Treatment Talk | Immunotherapy for Treating Bladder Cancer

June 9, 2021

With Dr. Peter H. O’Donnell and patient advocates, Lynn Sperling and Andrew Kunz

Year: 2021

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Part 1: What is bladder cancer immunotherapy?

Video (21 min) | Transcript (PDF)

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Part 2: The patient experience with bladder cancer immunotherapy

Video (8 min) | Transcript (PDF)

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Part 3: Question and answer about bladder cancer immunotherapy

Video (30 min) | Transcript (PDF)

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Part 1 | What is Bladder Cancer Immunotherapy

Stephanie Chisolm: Thank you again for joining us for Treatment Talks live bladder cancer video chat from the Bladder Cancer Advocacy Network. The immune system detects and protects the body from anything it perceives as foreign. However, cancers found ways over the years to evade our immune system, and bladder cancer immunotherapy is designed to help our immune system to recognize those cells and to reactivate the specific immune cells that help target and attack them.

While BCG has been around for decades and works as bladder cancer immunotherapy, there are now a number of new immune checkpoint inhibitors targeting the PDL1 receptor pathway that have been approved by the FDA for people with types of bladder cancer known as locally advanced or metastatic carcinoma. That’s the focus of today’s program.

We’re delighted to have a leading expert with us today from the University of Chicago. I’m going to introduce Dr. O’Donnell. He is a specialist in genitourinary malignancies, including prostate, kidney, testicular. But he really does specialize in bladder cancer.

Dr. O’Donnell is a well-published researcher with training in pharmacology and pharmacogenomics, the study of the genetic trait that cause differences between patient and drug response and side effects. I know some of that comes into play as we’re talking about these immune therapies.

And so, we’re also joined by two of Dr. O’Donnell’s patients, Lynn Sperling and Andrew Kunz, who I will introduce a little bit later on. Dr. O’Donnell, I’m going to turn it over to you. We know that immunotherapy is not a new therapy, but now it’s being used in many different ways. What do you think we should know about bladder cancer immunotherapy today?

Dr. Peter O’Donnell: Thank you, Stephanie. It’s really my pleasure to be here today. I see my charge as setting the stage for really the highlight of this hour, which is hearing from two people that I’ve had the privilege of getting to know over many years and really are the ones that are going through and have gone through treatments like this, Miss Sperling and Mr. Kunz. So I’ll set the stage and then we’ll move to that portion of the program.

What is Immunotherapy?

Dr. Peter O’Donnell: All right. So I first thought I’d say that let’s get the groundwork of the terminology when we’re talking about bladder cancer immunotherapy. Some people refer to these treatments as immunotherapy, some you might hear the words immune therapy, some you might hear the word immune checkpoint inhibitor. For our purposes today, they all mean the same thing. These are drugs that modulate or alter a patient’s own immune system to fight cancer. Next slide.

There are four drugs that are approved for use against bladder cancer that are bladder cancer immunotherapy agents, and I listed those on the slide here. I’ve listed both the common name or the generic name of these drugs and then the brand name. You might hear your doctor or your treatment provider refer to either.

Dr. Peter O’Donnell: The four drugs are atezolizumab, avelumab, nivolumab, and pembrolizmab. All four of these drugs are immunotherapies. They’re all given as intravenous treatments, IV treatments. They are administered over a portion of about 30 minutes’ time. The schedule can be anywhere from as often as every two weeks needing to get these fusions to as less frequent as every six weeks, depending on which specific drug your physician has chosen and which schedule for that drug they have chosen.

Dr. Peter O’Donnell: I want to start here before we talk more about these drugs in depth, with a brief portion of a video that I actually recorded with BCAN’s help. We’re going to watch about a minute of this to understand how immunotherapies actually work in the body. (Please visit https://www.youtube.com/watch?v=SnfFkrsGDOA to watch the video.)

So I’m going to say some of that another way, because I know that was quick, to understand how immunotherapies work. I think one of the best ways to really put it into context is to describe how immunotherapies are different from traditional chemotherapy treatments, which I think many patients are often familiar with or at least had family members or friends that might have been treated with chemotherapy.

So on the left, we’re looking at a representation of how chemotherapies work. Here they’re showing that the chemotherapy drug has toxic effects on any cell that it comes into contact with, that being a cancer cell on the left or a healthy cell, any healthy cell in your body.

One of the hallmarks that we think about with chemotherapy is that the side effect profile is often difficult or harsh, as is shown on the lower part of the left-hand part of the slide. Then we traditionally don’t think about chemotherapies as having longer lasting effects. That is the post-treatment protection is often of short duration.

So chemotherapies traditionally work while they’re being given about, but the effect will typically stop after the chemotherapy has to be stopped. What typically happens in almost every patient is that we have to stop chemotherapy at some point because the effects on the healthy tissues accumulate, the side effects accumulate, where we have to pause or stop chemotherapy at some point in almost every patient.

Now contrasted against immunotherapies on the right, where, as we’re seeing here, the immunotherapies unleash the patient’s own immune system to find and kill cancer cells. And so, they’re actually acting on the patient’s own healthy immune cells to use those cells to the body’s advantage.

And so, we think, for immunotherapy, unlike chemotherapy, that typically these drugs have a much lower side effect profile, that they’re very tolerable in a large majority of patients who received immunotherapies. A clear advantage to these types of drugs.

Dr. Peter O’Donnell: We also have this very interesting effect of immunotherapies, that even in patients who stop immunotherapies, who are not actively continuing to receive those ongoing infusions, we can see that in a number of patients, there will be a post-treatment protection effect. That’s believed to occur because we think that these drugs can actually train the person’s own immune system to recognize those cancer cells, and that even when we withdraw the immunotherapy, and immune system remains trained and has a memory to learn how to keep those cancer cells at bay. Next slide.

The last thing I’ll do, to put this into context, is to try to compare and contrast a third type of therapy that you might have heard of, and that is targeted therapies, which are on the middle part of the slide. So now we’re thinking about differences between chemotherapy, targeted therapies, and immunotherapies. There are some targeted therapies that are approved for bladder cancer treatment. We don’t have time today to focus on those.

Dr. Peter O’Donnell: But if we look at this slide, how do they work? Again, chemotherapy generally targets any rapidly dividing cell in the body. Hopefully has preferential effects against cancer cells, but also clearly damages normal cells in our body. Targeted therapies try to find a specific target on the surface of a cancer cell to then destroy that specific cancer cell because it has the target. Immunotherapies, as we’ve said, use our own immune system to stimulate the immune cells to identify and treat the cancer, kill the cancer cells.

Side effects. Again, with chemotherapy, people generally know, have lots of different effects that are difficult for patients to tolerate, including hair loss, gastrointestinal effects like diarrhea and nausea, and many other effects on the body’s own immune system, for example, where the bone marrow can be damaged by chemotherapies.

Targeted therapies can have specific problems related to the specific target. Those can sometimes include liver problems, diarrhea, skin rashes. Again, we won’t have time to focus on those today.

For immunotherapy, what we’ll talk about at the end of this session is that really the side effect that we worry about. Again, it’s infrequent in most patients, but that is if the immune system gets revved up too much. If we overactivate the immune system, our own immune cells can start to attack itself. That is they can attack normal tissues in our body like an autoimmune reaction, which many patients are familiar with.

Dr. Peter O’Donnell: The limitations of each of these. For chemotherapy, well, cancer cells can develop a resistance to chemotherapy, which means that they can start to grow even when the chemotherapy is being given. As I already mentioned, there’s a limitation to the amount of chemotherapy that a person can tolerate in their lifetime because of the damage to normal tissues.

For targeted therapy, we also see cancer cells developing resistance. For immunotherapy, resistance can happen, but perhaps is less likely, especially in patients where immunotherapies are working. It’s tailored because it’s using the body’s own immune system. One downside is that these therapies are still very expensive to give.

You might say, “Well, I’ve heard about PDL1. What’s that?” So how are we talking about immunotherapies without talking about PDL1? And so, I’ll draw a connection to something that we saw in the video, which is that protein that’s expressed on the surface of tumor cells. It’s actually being shown on this slide.

If you look at the right, where we’re seeing a collection of tumor cells, they’re expressing that protein, which is actually called PDL1. It’s a protein that some tumors can express on the surface. That expression of PDL1 engages a receptor on the T-cell, which is the immune fighting cell. That T-cell then engages with the PDL1, and that’s what causes the T-cell to be turned off. It’s what allows the tumor to hide, as we talked about in the video, so that that T-cell, that immune system can’t actually see the tumor any longer and can’t activate to kill the tumor cell.

So PDL1 ends up being important. It’s important in bladder cancer treatment. We don’t always have to test for PDL1 when we’re thinking about using immunotherapies. But in general, if your tumor is expressing PDL1, or if the cells around the tumor are expressing PDL1, there’s a higher likelihood that immunotherapies will work for you.

They still can work in patients without PDL1, and your physician doesn’t always need to test for this before they use immunotherapies. There are certain specific scenarios where your physician may need to test for PDL1 before they can prescribe immunotherapy. But in general, we’re able to prescribe immunotherapies regardless of PDL1 status in bladder cancer.

Dr. Peter O’Donnell: The last thing I’ll say about this idea of immune-fighting cells getting activated is that we actually know that in a person with bladder cancer, if those immune cells can be turned on, can be revved up, and actually infiltrate into the tumor. So wherever that tumor might be in your body, whether it’s in the bladder itself or if your tumor has, unfortunately, metastasized or spread somewhere else in the body, and if we did a biopsy of that tissue and took a sample, on the left-hand side, I’m showing a slide of bladder cancer under the microscope where you don’t see many immune-fighting cells infiltrating into that tumor.

The immune cells on this slide would be brown, staining brown. You could see maybe just one or two of those cells infiltrating into this patient’s cancer. We call that a low number of immune cells, sometimes called killer T-cells. Low number on the left.

On the right, we see a large number of these brown staining cells, which are the immune-fighting cells, infiltrating into the bladder cancer sample. What’s been shown in many instances, in elegant work, is that if your cancer has infiltration of these immune-fighting cells, your outcomes are much likely to be better from a bladder cancer standpoint. You’re likely to respond to immunotherapies better and you’re likely to live longer.

Dr. Peter O’Donnell: The last thing I’ll say is where do we think about using immunotherapies? Maybe this will be a great topic for the question and answer portion, is thinking about, well, when would your doctor actually think about using an immunotherapy?

There’s three main settings right now in 2021 where immunotherapies have a role for the treatment of bladder cancer according to FDA approvals. The first treatment setting is one that patients may not know as much about. It’s more recent. It’s happened only in the last couple of years.

That is actually for patients after BCG treatment, before the bladder has actually needed to be removed, specifically patients, as I’m showing on the left-hand part of this slide, that have tumors that earlier. They’re not as far advanced. You can see some of those tumors are described T2 or T3 or T4. These are more advanced tumors that have invaded into at least the muscle or in deeper layers of the bladder.

Those patients right now, we don’t think about using immunotherapies. Those patients need their bladder removed and they probably need chemotherapy as well.

For patients that have lower stage disease, you can see on this slide T1 or CIS, which means carcinoma in situ. If you have those features, you may be eligible to think about using immunotherapy, a drug specifically called pembrolizmab, which I mentioned at the beginning, one of the four immune therapies that’s approved.

Pembrolizmab may be an option for you if BCG is no longer working. It may allow us to decrease that tumor, keep it from coming back in the bladder, and delay the need for your bladder being removed.

That’s a less common instance of how we use immunotherapies, at least right now. More commonly, we use these immunotherapies when, unfortunately, the cancer has already spread outside the bladder, as I’m showing on the diagram on the right. Many patients know that bladder cancer can spread basically anywhere in the body. Common locations where bladder cancer can spread is in the lymph nodes, into the liver, into the lung, even into the bone.

Dr. Peter O’Donnell: And so, there are options where if your cancer has spread, to use immunotherapy as the first treatment that you would receive for metastatic bladder cancer. In specific instances, we will think about using immunotherapies as the first-line treatment if, for example, a patient cannot tolerate traditional chemotherapy.

Chemotherapy is usually the first choice for most oncologists if you have metastatic bladder cancer, but a small portion of patients might be able to be spared chemotherapy altogether and receive immunotherapy as the frontline treatment. Those patients, again, they have some reason why they can’t receive chemotherapy, and those patients need to have high PDL1 status, as we talked about earlier.

The more common reason is the third one that I’m listing on the slide at the far right, which is that if you’ve already had metastatic spread of your bladder cancer, you receive that frontline chemotherapy. There’s now a role for using immunotherapy after chemotherapy in one of two different ways.

One is that your doctor can go ahead and, as soon as you’re done with that initial chemotherapy, transition you or switch you straight into what we call maintenance immunotherapy. This is something that’s new over just the past year in bladder cancer. A large study was published in the past year that showed the patients who come off of their frontline chemotherapy and go straight into a maintenance immunotherapy approach live longer than patients who just get chemotherapy alone and then are followed.

So the idea of maintenance immunotherapy, which has specific evidence around the drug avelumab, which I mentioned earlier, is now becoming adopted widely in the treatment of bladder cancer. So if you haven’t heard about this, you should ask your doctor about whether there’s a role for maintenance immunotherapy for you.

The last option, as is said in item number three on this slide, is that some patients will go through frontline chemotherapy and then they would choose to be followed, that is to watch their cancer after the initial chemotherapy has worked.

Typically, doctors will adopt a period of regular scans that will be done every three to six months. Then if one of those scans should, unfortunately, show that your cancer is growing again, we don’t typically go back to the chemotherapy. That’s when we would go to immunotherapy as a second-line treatment after chemotherapy has stopped working. These are very common instances where immunotherapies are given.

Dr. Peter O’Donnell: This is my second to the last slide, which is that we do have to acknowledge that just like any therapy A and medicine, any medicine that you would take certainly can have side effects. I already said that compared to chemotherapy, immunotherapies are much more well-tolerated in general for bladder cancer patients.

I tell my patients that probably about nine out of 10 patients that get immunotherapy are going to feel generally well. They’re going to actually say, “Doc, I see the bag hanging up there, but I don’t feel like I have any side effects from the therapy.”

One out of 10 patients will have a more serious reaction in the body to the immunotherapy, and that is sometimes what we call an -itis. You can see that a lot of the words ending on this slide end in I-T-I-S, which means an inflammation of a specific organ in the body.

The most common inflammation that we see is on the skin, which is the patients can get a rash or itching or discoloration of areas of the skin. These are the most common type of immune-related side effect. Most patients, these are minimal and tolerable and can be treated with even topical treatments.

In other instances where we see more severe reactions against the immunotherapy, this gets to what I was saying earlier about an autoimmune-like reaction, where your body’s immune system has revved up so much that now your own immune system is attacking a critical organ. It can attack the lungs, the liver, the gut, even the heart or the nervous system. These are serious events, and these patients often need to be hospitalized for high-dose steroids to calm down the immune response.

The good news is that, in many cases, that inflammation, that -itis, can be reversed with the use of steroids. The question really is then whether a patient can ever go back to immunotherapy if your body has had one of these very high stimulation of the immune system adverse events. That’s a discussion that you would have with your doctor.

But again, in general, compared to chemotherapy, I can tell you that my patients would choose immunotherapy every day of the week from a side effect profile. Next slide, please.

Dr. Peter O’Donnell: So in summary, immune therapies have really revolutionized the treatment of bladder cancer. All of these immunotherapies were approved within the last five years. And so, we’ve seen a dramatic change in how we can approach the treatment of bladder cancer and a huge increase in the number of tools that physicians have to combat this terrible disease.

These therapies have clearly increased patients’ chances for survival, even patients with metastatic disease. They work differently than chemotherapy, they’re generally well-tolerated, and they are options in multiple different settings of bladder cancer. So I’m going to stop here.

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Part 2: The Patient Experience with Immunotherapy

Video (8 min) | Transcript (PDF)

 Stephanie Chisolm: We’ve had some really good questions come in. But I do think it’s really important to really understand that patient experience. So if you don’t mind, we’re going to start with ladies first, Lynn. I know that you went through chemo and then you went on the immunotherapy. So can you tell us a little bit about your experience.

Ms. Lynn Sperling:From what Dr. O’Donnell just talked about, I seem very typical. I had six rounds of chemotherapy. There was some progress and the cancer was less. Then when it was stopped, it started to grow again. My oncologist at the time said we could try another chemotherapy or there’s a drug trial at the University of Chicago on immunotherapy. Would you be interested? My husband and I discussed it. We said definitely yes, and we went to see Dr. O’Donnell.

We were part of a drug trial. I was on Keytruda, the one … I don’t know how to say the one. I have been off of infusions for a couple of years, and each of my CT scans is great because they’re still the same. There’s no return. I’m up to six months checkups since. So at first it was three months and then nine months. Now we’re up to six months rather. So hopefully the news is continuing to be great.

Stephanie Chisolm: That’s awesome. Being in a clinical trial is a big step for many people, but it was great that you were able to benefit from that. So let’s go to Andrew and then I’ll ask you both some questions. Then we’ll just open it up for the general questions. Andrew, you started out with BCG back in 2011. Then you got into the Keytruda study. Do you want to tell us a little bit about your experience?

Mr. Andrew Kunz: Yeah. I was initially diagnosed in 2011. I had a series of BCG treatments. The cancer came back in late 2015 then. That’s when. I saw Doc O’Donnell and he got me on to the pembrolizumab, the Keytruda study there, which was very effective. It was effective enough for me to have my bladder removed then that following summer. After that, I went through a series of scans. Then cancer came back again in February of 2020. That time it was a tumor on my spine.

What happened then was he got me into a study that was basically radiation, three shots on a Monday, Wednesday, Friday, and then two immunotherapy drugs, nivolumab and avelumab. That study ran for a year, and I’ve been off of it now for almost a year and a half. At this point, I have monthly infusions of nivolumab and scans every four months, and I’m feeling fine.

Stephanie Chisolm: So immunotherapy requires patients to make a time commitment. Has that been an issue for you? Lynn, I know you’re no longer getting the actual immunotherapy treatment. Andrew, you are. How do you make that decision to commit to that long-term treatment option?

Mr. Andrew Kunz: Oh, it’s no big deal. It’s just like one day a month at the hospital. I’m getting to be a regular over there with the nurses and everything else. But I don’t mind it at all. It’s the very least that I could do. The side effects, as doc was mentioning earlier, literally a little bit of itching and that is it.

Ms. Lynn Sperling: I think sticking with it has been really wonderful. It seems to be working and gives me a real positive hope for the future.

Dr. Peter O’Donnell: Stephanie, just about one difference that I touched on on the presentation, but we didn’t get to expand on, is Mr. Kunz and Miss Sperling have had a difference in their treatment courses in that for Mr. Kunz, when we stopped the immunotherapy, his cancer did come back. For Miss Sperling, we’ve been able to stop the immunotherapy now for a couple of years. Luckily, the cancer has not recurred. So that’s an area of debate among bladder cancer physicians is when can we stop immunotherapy and hope that that immune system has been trained to do its job on its own.

In some patients, that training, that memory of the immune system doesn’t seem to be there and you need to keep giving the drug. In other patients, it seems like we’re able to stop the immunotherapy and the patient will do quite well. I know that was a point of debate for both of you. I don’t know if you want to comment on that decision that we had to wrestle with about whether to stop or not.

Mr. Andrew Kunz: Well, we did discuss it. I think, at your recommendation, we went ahead with it. I think that’s a real important thing for what I’d recommend for other patients, is you need to trust your doctor. You need to realize that he or she sincerely wants you to heal and sincerely wants you better. The recommendations they’re giving you are for your benefit. So it wasn’t really a very hard decision at all for me. I don’t know about you, Lynn.

Ms. Lynn Sperling: I had the same. I was confident that Dr. O’Donnell … He recommended that I was ready to stop the infusions, and I trusted his judgment and was confident that that was the right decision.

Stephanie Chisolm: I think that says a lot that you really do have to have those conversations with your provider and you have to trust that. So if in fact it does stop working, Dr. O’Donnell, do you go back and restart the same immunotherapy that had worked or do you try a different one?

Dr. Peter O’Donnell: Yeah, great question. In Mr. Kunz’s specific case, we tried a different one. It was specifically because he had a different clinical trial that was available, and he was really interested in this idea of trying to combine two immunotherapies. It’s something that I didn’t actually touch on the presentation. But in this disease, in bladder cancer, we don’t actually use more than one immunotherapy at a time. We only use one immunotherapy at a specific time. In other cancers, they actually can use more than one immunotherapy at the same time.And so, that’s being studied for bladder cancer right now. Mr. Kunz was particularly interested in that idea, that after his initial single immunotherapy stopped working, he was interested in trying a trial where he got two drugs, as he mentioned. And so, that was really the decision there. In some patients, I have switched the immunotherapy. If one wears off, then we can switch to a different one. But in most cases, if an immunotherapy stops working, we’re thinking about them using one of those targeted drugs that I talked about as the third step.

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Part 3: Question and Answer about Immunotherapy

Video (30 min) | Transcript (PDF)

Stephanie Chisolm: Okay, that’s really helpful. I want to go to some of the questions that have been submitted. I’m going to start with this one because there’s been all sorts of things on the news these days about people with immune-compromised systems, because they’re on immune therapies, not necessarily showing any benefit from the COVID vaccine. So the question is do immune therapies degrade or negatively impact the COVID-19 vaccine efficacy? If so, what precautions do you recommend?

Dr. Peter O’Donnell: Yeah, great question here. So I haven’t seen any data in bladder cancer that suggests that the COVID vaccine is less effective if you’re getting immunotherapy.

There was some data, especially out of New York, during the earlier parts of the pandemic, that some patients who were on immunotherapy treatments, that they were having worse outcomes if they contracted COVID, that those patients were actually doing worse, which almost seems counterintuitive.

If you’re on a drug that’s stimulating your immune system, you’d think, well, maybe I’d be able to fight off COVID better. But actually it seems like those patients were getting really strong inflammatory responses and having complications in the lungs because of the over-inflammation in the lungs.

With respect to the vaccine now, I’m counseling all of my patients, certainly cancer patients but all patients, to go ahead and get the COVID vaccine. What we’ve done for patients that are on immunotherapy is that if the patient’s been on immunotherapy for a long time, we’d go ahead and just get the COVID vaccine. If a patient’s thinking about just starting an immunotherapy or a chemotherapy, we’ve tried to separate the timing of those by at least a couple of weeks. But I don’t know of a data that the vaccines do not work. I have not seen that.

Stephanie Chisolm: Okay. I think we’re just now beginning to really start looking at all of these things. So I’m sure that there’s going to be evolutions of our knowledge and articles that come out that are demonstrating whether this is an issue or if you need to have an extra booster or whatever. So I think that there’s a lot of TBD, to be determined, when it comes to understanding the vaccine since it’s so new and then how does this impact us with immunotherapy. So thank you. That’s a great thing, great question to have answered. I have a couple other questions that I will ask. What do you think about beta-glucan, glucan with immunotherapy, Dr. O’Donnell?

Dr. Peter O’Donnell: Yeah. This is one that not a lot of my patients have asked about. I know that beta-glucans are being explored for the treatment of lots of different types of cancers as a way to boost immune responses. But they’re not proven yet. They still have an experimental role in cancer treatment. I haven’t had personal experience with using them. I don’t know if Mr. Kunz or Miss Sperling have used other supplements or nutrients to try to boost immune responses.

Ms. Lynn Sperling: No.

Mr. Andrew Kunz: No.

Stephanie Chisolm: Which leads to another question: is there anything that patients and their families could do to enhance this immune response, whether it’s diet or exercise or anything else that they should be paying attention to as they’re going through the treatment?

Dr. Peter O’Donnell: Yeah, I don’t know. Mr. Kunz or Miss Sperling, do you want to comment on that? Because that’s something I think we have talked about at various points, the things you’re doing in your own lifestyle. Then maybe I can chime in as well. Patients ask this all the time. “Now what can I do, doc? Is there anything else I can do?” Are there things that you feel helped both of you?

Mr. Andrew Kunz: Well, I like to walk and walk, about three and a half miles a day. When it’s nice, I’ll play golf once a week. So I do just regular living, I guess, is the only way to put it. It’s not holding me back in any way. Lynn?

Ms. Lynn Sperling: Yeah. I go to an exercise class three times a week. It’s a sitting exercise. It’s called sit and get fit. I think a positive mental attitude too, being social, being with friends is also very helpful.

Dr. Peter O’Donnell: I love that. I’m a big proponent of the idea of some form of exercise, because I think there’s clearly data that exercise improves immune responses in general, even in the absence of immunotherapy. So I think it’s healthy for the immune system in general. I love the mind-body comment there, Miss Sperling, because there’s a lot of data actually around that, that positive influences in your life can actually have positive outcomes.

Stephanie Chisolm: Yeah, attitude is everything. I do believe that. Attitude determines your altitude in many cases. I think that that really does apply here. But it’s not always the case because there are plenty of people that have real issues.

Stephanie Chisolm: So if you have immunotherapy and it causes your immune system to overreact, Dr. O’Donnell, can you explain how the steroids help quiet things down? Do you gradually start back? Do you start back with a lower dose? How do you fix that problem and still maintain the benefit of the immunotherapy?

Dr. Peter O’Donnell: Right. So this is where you’re really going to need to rely on your doctor, understanding what severity of the inflammatory response are we seeing? Some small degree of inflammatory response, like Mr. Kunz talked about a little bit of itching that he has, I actually tell my patients it’s probably a good thing. It tells me the immune therapy’s doing something in your body. It’s activating, that you’re getting a little bit of a response. As long as you can still function and it’s tolerable, then we wouldn’t do anything differently. That would be what we call the least severe form of an inflammatory response. A second grade of it would be where now it’s starting to cause you to be a little bit limited in what you would be able to do. For example, a rash that’s covering a good portion of your body, where now it’s requiring more intense treatment than a large amount of cream over your areas of skin, where it’s limiting your ability to walk because of skin folds being rubbed against.

That’s where we start to say, all right, now this is becoming a little more severe and we’re going to probably pause that immune therapy, meaning we’re going to withhold the drug for a while, give some topical treatments to the skin there, and maybe even a short course of an oral steroid, a steroid pill like prednisone.

Dr. Peter O’Donnell: Then beyond that are what we call the higher grades, the more severe. We call them grade three and four immune events. These are ones where the patient has clearly had organ dysfunction. For example, a patient has severe diarrhea because the gut has become so inflamed, or is having shortness of breath, or lowered oxygen saturation because the lungs have been inflamed. These would be instances where your doctor should hospitalize you immediately, and you’re going to get high dose IV steroids through the vein, a drug like prednisone or a similar drug through the vein, to calm down that immune response.

Typically, doctors will need to use that high-dose steroids for at least 48 hours in the hospital. Usually within that first 48 hours, we see patients dramatically improving. The diarrhea will quickly reverse, the skin rash will quickly improve, the breathing will improve. And so, all of those are the metrics that your doctor is looking for.

Then what they will often transition you to is then an oral pill of steroids that often has to be tapered over a period of at least a month. So they’ll discharge you from the hospital, you go on an oral steroid, and that steroid dose will be slowly lowered over the course of a month or six weeks until the steroid can be taken off.

Then the real question is once that steroid comes off, is your body going to re-inflame? Is the immune system going to reactivate? I talked a little bit about the idea of your immune system getting a memory to it. And so, it can have a memory around these side effects as well.

And so, sometimes when we stop the steroids, the immune effect that you were having flares right back up. That’s troublesome because then we have to put a patient back on steroids, and many patients know that steroids for long-term are not fun to take. They can cause patients to have swelling. The face will puff up. You get very hungry and people will gain weight. You can retain fluid. There’s lots of side effects of long-term steroids.

And so, that’s the problem when we get these severe immune adverse effects. Really your doctor then has a real tough question about whether they could ever go back to immune therapy.

One little trick that I have done, and I’m a believer in this, is that if you’re patient gets a severe immune related adverse event and then improves, and you have a discussion where that cancer is then growing again one day and your patient says, “Doc, I want to fight. I want to do everything I can,” and you have no other options, I’m willing in those cases to consider going back to the immune therapy. But that’s when I switch it.

We have for drugs that are out there on the market. I definitely wouldn’t give the same one again. I’d switch it to a different type in hopes that that inflammatory reaction doesn’t come back in the same way.

I know somebody was asking a question too, Stephanie, about lowering the dose of the immune therapy. Generally, that’s not helpful. With chemos, we will reduce the dose and the side effects usually improve. With immunotherapies, we don’t see that.

Stephanie Chisolm: Okay, that’s great. Well, I remember in your talk, you had that really lovely slide that, to me, was very encouraging, where you’re showing the difference between the killer cells going after the tumors with those immune therapy.So that leads me to another question that came in. To what extent is the presence of immune cell infiltrates in the tumor biopsy of predictive value? Do they even check the tumor to see if those killer cells are activating? How do they know … Unless they actually see tumor shrinkage, that it’s starting to work, that you should continue on this therapy. How do they know that?

Dr. Peter O’Donnell: Yeah, right. So in most cases, we don’t do a follow-up biopsy. It’s not that we start the immune therapy and then we do a biopsy and try to see if those immune cells have infiltrated. The slides that I showed you there have been from research experiments where this has been looked at to show that it actually correlates, that the infiltration of these immune-fighting cells is actually correlated with the patients who do better.

But in a regular practice, that’s a lot to put on a patient to say we’re going to do a biopsy just to see if those immune cells have infiltrated. Usually you can tell, like you said, Stephanie, by doing that scan. If the scan shows that the cancer is shrinking, now we know that probably those immune cells are getting in there. One thing that we’re thinking about for the future, though, is what we do if a patient doesn’t seem to be responding to the immunotherapy? It probably tells us those immune cells aren’t getting in there. Is there a way to try to do something else to those immune cells and really kick those immune cells, those killer cells to get in there?

That’s where the field is probably moving, the idea of these double immune therapies, where maybe in a given patient, for whatever reason, they’re not responding to one immunotherapy, but that second one might help those cells to get in there. We’re learning about that. We’re also learning that there’s actually different types of bladder cancer, that patients probably are familiar with that, and that there are now tests where we can categorize a patient’s tumor into ones that are likely to have the immune cells that it’ll infiltrate, that might already have been immune cells that are sitting in there and they just need to be turned on, or cancers that don’t have any immune cells. We call them immune deserts. For whatever reason, that cancer just cannot find immune cells in it. And so, those are tests that your doctor could do nowadays, although they’re not done in routine clinical practice.

Stephanie Chisolm: Okay. You mentioned, Dr. O’Donnell, that BCG that was given to patients with non-muscle invasive disease, who didn’t respond to the BCG could possibly get pembrolizmab. Is that something that’s given intravesically like BCG and do you have to be in a clinical trial, or is that something that you can just get off-label perhaps?

Dr. Peter O’Donnell: This is on-label. This is an FDA-approved indication for pembrolizmab, the Keytruda drug, now, as of the past couple of years now. So it’s more recent, and I’m actually seeing that not a lot of the patients are aware, but even doctors are still slowly recognizing that this is an option.

So it’s exactly what you said, Stephanie. The patient that whether cancer hasn’t yet invaded into the muscle layer of the bladder, they’ve been through BCG, and technically those patients also have that CIS component, that carcinoma in situ, feature of their bladder cancer, those patients are eligible to get pembrolizmab on-label as a way to try to prevent further deep progression of that bladder cancer.

In my own practice, I’ve used it rarely. It’s just we’re having trouble finding a lot of patients that fit that very specific label indication right now for pembrolizmab. But a lot of us wonder if we’re going to start using immune therapies earlier and earlier in the disease course. That’s one example. Why wait until you get metastatic disease to use bladder cancer immunotherapy? Could we use it earlier? Could we use it around the time of your bladder being removed or, in this case, as you’re saying, even earlier before it’s invaded the muscle?

Stephanie Chisolm: Right. So now, as a medical oncologist, you’re used to using chemotherapy. So if a patient benefits from chemotherapy, is the recommendation moving towards all patients going to some kind of maintenance with bladder cancer immunotherapy? Is that where we’re really heading, just make sure once we get it knocked down that it stays down? Is that what we’re looking at?

Dr. Peter O’Donnell: Yes, that’s become the new standard where I think almost all patients are really offered that now, this idea of maintenance. I mean in Mr. Kunz’s case, we’re doing exactly that. We’re doing a maintenance bladder cancer immunotherapy approach where we’re going to probably do this indefinitely. If it’s not broke, why fix it, that kind of idea.

Stephanie Chisolm: Right. If, for whatever reason, then, if bladder cancer immunotherapy no longer is effective, if it’s not getting that response, then you’ve got the targeted therapies as yet another option. So there are still arrows in the quiver, but you don’t necessarily focus just on the immunotherapy because there are still other options. So, for instance, in Lynn’s case, if her cancer were to come back and she didn’t respond to immunotherapy the next time, there would be other options.

Dr. Peter O’Donnell:  Yeah. What you’re just asking about, Stephanie, I see that in the chat, that someone’s asking about that, this idea of waiting for the cancer to return. We’re moving away from that in bladder cancer now, just over the past year, this idea of going straight from chemo and going to that maintenance immunotherapy.

Stephanie Chisolm: Kind of like with your car. You don’t necessarily wait for it to breakdown before you get it fixed. You do routine maintenance to just make sure it keeps running smoothly, I guess, in that case.

Lynn, this is a question for you. There is a question, do you still have your bladder and were there tumors that were high-grade tumors? Somebody is receiving BCG and they’re in an 18-month trial. They want to know do you think bladder cancer immunotherapy is something they should consider? So, Lynn, if you’d talk a little bit about your experience and then Dr. O’Donnell, as the expert, could weigh in on that.

Ms. Lynn Sperling: I still have my bladder. I originally had some surgery to remove the cancerous growth in my bladder, and it had escaped to the lymph system. That’s why they were treating me with chemo, and that’s how I got referred to Dr. O’Donnell. But, yes, I do still have my bladder.

Stephanie Chisolm: Well, does immunotherapy have an effect on tumor still in the bladder?

Dr. Peter O’Donnell: I mean that’s what I was talking about before where we’re seeing immunotherapies have an effect on even tumors that haven’t innervated the muscle. We’re wondering whether immunotherapies will have an effect on tumors that are muscle-invasive. I think one of the questions is around that. If you have a muscle-invasive tumor, is there a role for immunotherapy there?

That’s still under exploration, but there’s been a couple of trials now published that show that even patients with tumor invading the muscle might have very nice responses to bladder cancer immunotherapy. Not everybody, but some portion of the patients are having a response to that bladder cancer immunotherapy.

And so, the idea is that maybe we can use bladder cancer immunotherapy either before we take that patient to bladder surgery to shrink down the tumor and try to eradicate any microscopic cells that have escaped, or one study that just came out this year, which was really exciting to all of us in the bladder community, is for a patient that’s gone through bladder surgery and yet they have high-risk features, that that bladder had tumor that was maybe farther invaded than we hoped, those kind of patients are at high risk for that cancer coming back because the cancer cells had an ability to perhaps spread where the surgeon can’t even see that they’ve escaped beyond the surgical field. Those patients now might be candidates in the near future for using immunotherapy as a preventative to prevent the cancer from coming back.

So it goes to that whole topic we were talking about, preventative maintenance or maintenance bladder cancer immunotherapy. If your cancer’s already spread and you’ve been through chemo, we’ll now do a maintenance immunotherapy. In the near future, I believe we might be thinking about immunotherapy post-surgery to prevent the cancer from coming back. It’s still unproven, though.

Stephanie Chisolm: I know that you’re involved in many research trials. Do you see that there might be something five or 10 years down the road where perhaps bladder cancer immunotherapy would be used as a first line in muscle-invasive disease in lieu of getting your bladder removed? Do you think that that’s something that we’re just trying to understand if that’s a benefit? Where are we going in that direction?

Dr. Peter O’Donnell: Maybe. I want to be careful answering that one because patients need to be clear that if your cancer has invaded into the muscle, the gold standard, the standard of care, is that that bladder needs to be removed to save your life. And so, we really get into dangerous ground thinking about trying to spare the bladder there in those patients, because I’ve seen too many times where patients delayed having their bladder removed and they die of bladder cancer.

So maybe. Maybe we’ll be using bladder cancer immunotherapy along with bladder removal. I know that there’s one question in the Q&A about combining this with radiation treatments. Some patients who opt to try to keep their bladder will use radiation treatment, treating the bladder cancer in its place without removal of the bladder. That is an option in some patients even for when it’s invaded into the muscle. And so, there’s actually studies going on now to say can we combine immunotherapy with radiation to have even better outcomes for saving the bladder in place?

Stephanie Chisolm: Right. What you were mentioning before was a little bit more like neoadjuvant chemotherapy. I always use the analogy that’s like putting the evil genie back in the bottle before you take the bottle and throw it away. It’s what happens with removing your bladder. You want to make sure everything gets into that bottle and then you take it out.

I think it’s really relevant because a small portion of our patient community has what’s known upper tract disease, where their cancer is not necessarily directly in their bladder, but perhaps up in the ureters or even in the renal pelvis of their kidneys. Is immunotherapy being used in that case at all? Have you seen any benefit for those patients?

Dr. Peter O’Donnell: It’s being studied there. Although patients who have upper tract urothelial cancer, the type of cancer is actually the same. Urothelial cancer, it can start anywhere along the urinary tract. I saw one question asking about urethral tumors. That’s the very end of the urinary tract. That can be urothelial cancer. The bladder, of course, is urothelial cancer. Then the ureter, which is the tube connecting the bladder up to the kidney, that’s urothelial cancer. Even the first portion of the kidney itself, what we call the renal pelvis, is actually urinary cells. And so, anywhere along that whole tract is where urothelial cancers can form.

And so, we end up treating the urothelial cancer wherever it forms along that tract in a very similar way. If it spreads, if it metastasizes from an upper tract urothelial cancer, immunotherapy certainly have a role.

The last thing I’ll say about upper tract cancers is that we’re learning that they do have some differences from bladder cancer, and that is much more likely that a patient might have a genetic syndrome that predisposed them to getting an upper tract cancer. Lynch syndrome, for example, is a genetic syndrome that maybe some people have heard of. It’s commonly known to cause colon cancers and endometrial cancers, but it’s now more recently been shown to be associated with urothelial cancers of the upper tract. So your doctor should be thinking about whether maybe you have Lynch syndrome if you develop an upper tract urothelial cancer.

The other genetic aspect that we definitely realize nowadays is that you’re much more likely to have one of these mutations in a specific gene we call FGFR, which has a targeted drug that’s now FDA-approved. We didn’t get to talk too much about targeted therapies. But if you have an upper tract urothelial cancer, your doctor should be thinking about these genetic aspects.

Stephanie Chisolm: Okay. A good question that’s in here relating to starting chemotherapy. It’s necessarily related to immunotherapy. How long do you go on chemotherapy before you say, “I give up on this. It’s not really working for you. Let’s go to immunotherapy”?

Dr. Peter O’Donnell: I feel like I’m talking so much. Miss Sperling, do you remember how we made that decision with you? I’m putting you on the spot a little.

Ms. Lynn Sperling: Six rounds. That’s when the oncologist said I had some choice to make. And so, it was three weeks on, one week off, and that there were six of those before they decided that I could talk to you about immunotherapy.

Stephanie Chisolm: Six months then? If there were three weeks on and a week off, or two weeks off, it’s like six months before you could really be considering or should be considering, because we still know that chemotherapy is still the gold standard. It’s still what’s recommended first. That’s the first line in many cases, right?

Dr. Peter O’Donnell: Right, for most patients. Miss Sperling is exactly right. Generally, the rule of thumb is that you don’t go beyond around six rounds of the chemo. After six rounds, the side effects really just accumulate. Very difficult for a patient to tolerate beyond six rounds. And we really don’t see a lot of bang for the buck after six rounds of chemo. The effect is usually completely gained at that point. I tell my patients, “We’re going to try to plan for somewhere between four and six rounds of the chemo. I’d like to get you through four, if we can, at a minimum. Then we’ll see how you’re feeling and we’ll play it by ear. After four, we’ll see how you feel, if we can go to number five. Then we’ll see if we can get to number six.” But if you have to stop, I tell my patients don’t feel bad if you have to stop after four rounds of chemo, and then we can switch to the immunotherapy maintenance like we talked about.

Stephanie Chisolm: Okay. So this is a very specific question, you may not have the answer, but how do you tell if symptoms are a side effect or possibly a cancer recurrence, such as genital ulcers that would be down in that area? How do you discern that that would be perhaps a side effect or is it a recurrence of your cancer?

Dr. Peter O’Donnell: Yeah, that’s a real tough one because I rely really on what was the presenting symptoms with that patient when they were found that they had cancer in the first place. I do get a little nervous if the patient now is starting to have a similar symptom as when their cancer was first found. That really sticks with me. I’ve had many patients that say, “You know what, doc? I’m developing a symptom that I … It was exactly like when my urologist first found the cancer.” That is something that I would pay attention to and probably think about re-scanning that patient to see what’s going on. Immune-related side effects like rash, they’re usually more generalized and not specific to just one area of the body.

Stephanie Chisolm: So, Dr. O’Donnell … And, Andrew, you’re still on the immunotherapy … is there an upper limit to how many years you should be on this treatment? Are there things you should watch out for longterm?

Mr. Andrew Kunz: I’m feeling fine. Each month before I go in, I have my blood tests and doc goes over it. They don’t mix the chemicals until he approves that I’m good for that treatment. So I don’t have a problem with it because I know that I’m being watched closely each month.

Dr. Peter O’Donnell: Yeah, I’ll say that there really isn’t an upper bound. Some of the trials have proposed stopping the immunotherapy after two years. It’s a bit arbitrary. There’s not a lot of evidence around that. Miss Sperling, I think in your case, it’s what we did. So there are some data that suggests you could stop after two years if you’ve had a really nice response. But in other cases, a lot of my patients I counseled that we’re going to do this indefinitely, as long as you’re not having side effects from it, because I’ve, unfortunately, had a number of patients where when we do stop, the cancer then starts coming back.

Ms. Lynn Sperling: I was just wanting to add that I actually had full knee replacement after I stopped the immunotherapy, and it went fine, with the doctor’s permission and everything. I had been putting it off and putting it off. But that went very well. So I now have two new knees.

Dr. Peter O’Donnell: Miss Sperling, I remember, in your case, one of the reasons that we ended up deciding to stop the immunotherapy was you did have some sort of chronic fatigue that we thought was related to the immunotherapy. I think that did get better after we stopped.

Ms. Lynn Sperling: A little bit.

Dr. Peter O’Donnell: So these are the kind of things we raise, Stephanie.

Stephanie Chisolm: So what others things should people be aware of if they’re going into their third year of immunotherapy? What are some of the things that maybe they should consider having checked? Is there something metabolic that they should be aware, something that they should be telling their doctor? Because they might not think to tell them about something that doesn’t seem like an immune response problem.

Dr. Peter O’Donnell: Yeah. I mean, of course, we’re checking blood work before every infusion. We still do that. No matter how many years you’ve been on it, we’re checking blood work to make sure there’s no inflammation of the liver, to make sure the kidney function is okay.

But actually, in general, if a patient is going to have one of these one out of 10 severe side effects from immunotherapy, it typically happens in the first six months. Not every time, but almost all the time. If you’re going to have one of these severe effects, it’s going to happen earlier on. I do not generally see patients that are three years out getting out-of-the-blue new side effects from immunotherapy. It just doesn’t happen.

Stephanie Chisolm: That’s just good to know. Well, we’re coming towards the end of our program. I think you covered most of the other questions. There’s a question in here about is there a difference between the side effects or the effects of Keytruda and avelumab, and which one might have more side effects. But how do you as a clinician pick … Because you can prescribe all of the different approved treatments. How do you decide which one each patient should go on?

Dr. Peter O’Donnell: Yeah, it’s a really tough question and it gets a little bit technical on the answer. I will say that we think maybe some of these four immunotherapies have small differences in their side effect profile, whereas some patients might be less likely to get, for example, the lung reaction with certain of the drugs compared to others. But, in general, they probably are all about the same.

One that has stood out and probably gets the most common use is pembrolizmab, the Keytruda drug, because that drug has had a definitive trial in patients with metastatic disease that showed that it really elongated the survival for patients, where some of the other drugs haven’t shown that. The avelumab drug has shown that survival benefit as a maintenance, like we talked about.

So most of the time, if your doctor’s thinking about that maintenance strategy right after chemotherapy going into a maintenance immunotherapy, avelumab has the best evidence. For patients that have been through chemo and they adopted that wait and see and then the cancer came back, pembrolizmab has the best evidence.

I think oncologists always want to use the drug that has the best evidence around it for a given treatment setting. So that’s probably how we end up picking.

Stephanie Chisolm: Yeah. I think this has been an incredibly useful program. I’d like to thank you, Lynn and Andrew, for sharing your stories and your experiences. Dr. O’Donnell, as always, you’re amazing. We appreciate your sharing all this information.