A Revolution in Bladder Cancer Treatment

Alicia: This is the Good News About Cancer. I’m Dr. Alicia Morgans. 

Chuck: And I’m Dr. Chuck Ryan.

Alicia: We're oncologists, and we've spent our careers working to understand cancer. We believe that there's more progress now in research and treatment than ever before, and we're here to share that with you.

Chuck: In each episode of this show, we talk with one of our colleagues about a promising development in oncology. We'll break down what's new, why it matters, and how it points the way forward.

Tom: We've gone from an environment where we're expecting things to go wrong, inevitably, either quickly or slowly, to we're now expecting something good to come from this. 

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Alicia:  You know, we are in the second year of our podcast, which is amazing, and the more we record, the more I realize that I feel like we're living in a golden age of oncology discovery and treatment. 

Chuck: A golden age of cancer research, a golden age of cancer discovery, absolutely. Uh, you know, in the last 10 years, we've seen just tremendous progress, including in genitourinary or GU cancers, and that's the group of diseases that you and I both treat. 

You know, one we should really give attention to – it's long overdue – is bladder cancer.

Bladder cancer’s a really difficult disease. My wife lost both of her parents to this disease, and it's a very, very difficult disease to treat historically. It causes a lot of sickness, a lot of disfigurement, and it's really been one of the horrible cancers over the years. But in the last few years, things have really accelerated in a positive way.

Alicia: I agree. Earlier in my career, I used to treat a lot of bladder cancer – which we also call urothelial cancer, just to make sure everyone knows, because it includes some different cancers from the organs like ureters and the urethra that are just around the bladder. 

And these cancers can be tough to treat, but this story that we're going to talk about today is not just about new treatments, but really about new ways of treating cancer and in harnessing some tools that we haven't used before to treat this incredibly difficult-to-treat cancer. 

We now routinely use immunotherapies that harness the patient's immune system to attack the cancer, and antibody drug conjugates that target chemotherapy to the cancer, using targeted molecules or antibodies to get the drug where it needs to go.

And for bladder cancer specifically, those are pembrolizumab or pembro as it's nicknamed, also called Keytruda, that's its brand name. That's an immunotherapy. And enfortumab vedotin, or EV, which is an antibody drug conjugate or ADC. And they partner together incredibly well in bladder cancer to make the pair EV pembro, which we're also going to talk about.

Chuck: And there's no better person to talk to about this than Dr. Tom Powles, who's head of the Barts Cancer Center in London. We've both known him for a long time, and he's been involved with many of the studies that led to this amazing progress. 

I'll never forget the standing ovation in the crowd at the European Society of Medical Oncology meeting a few years ago when he presented these data. It was quite a remarkable thing because you can see at that moment that the standard of care around the world. Has changed and that's why we all go into research. That's why we do what we do. So let's listen to him tell the story.

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Alicia: Tom, we are so excited to have you join us to talk a little bit today about bladder cancer and the amazing good news story that it has become. And welcome, thank you.

Tom: Thank you for inviting me. I'm super excited about being here. 

Alicia: Wonderful. So Tom, you know, I think a lot of people may or may not be familiar with bladder cancer, and the number of people it touches and, and all of that. It actually is one of the more common cancers, though not one of the most common that we see.

I wonder if you can share a little bit about what it means to have bladder cancer– what it meant, back when you were maybe earlier in your career taking care of people with bladder cancer, what that looked like, and, and just sort of give us some insight into what bladder cancer has been in the past.

Tom: So it's the ninth commonest cancer. About 600,000 cases globally every year, about 300,000 deaths every year. And we call it urothelial cancer. It's essentially a cancer of the waterproof lining. And it's quite strongly, but not exclusively, associated with smoking cigarettes. It's– despite being a top 10 cancer of being so, so many deaths – is a bit underplayed. Men more than women, for what it's worth. 

Chuck: Yes, for sure.

Tom: There are other risk factors as well. Tends to happen older rather than younger patients. 

So early on in my career, urothelial cancer was a cancer which was largely seen as being, in the end, untreatable.

We were giving chemotherapy drugs, often they were platinum based chemotherapy drugs, that's the type of chemotherapy. And it was disappointing because often patients would initially respond, but the cancer would come back so quickly. 

On top of that, we tried to cut the cancer out earlier in the disease. So for those cancers that had not yet spread or we couldn't see they'd yet spread, we would cut them out surgically. But then we would follow those patients up, and it was disheartening because many of them, the cancers had already spread. We just couldn't see it on a CT scan. We couldn't see it on radiology.

So six months after the operation, in half the patients, you would do a scan, you thought the patient had been cured, but suddenly the cancer’s come back. And then of course you would give the chemotherapy again and it wouldn't work, and the cancer would come back and the patient sadly would die.

And many patients just weren't fit enough for these treatments. So it was this combination of the treatments weren't effective, the surgery was disappointing, and many patients weren't well enough anyway. And of course we were doing trials with different combinations and different ideas, and none of the trials were working. So for a long period of time, it felt…it felt hopeless, for a long period of time.

But there was always this light at the end of the tunnel, because we knew in some patients the surgery worked. And we knew that in many patients, the chemotherapy made the cancer smaller, but it came back. How do we keep the cancer under control, and why is that group of patients responding and the others not responding? And so while I say it felt hopeless, there was always that light. And actually, it turns out that light was much brighter than we expected.

Chuck: Just kind of walk us through, if you could, Tom, the landmark findings that you were involved with and others in terms of figuring out that there was another approach, there was a way to go beyond chemotherapy.

Tom: So I've spent a lot of time doing urothelial cancer trials. In fact, I led a whole string of negative urothelial cancer trials, famously, over a long, long period of time.

And then one day, and I remember it really clearly. We started using a series of immune therapies, immune checkpoint inhibitors. Now, cancers are complicated. They have lots of mutations. They should be easily visible by the immune system, easily! Particularly urothelial cancer that has loads of mutations. And so why, how is it hiding? 

And the way it's hiding is it's hijacked our own immune system. It's developed a whole series where it's surrounded itself by a series of proteins, which essentially are able to evade the immune system. And so the T cells come by. Nothing to see here. And they move by. And these immune checkpoint inhibitors were able to remove that immune protective coat, make the cancer visible. 

And I remember now, I think we treated the first patient who responded in the world to an immune checkpoint inhibitor. His name was David. And he traveled 300 miles, told no treatment available to him, advanced disease, metastatic disease, had had all the treatments, they had all failed. This was 15 years ago. David was given three months to live. David is still alive. 

Chuck: Wow

Tom: He's well. He sails his boat every weekend. He has barbecues for the whole family. And David phones me from time to time asking me about other patients with other cancers saying, “Surely there's something for this cancer now, Tom!”

Alicia: It sounds like we have a great treatment in our immunotherapy approaches, and this was a revelation for those with bladder cancer and a revolution in the way that we attack this disease. 

But there are absolutely more wins in bladder cancer and actually you've been very involved in them. And this is a whole additional category of drugs, antibody drug conjugates, and one in particular called enfortumab vedotin.

I wonder if you could share a little bit about the success story of enfortumab vedotin, or EV, as some people call it, and the way that this contributed to transforming the landscape of bladder cancer.

Tom: So Alicia, you know, the problem with immune checkpoint inhibition is in that advanced disease where the cancer had come back, despite treatment, it worked really well, probably in one in six patients. One in six going into durable response. And of course the question is what do we do about the other five? 

So we thought let's move it earlier, but it didn't get better. It stayed the same. We were still only curing that same sixth of patients. And by the way, curing a sixth of patients with late cancer, that's not great. You know, I said at the beginning of the show, I said, you know, we've got 300,000 deaths a year. Knowing that only half the patients are able to get treatment for advanced disease. And knowing that we're only treating a sixth of those that have been heavily pretreated, that's, in the end, that's not the footprint we're looking for.

And so in the end, I was, you know, on the record saying this first chapter was good, but we've not fulfilled our ambition. There must be at least three more chapters in this book before we cure bladder cancer. At least three.

But then I spent quite a lot of time with a guy called Ira Mellman, who I think is, he was from Stanford. I think you know, he's brilliant. And it looks like there is a group of patients who are pre-programmed to respond to single agent immune checkpoint inhibition in bladder cancer. And it doesn't seem to matter where on the journey they appear. As a single agent, they are gonna respond and chemo with the chemotherapy paradigm seems a bit different

We then sort of then said, okay. Chemotherapy is struggling a bit, immune checkpoint inhibition, transformative for some, but not for most. And then this new group of drugs came along. The antibody drug conjugates. And let me just tell you a little bit, if I may, about what exactly they are.

So there are three crucial components to them, and each one is equally important. The payload is often a chemotherapy-like payload, and for the purposes of this show, I would think of it as chemotherapy.

Chuck: Yeah.

Tom: But unlike chemotherapy, it's attached to an antibody, and the antibody targets particular proteins on the surface of cancer cells.

And there are some cancers which almost exclusively express some particular proteins. A normal tissue does not express those proteins, and that means you have targeted chemotherapy. 

What happens is the antibody attaches to the cancer cell, it is internalized. And then there is a linker molecule between the antibody and the payload, and that has to disassociate. If you don't rate that linker molecule down, the drug never becomes active. So that's essentially lighting the fuse.

That is antibody drug conjugates. EV, enfortumab vedotin, is exquisitely active in urothelial cancer, and the reason why that's the case is almost all urothelial cancers express a protein called nectin-4. It is somewhat exclusive. It's also expressed in the skin for what it's worth. 

And I had a patient of mine, wanted to take part in a trial. He was in a bed. He was really struggling. He was a golfer. He'd been playing golf three months earlier. 

And essentially what happened was, he came in, you know, he had bone metastasis. Most of the symptoms were cancer-related. Guess what? We gave this drug. Six weeks later, he was playing golf again.

Chuck: Wow. 

Tom: And this drug, and I don't, and it's because I think of a high expression of nectin-4, but the payload seems particularly active in this disease. Because when you give this drug to other cancers that express nectin-4, it's not as transformative. So it's the combination of an extremely highly expressed protein and what appears to be exquisitely sensitive payload, incredible single agent activity.

This patient, you know, I knew then we had a drug. And I thought it was the best drug. But the real transformation happened when we gave it with immune therapy.

Because in the combination with immune therapy, something really unusual happened. In metastatic disease, where the median survival historically was between nine and 12 months, if you give this combination, you cure 30% of patients. 30% go into long-term durable remission. That was unheard of, number one. 

The median survival was tripled to about 36 months. Progression-free survival was doubled. And these were the sort of transformative results that mean now this has become the global standard of care. And when I see bladder cancer patients, I no longer say, you need to get your affairs in order, you may not be here in a year's time, and this disease will kill you at some point. The dialogue now is one third of patients are going to go into a long-term durable remission.

Chuck: You talked earlier about the three chapters in the book. The first was the treatment of metastatic bladder cancer. The second chapter in your book is what?

Tom: So the second chapter is EV pembro, essentially.

So the second chapter is in advanced disease. 

Chuck: Immunotherapy is the first chapter. 

Tom: Yep. And the third chapter of this book is actually the cure of these patients. And I think there are three ways of doing that. 

I think, number one, I think we need to do better patient selection and better biomarker selection. EV pembro is transformative. But it's not for everyone. 

And Chuck, there is a second generation of antibody B drug conjugates, and this is the third chapter. There's Disitamab vedotin. It doesn't target nectin-4, it targets her-2. There's sac-TMT, it's a new protein and a new payload. 

If we have Enfortumab vedotin, is it a Black Swan event? Or actually are there multiple antibody drug conjugates that are going to transform this disease? 

And we are doing triplet trials! So for example, there's a study where you can target FGFR-3, a particular protein, with an oral tablet. If you do that plus EV pembro, can you go up to 50%, 60%, 78%, 90% can you get there? If we're giving triplet therapy, when you give two ADCs together instead of single agent response rates of 40% Enfortumab vedotin in heavily pre-treated patients, two ADCs together goes up to 70%. What happens when you add an immune checkpoint inhibitor on top of that?

And the final bit, and this is super important to me, is at the moment we're putting these patients through debilitating surgery. These massive operations. It’s the biggest operation in the eighth decade of your life, removing your bladder peeing into a bag. If we're giving EV pembro and in 60% of those patients, we're getting rid of that cancer, do we need to do the operation? 

And if we give the third drug in that perioperative space, can we make that 60% 90%? Can we stop doing the surgery? Can we cure bladder cancer with systemic therapy? I think we can. I think it's within sight, honestly. And so that is the third chapter.

Alicia: As we start to wind down, it would be, it'd be wonderful if you could just give patients and their loved ones sort of an overarching message. Because they do walk into your clinics. They are going to come in, in whatever state they are, with whatever disease, whether it's early or bladder cancer or urothelial cancer, whether it's more advanced and has spread.

What is the one message you try to make sure that they hear before they leave? Because they may come in with the older view that this diagnosis is tremendous, traumatic, and is going to end their life in a very short period of time. So what is it that you say now?

Tom: The dialogue, the narrative, is different from that. 

I don't want people to walk away from here saying, oh my goodness, couple of squirts of a little drug and bladders, cancer's gone forever. That's not where we are. It's a real investment. In time and side effects to get these drugs into you and tolerate them well. And there's a real skill to giving them.

You know, I just wanted a caveat because I sometimes get carried away and I talk very positively. But we're not out of the woods with the adverse events, and there's a lot of work to be done there. Number one. 

What message do I say to patients who I see now? I just tell that story about all of those negative trials and I didn't believe that anything would work. And I say go and speak to patients in the waiting room.

Chuck: Yeah. 

Tom: Chat with the person next to you. You'll find he or she's been here for years and is in a long-term, durable remission. I'd say to patients, the beginning of this journey, particularly with the cancer, and when you start a new drug with side effects, that journey can be difficult. But we are in a position now where we're expecting responses. We're expecting remissions, we're expecting some form of elimination. We are expecting good results. 

We've gone from an environment where we're expecting things to go wrong, inevitably, either quickly or slowly, to we're now expecting something good to come from this. And those patients that don't do well, we look at ourselves and say, how did we leave that person behind?

Chuck: That is a theme that has come through in our conversations. We talked to Dr. Michael Morris about radioligand therapies, and he made the point that for generations now, we told patients that they should expect to suffer and may not benefit, or something along those lines. And, that narrative has shifted to the point where now we, patients can expect to live a good life.

And I would say, and I'm sure you both would agree, as a treating oncologist, it's a humbling experience to sit in a room with a patient and think that this is a person who were it not for what we were able to do in the last 10 or 15 years, this person would not be here. It's a very humbling, it's a very inspiring thing, and as you point out, it's very common now, which is wonderful.

Tom: I mean, we've been so lucky. I make the parallel of surfing. You know, I, I'm a terrible surfer by the way. But you can wallow in the waves waiting for waves to arrive for years and years. And here in a short period of time in cancer development, we've had these beautiful sets of waves of new treatments coming in, one after the next. Many of which are making a huge difference after spending literally a decade wallowing in the water waiting for these waves to arrive.

Chuck: Tom Powles, it's a wonderful opportunity to sit down and talk with you about all of the great developments in bladder cancer. Not only what it means for patients with that disease in the present moment and in the future, but also what it tells us about the progress that we are making against cancer in the big picture, through the development of novel therapeutic strategies, novel types of anti-cancer therapy, and the type of thinking that you're doing in terms of combinations, and moving treatments into earlier and earlier stages of the disease. 

It's really been remarkable to watch you and your colleagues who have done all this work achieve such great success. And I'm honored to have you on the podcast. Thank you so much for joining us.

Tom: Honored to be here. Thanks, Chuck. Thanks Alicia. I'm really grateful.

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Chuck:  Alicia, you and I both treat bladder cancer – at least we have over the years – and I think we've probably seen some of the tragedy that this disease can cause, but we've also been witness to some of the great progress, and it is just a remarkable feeling. 

I'm just thinking right now of a man I treated who had surgery and his bladder cancer came right back and lots of big tumors, lymph nodes all throughout the abdomen. I put him on an immunotherapy drug and about three months later, these tumors are pretty much gone and the patient continued to live a normal life, and we just didn't see that happen before these drugs. 

We were giving people chemotherapy and if they were benefiting from it, that was great, but it was coming at a cost of toxicity and lots of time spent in the hospital and worrying about the immune system and worrying about the side effects of the drugs.

Alicia: I would say that the development of immunotherapies and the use of them in bladder cancers was so transformative that I remember calling people who we were putting on hospice and saying, “We have a new– we have a new option for you. You can come in and we're gonna give it a shot.” And it was amazing to see people have their pain go away and to have more time. And it was actually really good time. And that's not to say that everything's perfect with any treatment, but this was– this was an amazing development. 

You know, the other amazing development in bladder or urothelial cancer has been the integration of these antibody drug conjugates. Because these drugs have been difficult to deliver for many years, but now are something we use every day in so many patients. 

Chuck: You know, we've talked for years and years about having quote-unquote the magic bullet. Well, this is maybe not magic. This is science, but it's directing a payload. And you know, elsewhere on the podcast we've talked about radioligand therapies, which are a similar idea. It's payload-directed therapy. We have something that can hit the cancer directly, something that can– a molecule that binds to a molecule in the cancer and it delivers a chemotherapy, a radioisotope, and maybe even in the future, a T-cell. So there's a whole new world opening up around this sort of targeted delivery of anti-cancer drugs.

Alicia: There are so many options, and the more we can target these therapies, the less side effects we'll have and hopefully the greater impact we'll have on the cancer. So whether we use them alone, whether we use them in combination, and whether we develop new things which we're doing every day, there is absolutely hope for many more good news stories about cancer with these kinds of approaches.

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Chuck:  Thank you for listening to another episode, installment, version of the Good News about Cancer. I'm Dr. Chuck Ryan at Memorial Sloan Kettering Cancer Center in New York. 

Alicia:  And I'm Dr. Alicia Morgans at Dana-Farber Cancer Institute in Boston. The views we express on this show are our own and do not represent the views or opinions of the institutions where we work.

Chuck: Thanks to Lilly for support of the show. Our production partner for this series is CitizenRacecar. This episode was produced by Anna Van Dine with post-production by Alex Brouwer.

Alicia: And there's a whole lot more good news to talk about, so make sure you subscribe to this wherever you listen to your podcasts. And if you like the show, share it with someone you think might find it interesting.

Chuck: We’ll be back again soon with another edition, installment, rendition of the Good News About Cancer.