control, reducing pain, or is there something that this person’s having in terms of shortness of breath from something in their lungs and we need to either use radiation or use other methods, even oxygen potentially to try to help that person.

So what can we do to deal with the symptoms? And I think there are more symptoms as the disease gets further and further outside of the bladder. And so we just need to think creatively about not just treating the cancer overall, which, of course, we need to do, but also making sure that if there are other things that we can recognize and reverse, we take care of those as well.

Stephanie Chisolm:

Right. So is that where you as a medical oncologist, would involve a palliative care team to help that patient?

Dr. Morgans:

Absolutely. I say absolutely, because I’m very comfortable with palliative care, because of the way I think of palliative care. I think of palliative care as a team that is expert at symptom management. These folks know how to deal with any symptom that comes your way, whether it is pain, whether it is constipation, whether it’s nausea or fatigue. They have ways to deal with that and are just as specialized and just as aggressive at going after those symptoms as I am specialized and aggressive in going after the cancer itself.

Dr. Morgans:

But I feel very comfortable with them, because I know their expertise and I know their goals. And I know that I don’t just involve them when I’m trying to talk to somebody about hospice or end of life, but there can be mixed emotions when we talk about palliative care. And I recognize that and so do the palliative care doctors. And I think that we as a community, need to support each other in those perceptions. And so I do talk to patients and say, “Look, I want to involve them because they are expert.” But I always ask a person, “Are you comfortable? Can we talk about what that means?” Because sometimes that word, palliative care, is very upsetting.

Stephanie Chisolm:

Yeah. I think a lot of patients think that, that means there’s nothing left for them to do and yet they can still help manage those symptoms. So I think that’s really important and patients should ask about it and not be afraid to at least inquire if there’s something that someone on that team can do to assist in them being able to stay on a treatment for a longer period of time so it has a better chance of working. We do have one question that came in. Has CAR T-cell therapy been used in bladder cancer treatment? Or is this still early to talk about that?

Dr. Morgans:

So it’s still very, very early days to talk about that, but CAR T is something that in solid tumors in general is of high interest. Now, of course, CAR T are these programmed T-cells that are trying to go after specific cancer cells in the body. They’re used in blood type cancers pretty frequently now or more commonly now, and they’re even used against cancers that kids are facing. So they’re used in pediatric patients. But they are still in their very early days in solid tumors. And we think of bladder cancer as an organ tumor or a solid tumor. So early days here.

The one caveat I would say about CAR Ts is that we have to be respectful of this particular approach to treatment. These are treatments that can be highly effective, but can be highly toxic. And we as a field are trying to figure out how to best support patients to go through that treatment. And sometimes that treatment in its best case scenario or in its expected scenario is delivered in an ICU type setting, because we do expect that there will be changes in blood pressure and organ dysfunction, kidney failure, liver failure, lots of problems that we can expect because it’s actually part of the process that the cancer cells are dying in a way that is… It’s a very highly potent treatment that causes all of this against the cancer, but also causes problems with the regular body function.

So, especially as we’re dealing with and helping to care for older adults with bladder cancer or urothelial cancer, we have to be really cautious there. We don’t want to cause harm when we’re trying to help. But it is important to just be respectful of the treatment, but it is something that early days, but I’m sure is very, very high interest.

Stephanie Chisolm:

Absolutely. Well, again, this has been phenomenal. And there’s one more question. Perhaps, we have time. Does expression of PD-L1 on the tumor play a role in how well the patient is likely to respond to chemotherapy. Is there a pattern that you’ve seen?

Dr. Morgans:

So great question. So it’s not supposed to necessarily show how well someone might respond to chemotherapy, it’s supposed to show how well someone might respond to immunotherapy. But in general, the higher the PD-L1 expression, it looks like the better the person does, whether they’re getting PD-L1 targeted treatment immunotherapy or chemotherapy. But it’s not a one to one correlation. So you could have very low PD-1 or PD-L1 expression and still respond to immunotherapy. You could have very high expression and not respond to immunotherapy. So it’s not perfect. But we in general think the higher expression, maybe the better response to any therapy and the higher the likelihood that someone will respond to immunotherapy, but it’s not perfect.

Stephanie Chisolm:

Right. So that was something that when it first came out was really noticeable. And people started talking about it. If they didn’t have it, would they still get this treatment? And then you found out that you could still respond. So I think that, that’s really encouraging that again, the science is still going on and there are all these trials that are still happening around the country. Dr. Morgans is certainly doing her share of clinical trials at Dana-Farber. BCAN is certainly supporting bladder cancer research to make sure that we’re always moving that needle forward.

And I think since BCAN began in 2005, we didn’t have a whole lot going on and we’ve seen leaps and bounds over the last five or six years. And I do think it’s an exciting time. And it’s really exciting because of young and inquisitive clinician researchers like you. And you’ve done an amazing job breaking this down for everybody. And we really do appreciate it.

I’m going to go ahead and end the program, because we’re right on time now.