Transcript of How Avelumab Can Help Patients With Locally Advanced or Metastatic Bladder Cancer With Dr. Tom Powles

August 15, 2023

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Voice over:

This is Bladder Cancer Matters, the podcast for bladder cancer patients, caregivers, advocates, and medical and research professionals. It’s brought to you by the Bladder Cancer Advocacy Network, otherwise known as BCAN. BCAN works to increase public awareness about bladder cancer, advances bladder cancer research, and provides educational and support services for bladder cancer patients and their loved ones. To learn more, please visit bcan.org.

Rick Bangs:

Hi, I’m Rick Bangs, the host of Bladder Cancer Matters, a podcast for, by, and about the bladder cancer community. I’m also a survivor of muscle invasive bladder cancer, the proud owner of a 2006 model year neobladder, and a patient advocate supporting cancer research at the Bladder Cancer Advocacy Network, or as many call it, BCAN, producers of this podcast. I’m pleased to welcome today’s guest, Dr. Tom Powles. Dr. Powles is director of Bart’s Cancer Center at St. Bartholomew Hospital in London and trained at Imperial College. He is a professor of urology cancer with a focus on drug development. Dr. Powles has written over 300 research papers and leads the European treatment guidelines, the European Society for Medical Oncology, or ESMO, guidelines for bladder and kidney cancer. Research he has led has resulted in the approval of four cancer therapies. Dr. Powles, thank you for joining our podcast and thank you for your work on the four cancer therapies.

Professor Tom Powles:

Thank you for your sweet introduction. I think bits of it were accurate, which is always good.

Rick Bangs:

We strive for that here.

Professor Tom Powles:

I won’t tell too many more jokes. I apologize. How are you Rick, are you well?

Rick Bangs:

I’m well. I’m well and I’m excited. I’m excited because we’re going to talk about a trial that I think is very interesting to our listeners. And so you recently presented results on this clinical trial. It was called JAVELIN 100, and it was about immunotherapy, which is obviously a hot topic in bladder cancer, and a specific drug that’s called avelumab. So I think we should start by talking about the relevant population. Who are these patients and what were their treatment options before the avelumab JAVELIN 100 trial?

Professor Tom Powles:

Thanks, Rick. So these are urothelial cancer patients. They’re patients who have a urothelial cancer of the bladder or the upper tracts as the origin of the disease. But these patients are not curable with surgery alone. These patients are described as having advanced disease and that means either metastatic disease, which is by far the most common part of the population, lung metastasis, lymph node metastasis, bone metastasis, liver metastasis, that advances this picture, or secondly, there’s a group of T4b, locally advanced disease, that means it’s kind of not operable. So it’s gone essentially through the bladder wall and gone into surrounding structures and surgery’s not possible. So we’ve got advanced urothelial cancer. That’s the first and most important part. That covers the histology and the anatomy of the disease, and to some extent the curability of the disease.

There’s a second really important part to this is the patients need to be fit and well, obviously, so they have to have a performance status of zero or one. And what that really means is they’re able to walk around and perform normal day to day functions because they’ve got to be fit enough for systemic therapy, for immune therapy. And then the third and final really important inclusion criteria, which is slightly different from some other trials, is these patients need to have completed four to six cycles of chemotherapy. Chemotherapy is the standard of care for this treatment with either gem-cis, gemcitabine cisplatin or gem-carbo, gemcitabine carboplatin. And those patients need to have had four to six cycles of that and their cancer needs to be under control. So the cancer can’t be growing on chemotherapy. And the reason why I excluded those patients whose cancer was growing on chemotherapy is two reasons. Number one is the trial has got a best supportive care onto it, no active therapy onto it, and that would be unethical in patients whose cancer was growing.

But number two is, the important thing about the trial, the hypothesis behind using immune therapy sequenced directly after chemotherapy, is that we feel that immune therapy is active in subgroups of patients with urothelial cancer. But we feel that for many patients, particularly in the first line setting, the cancer’s growing too fast for immune therapy to work. So you’d get control of the cancer, and the way you do that is by giving chemotherapy, and once the cancer’s under control you’ve then bought a series of months for the immune therapy to work. But if you just give first line immune therapy in cancer that’s growing, in many patients you just lose control. So I talk about sort of this patient population as the optimal place, in my opinion, to explore single agent immune therapy in urothelial cancer.

Rick Bangs:

So I didn’t hear you mention MVAC, but you did mention gemcitabine cisplatin or gem-cis. So would patients who’ve had MVAC be included?

Professor Tom Powles:

They weren’t included in the trial. And the reason why that was the case is we wanted to keep the population as homogeneous as possible. It’s important for a clinical study not to give too much variability. And the timing of the cycles of MVAC, dose 10 MVAC is given more intensely over a shorter period of time and we just felt it would confuse the issue a bit. But the reality is that MVAC is essentially cisplatin based chemotherapy. It works along very similar principles to normal gem-cis chemotherapy. It’s not been shown to be a lot better than gem-cis chemotherapy. And I’m happy to have that debate, but I think there are more similarities than differences between gem-cis and MVAC and I’m not super keen to try and spend too much time trying to divide that two populations.

Rick Bangs:

Okay, that makes sense. All right, and then you use the term best supportive care. So what does that mean from a patient perspective? What am I seeing? What am I getting?

Professor Tom Powles:

So maybe it would be a good time to talk about the trial design because the design has, after the completion of chemotherapy, the standard of care prior to this trial was to stop the chemotherapy, and between four and six cycles of chemotherapy was the standard and that’s what we did. And then you do CT scans every two or three months. I think most people do them every three months. We did it a bit more frequently than that. And sadly we just wait for the cancer to come back, and when it does come back we would then give second line immune therapy or more chemotherapy. I mean, these days you might want to give an antibody drug conjugate as well, but I think that’s a more complicated discussion.

Essentially, I think what your listeners need to know is at the time the trial was designed, first line chemotherapy, when it’s complete a CT scan providing the cancer’s not growing, watch things, and then the median time to progression for the cancer to come back it’s only about three or four months, and that’s the disappointment there. And so our intervention to give immune therapy was to delay the time for the cancer to come back, but more importantly improve the overall survival of these patients.

Rick Bangs:

All right, and now this drug avelumab, what’s its history? Is it used in other cancers? Started in other cancers?

Professor Tom Powles:

Yeah, it started in Merkel cell cancer which is a rarer cancer, not widely talked about because it’s a relatively rare cancer. It was then developed in kidney cancer, more famous of course, and got a license in kidney cancer. It was explored in a broad spectrum of cancers. It’s essentially a PD-L1 inhibitor. I mean, I think for the listeners, I would look at it as a drug which has more similarities to atezolizumab which is also a PD-L1 inhibitor, than nivolumab or pembrolizumab, both of which are PD-1 inhibitors. And I think there are subtle differences maybe between the drugs within the classes, but I think there are major differences between PD-1 and PD-L1 inhibitors.

And that’s because of where PD-1 and PD-L1 is expressed. One’s expressed on T-cells, PD-1, the other on antigen-presenting cells on tumor cells, PD-L1. And essentially PD-L1 inhibition spares PD-L2 binding, I won’t get into too much detail around that, but I think it’s important for listeners to recognize that all of these drugs are not identical and I think differentiating between PD-1 and PD-L1 inhibition is entirely reasonable. And this is a PD-L1 inhibitor.

Rick Bangs:

Okay, all right. So you talked a little bit about design. Let’s talk about the questions that you hope to answer about avelumab in this particular trial, the JAVELIN 100 trial.

Professor Tom Powles:

Yeah, so what we did is at the completion of chemotherapy, once the patients had had four to six cycles and their cancers were not growing and they hadn’t got any of the other exclusion criteria, so there were no exclusions, no active immune type diseases or infections, those patients who had completed the chemotherapy, their cancer wasn’t growing and they were still fit and well, we randomized 700 patients in a one-to-one manner to either receive two weekly avelumab after the completion of this chemotherapy or best supportive care where we would keep an eye on them on a regular basis and do regular CT scans. The CT scans were done at identical time points in the two arms of the trial. As you would expect, patients were having regular follow-up appointments to make sure they were okay. We were making sure the drug was safe, the drug had already been approved, as I said before, in kidney cancer and in Merkel cell cancer so we knew the drug was pretty safe already.

The primary research question we were asking was could we show that there was a progression-free survival… sorry, an overall survival benefit. So did patients live longer in that group of patients, those 700 patients? And the way we do that is we use the Kaplan-Meier method and we get estimation at specific time points at the reduced risk of death associated with the intervention. And the primary endpoint of this trial in the initial analysis showed a 31% reduction in the risk of death associated with avelumab compared to best supportive care. That was true across broad subgroups of patients, so that was true irrespective of whether you had gem-cis or gem-carbo. It was true about whether you were PD-L1 biomarker positive or negative. It was true whether you had lymph node disease or visceral metastasis. It was true whether the cancer originated from the bladder or the upper tracts.

So essentially we hit that primary of overall survival endpoint across broad subgroups of patients. We also looked at, as I said, the PD-L1 biomarker and we also looked at progression-free survival, the time to delay the cancer to grow. The median overall survival was 21 months in the study arm. The progression-free survival was shorter at about five months, so it could keep the cancer under control for about five months. Progression-free survival actually though is really short. The best supportive care, progression-free survival, is essentially the time for the first scan to occur at about two months. So the immune therapy had a big shift on overall survival. Now people ask me two things about this. Number one is, what would happen if you just waited till the cancer comes back and give immune therapy then? I think it’s important to recognize that if the cancer did come back in the control arm, the vast majority of patients, about 75% of patients, got subsequent chemotherapy or immune therapy, and over 50% of patients got subsequent immune therapy.

So many patients got that subsequent therapy. Some people come to me and say, “Well, why didn’t everyone get second line therapy in the best supportive care arm? How come it’s only 75%? Surely it should be 100%.” But the tragedy of urothelial cancer is, as I said before, the progression-free survival was sure only at a couple of months and we know in some patients you never get back in control of the disease. And that’s why the maintenance approach is important because you’re able to sequence the immune therapy while the patient is still well and their cancers aren’t growing. As soon as bladder cancer grows, you’re getting problems, bone metastasis with hypercalcemia, locally advanced disease with renal failure, liver metastasis, abnormal liver function tests and cachexia, weakness, tiredness. So this really is the best opportunity to give the drugs.

Rick Bangs:

Yeah, because once it gets some momentum it’s hard to derail it. So talk to me about side effects for this drug called avelumab. What are the side effects and can they be mitigated?

Professor Tom Powles:

The answer to the question is that chemotherapy for the vast majority of patients is associated with some side effects. Most patients get nausea, vomiting, tiredness, many of them get neutropenia. People feel pretty unwell on chemotherapy. And the reason we have to give chemotherapy in cycles is because you can’t give it essentially forever all the time because patients just feel pretty unwell. Immune therapy is very different from that. Immune therapy essentially stays in your body. It has a long half-life and it’s always kind of, while you’re giving it, it’s pretty much there. It’s not actually having a direct effect. Its predominant effect is not directly on the cancer cells. Its predominant effect is around reeducating the immune system then subsequently fighting the cancer and attracting immune cells. There are some caveats to that. There is some ADCC activity. I don’t want to get into too much detail about the immune biology of this, but there are potentially, with avelumab, some direct anti-immune effects associated with the antibody attaching to the cancer.

But the reality is it’s reeducating your immune system. Now the process of that reeducation of the immune system is inevitably going to have some side effects, because at any time there’s a careful balance between immune accelerators and immune inhibitors. What many people don’t recognize is that when we get an infection and we get loads of white cells and they collect in a wound or whatever it might be, that process is incredibly complicated and has multiple steps associated with it. And when the infection gets better, the white cells don’t just disappear by themselves. The process is reversed actively by the immune system. On top of that, you’ll be aware of autoimmune type diseases, and we all have the ability to recognize self. And actually what we have to do in our immune system is at all times have immune accelerators and immune inhibitors working in balance to make sure the accelerators aren’t attacking self tissue, and indeed autoimmune disease is recognized as an imbalance between the immune accelerators and inhibitors.

What immune checkpoint inhibitors do is, while they may have some direct effect on the cancer, the vast majority of their effect is about realigning that balance and getting the immune cells within the cancer to attack the cancer. And so inevitably that rebalance will mean that there’ll be more immune activation in the body and therefore established autoimmune diseases, skin rash, sore joints for example, the commonest two, are really quite common side effects of immune therapy. But, there are more complicated side effects. It can cause diarrhea. It can cause inflammation of the liver and the kidneys. It can cause shortness of breath by causing immune infiltration into the lung. It can cause very rarely cardiac damage, immune-related cardiac damage, and indeed immune-related brain and nerve issues. It commonly causes hypothyroidism and it can also cause adrenal problems and other endocrine problems such as pituitary problems.

Now that all sounds really scary, but actually in terms of very severe immune related side effects, it’s almost certainly less than 5%. About 10% of patients get into trouble with immune-related side effects, and if you give those 10% of patients steroids you can reverse those immune-related side effects actually quite easily. So that’s important. And then it’s also important to recognize that probably 70% of patients get actually very few side effects, maybe a bit of a skin rash, maybe some tiredness, maybe some temperatures, perhaps a sore joint here or there. But unlike chemotherapy, the vast majority of patients are actually navigating this journey relatively easily.

Rick Bangs:

So it’s all about striking a balance like Goldilocks and the three bears where you want things just right and then you can throw the steroid in if it gets a little bit out of control.

Professor Tom Powles:

Yeah, but we give flat dosing of the drug so once it’s in, it’s in. As well it has quite a long half-life so it’s important to recognize that we don’t dose the drug, it’s a flat dose, we don’t adjust the dosing, and once you’ve had it, if you don’t give steroids, you say, “Oh, don’t worry, we’ll just wait for the cancer treatment to work its way out,” because that’s what we do with chemotherapy after all, if you do that you’re going to get into trouble quite quickly. So you have to use steroids to reverse the process. And sometimes steroids don’t work in about 1% or maybe 2% of patients and we end up giving stronger drugs, stronger anti-inflammatory drugs like infliximab, which kind of reverses that process more aggressively. I’ve got to tell you, we’re in a position, I think, from a global perspective, where we’re managing immune related toxicity better now than we were five years ago.

Rick Bangs:

That’s important. That’s really important. So talking about side effects, that was one of the analyses that was done as part of your trial. And I think it’s important for patients to understand the things that as a researcher you’re considering when you look at results. It’s not just about how long people live, because things are multidimensional, right? I want quantity of life and quality of life and I want some balance. So there was something that was done here that is called Q-TWiST and I want you to talk a little bit about what that does because I really love the thing that it adds to the usual suspect, so overall survival and progression-free survival. I like the twist that it adds here. So could you talk about Q-TWiST?

Professor Tom Powles:

Certainly. So before I get there, I’m going to talk about quality of life too, if I may.

Rick Bangs:

Yeah.

Professor Tom Powles:

So I think that the way we assess toxicity right now in crude terms is looking at grade one to five adverse events. And essentially we look at grade one and two as being relatively mild, grade three and four being more significant side effects, and then grade five is something we’re desperate to avoid, which is treatment-related death. And we had very few of these on this trial. So that grading system’s pretty crude. You can have grade three nausea, and that’s nausea more than eight times a day. You can have grade one nausea, that’s nausea once a day. You could have grade three rash, which is three quarters of the body, where a grade one rash is just a small amount of the body. So we have a grading system for adverse events and that’s important for Q-TWiST because I’m going to come to that in a second. So keep that in the back of your mind.

We then also explore quality of life, and with quality of life we ask patients essentially somewhere in the region of 20 questions and they’re relatively common. Is this drug affecting the quality of your life? And you score zero to five. Zero, not at all. Five terribly, badly. And the second question might be is it making your sleeping pattern worse? And again, you measure zero to five. And number three is, is your pain worse? And you can imagine you come up with 20 questions along those lines. In this analysis that we did, drugs tend to be associated with a drop in the quality of life by about five to 10%, and it depends on obviously how toxic the drugs are. Some of the chemotherapy drugs are associated with a much bigger drop in quality of life.

And in fact we’re doing a study called DISCUS which is comparing three cycles to six cycles of chemotherapy, and we are looking to see if three cycles are associated with better quality of life. That’s a discussion for a different day. But the principle of quality of life is that we can measure toxicity using CTC grade one to five, but we could also get a pattern of quality of life. The problem with quality of life is that some of these questions appear to be less relevant and so we sometimes ask questions like hematuria. Now hematuria, that’s blood in the urine, that’s obviously not relevant for most of patients with advanced bladder cancers because many of them have had their bladders removed and so they’re not going to get hematuria. So there are shortcomings in quality of life. Now for what it’s worth, the quality of life data in the JAVELIN trial shows no significant difference between the two arms.

But that, as I said before, doesn’t mean it’s not associated with enough adverse events to require steroids in 10% of people. So the question is, is there other tools that we can look at to try and estimate the effect on the patient? And that’s where Q-TWiST comes in. Essentially what we’ve done with Q-TWiST is look at this in a slightly different way. The principle of Q-TWiST is to look at patients and their time without progression of disease or toxicity. And we’ve defined toxicity as having grade three or four adverse events. Now we know from the way the patient’s data is collected, we know how long these adverse events are there for, we know which grade they have. And so therefore, patients we think who have good quality of life, have the absence of progression of disease and do not have grade three or more toxicity. We can calculate the area under the curve, the time when patients are in that category, no progression, no significant toxicity, and we can compare that time period, that area, in the two groups.

And that’s the best supportive care group in the avelumab group. Now we know the progression-free survival is 50% longer, so the area at the beginning, it’s going to be twice as big with the avelumab arm. We know that because the hazard ratio is 0.5, which means the doubling in progression-free survival. But how much of that 50%, that doubling, is associated with significant toxicity? And it only comes to about 15%. So essentially the Q-TWiST analysis, the time without progression or toxicity, is significantly longer than the avelumab arm compared to the best supportive care arm. Now there is also something called Q-TWiST analysis, and Q-TWiST is a bit more complicated because again, because what that does is that it says how much… Because you can assume that that time with toxicity shouldn’t be considered as, we use the term dead time… and we probably could come up with a better term… but what I mean by that is time that’s valueless.

Because even time with toxicity, we think, is better than having no time at all. Some people might disagree with us on that. And so therefore we put a coefficient, that’s the Q, a coefficient into there to say, well, we’ll multiply it by 0.7 so your quality of life is only 30% compared to 100% percent if you’re having grade three or four toxicity. That increases that area further. That Q, that adjustment, is open to criticism because you might say how did you come up with that coefficient? So Q-TWiST analysis, area under the curve, progression-free without significant toxicity, and there is a significant increase in that associated with avelumab. Q-TWiST, the coefficient, complicates things a bit, essentially shows the same result.

Rick Bangs:

I just love this concept because it makes it clear that the researchers are considering it in a more dynamic way. So I think this is outstanding. So talk to me a little bit about the role that wearables could play relative to what you just talked about. So in the future, what might wearables be able to provide?

Professor Tom Powles:

Well, firstly, I’m really pleased you liked Q because I was a bit… I’m not skeptical about it, but there there’s always going to be criticism about it wasn’t our primary endpoint of our trial and it was an exploratory endpoint. And we’ve done lots of different analysis in the JAVELIN trial. We’ve looked at a huge biomarker piece, which was exploratory as well, and we showed that both innate and adaptive immunity were associated with response. We showed tumor mutational burden was important, and a number of the Pfizer folks have done fantastic biomarker work in that. We did other exploratory analysis to work out if there was a difference between whether you had four or six cycles of therapy, whether or not the benefits was isolated to one group, and it shows it’s beneficially respective of how many previous cycles you had. And we did further exploratory analysis looking at the time to start and you needed, in the study, to start within 10 weeks of completion of chemotherapy. Do you have to start within two weeks or… and it doesn’t seem to make any difference.

And so part of me felt that doing this Q-TWiST analysis, it was just another analysis, but actually I’m really pleased that patients feel that’s a patient focused type approach and you are interested in that. I mean, I’m inclined to agree with you, but I always get anxious when we do multiple analysis from the same study. I think it’s helpful too, but maybe we should do it in more trials. Maybe we don’t do it enough. You’ve asked specifically about wearable devices and I think wearable devices have an important role to play in the future. The reason why I think that’s the case is that what I’ve said to you today is I’ve talked about collection of adverse events and what happens is the patient says to the doctor, “I’ve had nausea,” the doctor writes down, “He’s had nausea.” The doctor then grades it and then the data manager people assess it and then the process goes round in circles a little bit with monitoring and adjustments. And so an event that took place three or four weeks ago from a patient might be translated incorrectly or inaccurately.

Rick Bangs:

Exactly.

Professor Tom Powles:

Whereas actually, we might be in a position where if a patient’s wearing a watch and we can just see that their activities had a huge drop or indeed we can see they’re doing less steps or their sleeping patterns have become disturbed or their heart rate’s gone a bit erratic or their exercise tolerance has gone down, these wearable devices that actually lots of patients now are using, it’s astounding what they’re wandering around with, there may be a whole load of information on that that can end up being much more useful. And that is the principle of what we’re trying to do in a study called DISCUS. One of our PhD students, Frankie Jackson-Spence, is leading that thrust with Enrique Grande from Spain and other people around the world, Yohann Loriot from Paris, and what we’re trying to do there is trying to collect in two arms patients on chemotherapy or immune therapy to see if there is a big difference in their activity.

And that’s something which we are excited about. I think in the end we’ll be able to observe people’s step count, their sleeping patterns, their heart rate, and work out more accurately what impact treatment is having on them and work out about recovery from treatment, because we know chemotherapy puts many patients to bed because of lethargy and we know that if we can maximize that that will give us perhaps a better surrogate quality of life than asking patients whether or not they’ve got hematuria and scoring it from zero to five.

Rick Bangs:

Yeah, I just love the possibilities here. You’re getting real time data. You’re not reliant on waiting to get to the doctor, to remember something that happened and the severity of it at the time, and it also can be proactive, right? I mean things may be happening that the doctor should know about and you can see it happening in real time. So I think there’s lots of exciting possibilities here. So who funded the JAVELIN 100 trial?

Professor Tom Powles:

So this trial is company sponsored, it’s sponsored by Pfizer, which is obviously a big drug company. They did that in collaboration with Merck Serono, they developed avelumab together. So I would see it as a Merck Serono-Pfizer study and I think it’s important to acknowledge that I have a number of conflicts of interest with them. I’ve been broadcasting this to many people, obviously having had the trial, and they also give me research funding for the DICUS study so I’ve got a number of conflicts of interest associated with that.

Rick Bangs:

Okay. All right, so standard of care, and most of our listeners are probably in the US, so standard of care would change at some point, hopefully sooner rather than later. So what’s your forecast on how that might work? Because I think our listeners would be interested.

Professor Tom Powles:

The current standard of care in the US is actually, I think, is relatively straightforward. So for advanced urothelial cancer, the current standard of care is four to six cycles of platinum-based chemotherapy followed by maintenance avelumab. For those patients whose cancers progress on chemotherapy, heaven forbid, those patients can switch to second line pembrolizumab, which I think is also a standard of care there. Atezolizumab is an alternative PD-L1 inhibitor, which I actually don’t have a huge amount of difference between that and pembrolizumab in urothelial cancer in my opinion. For those patients who progress after maintenance chemotherapy and maintenance of avelumab as the standard, or chemotherapy followed by pembrolizumab for those that progress, although most patients with rapid progression disease never get to third line, the standard of care is the antibody drug conjugate enfortumab vedotin in unselected patients. For patients with FGFR DNA alterations, the recent THOR study showed us that erdafitinib looks active as well.

And the hazard ratios of it… you can’t compare the two studies, they’re different populations… but the hazard ratios for the two trials are very similar and the response rates are very similar to each other. So for those patients without FGFR alterations, enfortumab vedotin is the standard of care for those patients, either erdafitinib or enfortumab vedotin are the standard of care, and those two drugs could potentially be sequenced and I don’t feel strongly about which drug you give first. There are other agents in the pipeline, FDA approved, such as sacituzumab govitecan, and I’d see that as a fourth or a fifth line therapy. It’s another antibody drug conjugate that’s changing the disease. That’s currently where we are. So the treatment pathway in urothelial cancer as it currently stands is pretty simple. Frontline chemotherapy, maintenance avelumab, enfortumab vedotin, unless you have an FGFR mutation in which case it’s erdafitinib or enfortumab vedotin.

Rick Bangs:

Okay, and I know in clinical trials sometimes there’s related work that’s done as part of the trial. So is there anything there that our audience might want to hear about?

Professor Tom Powles:

Look, I mean I think that the Pfizer folks have done some really nice translational research, and the current translational research that’s ongoing is looking at chromatin loops. If I can talk about chromatin for 20 seconds, that’d be great. It’s a concept which hasn’t been explored too widely in urothelial cancer or indeed with immunotherapy. Essentially the way DNA… it’s a really long piece of string and it’s packed up into tiny balls, and those balls that pack it up are chromatin, and it makes it really, really tight in cells, which is terrific and brilliantly designed of course, like everything in our body. And to get expression of proteins, you require these areas, these strands of DNA to come outside these chromatin balls… Like you know those sun spots in the sun that come out, these thrusts of plumes of fire… that’s essentially a loop of DNA coming out.

And essentially what happens from there is that’s the way we make protein. That’s an important part of the protein. And that structure is controlled, it’s called epigenetically controlled, and essentially what we’re doing at the moment is we’re looking at circulating biomarkers in the blood and we are looking at the control of this chromatin. And what we are showing is that the way the body controls the chromatin appears to predict response and resistance to immune therapy. And what that’s telling us is this is not all about the tumor, response and resistance to immune therapy is not all about the tumor, it’s also about the host. We’ve known that for years though, because we know that patients with immune deficiencies are predisposed to getting cancer and we know that some immune treatments work less well and we know that steroids can temper down the immune response.

So it should come as no surprise that by altering the host immune function, which both cancers do, but of course the host can do itself, that immune phenotype by the host has a role to play in response and resistance to therapy. And I think it’s quite an exciting concept and I’m working with people with that at the moment and those people are doing an amazing job.

Rick Bangs:

Excellent. All right, we’ll look forward to hearing more about that. So any final thoughts as we wrap up?

Professor Tom Powles:

I wanted to thank you for asking me on today. I haven’t done this before with you guys. And Rick, you’ve been fabulous and thank you for putting up with me. I hope I haven’t gone on for too long a period of time. I’d love to do it again. I think, what I’d like to say, if I may, is that there are going to be three important changes in advanced urothelial cancer in the near future. We know that there’s a study called 901, which is chemotherapy plus nivolumab, which is a frontline trial, which is straight out positive. We don’t know the results of that study yet but that is potentially practice changing. When I said in the US the standard of care is chemotherapy followed by maintenance of nivolumab, I left out a really important, really important study, which is Cohort K, which is enfortumab vedotin plus pembrolizumab.

So for those patients that are not cisplatin eligible, those carboplatin patients, enfortumab vedotin plus pembrolizumab has got a response rate of 68% of progression-free survival at 12 months and OS in 24 months in a relatively modestly sized phase one and phase two randomized trial. And essentially what that is pointing us towards is the combination of an antibody drug conjugate in immune therapy looking really active together. It’s got an accelerated approval in the US, so now the pathway doesn’t have to be chemotherapy and avelumab, it can be enfortumab vedotin and pembrolizumab for those cisplatin ineligible patients. But we also know there is a big randomized trial around the corner, EV-302, which is EV-pembro versus chemotherapy in both the cisplatin and carboplatin population. And if that trial was positive it would change the way we treat this cancer moving forward. Now in the US you might say that’s already changed, but I think it’s a provisional change and requires the confirmation from this randomized phase three study.

So I can see potentially me being asked back in years time, I don’t know when the trial gets out, but being asked back in the not too distant future, I hope, to talk about another big change in urothelial cancer. And the last thing I wanted to talk about with circulating tumor DNA, it’s possible from a blood test now to identify circulating cancer DNA which is being shed by the cancer. And this has an important role to play because it defines minimal residual disease, molecular residual disease. It defines disease that we can’t yet see on a CT scan. We’ve oversimplified urothelial cancer by saying there’s no cancer unless you can see it on an X-ray. And I think people will look back in the future at that as being extremely crude, because by the time you can see a lump of cancer on an x-ray there are probably a billion cells there and it’s too late for many patients.

And so circulating tumor DNA allows us to identify cancers much earlier, treat patients more quickly, and at that time it’s likely that their immune system is more intact. My feeling is that as cancers grow they have to paralyze the immune system a little bit to grow, whereas these earlier cancers may be struggling more with that. And it might be that our immune therapies will work better in this MRD, molecularly residual disease setting, and we may get better control of patients. And so it’s really exciting because we may actually be treating patients on blood tests and not CT scans.

Rick Bangs:

Wow. Oh, the possibilities here are really exciting, and I know just the one mention you made about people who are not cisplatin eligible, that alone was exciting. But all this together, this is really tremendous. So I’m hoping that you’ll need to come back very, very soon because this is really exciting work. So Dr. Powles, I want to thank you for giving us the latest on the use of the immunotherapy drug avelumab in patients with advanced bladder cancer who are not progressing after treatment with platinum chemotherapy.

Professor Tom Powles:

Thanks for inviting me, Rick.

Rick Bangs:

If you’d like more information on bladder cancer, please visit the BCAN website, www.bcan.org. In case people wanted to get in touch with you, could you share your Twitter handle or other information that you would like to share?

Professor Tom Powles:

I’m @TomPowles1.

Rick Bangs:

@TomPowles1. Excellent. Just a reminder, if you’d more information about bladder cancer, you can contact the Bladder Cancer Advocacy Network at 1-888-901-2226. That’s all the time we have today. Be sure to like, comment and subscribe to this podcast so we have your feedback. Thank you for listening and we’ll be back soon with another interesting episode of Bladder Cancer Matters. Thanks again, Dr. Powles.

Professor Tom Powles:

Thank you. Bye-bye.

Voice over:

Thank you for listening to Bladder Cancer Matters, a podcast by the Bladder Cancer Advocacy Network or BCAN. BCAN works to increase public awareness about bladder cancer, advanced bladder cancer research, and provide educational and support services for bladder cancer patients. For more information about this podcast and additional information about bladder cancer, please visit bcan.org.