The therapeutic landscape of advanced urothelial cancer has undergone a significant transformation in recent years with the addition of PD-1/PD-L1 targeting immune checkpoint inhibitors and novel antibody-drug conjugates to the treatment armamentarium. In this Clinical Insights on the Treatment Algorithm in Unresectable Locally Advanced or Metastatic Urothelial Cancer, experts in the field will discuss the latest evidence supporting the use of these therapies in clinical practice, including patient selection for cisplatin/carboplatin eligible and platinum ineligible and optimal treatment strategy in the first-line setting, sequencing of treatments and the management of treatment-related adverse events. An improved understanding of the role and application of immunotherapy, chemotherapy, antibody-drug conjugates (ADC) and targeted treatments to routine patient care will facilitate optimal management of patients with urothelial cancer.
During this Expert Interview, we will be discussing the novel drugs currently in development for LA/m UC, including ongoing trials and challenges. We are joined today by a leading expert in urothelial cancer, Dr Thomas Powles from the St Bartholomew’s Cancer Centre, London, UK.
The therapeutic landscape of advanced urothelial cancer has undergone a significant transformation in recent years with the addition of PD-1/PD-L1 targeting immune checkpoint inhibitors and novel antibody-drug conjugates to the treatment armamentarium. In this Clinical Insights on the Treatment Algorithm in Unresectable Locally Advanced or Metastatic Urothelial Cancer, experts in the field will discuss the latest evidence supporting the use of these therapies in clinical practice, including patient selection for cisplatin/carboplatin eligible and platinum ineligible and optimal treatment strategy in the first-line setting, sequencing of treatments and the management of treatment-related adverse events. An improved understanding of the role and application of immunotherapy, chemotherapy, antibody-drug conjugates (ADC) and targeted treatments to routine patient care will facilitate optimal management of patients with urothelial cancer.
During this Expert Interview, we will be discussing the novel drugs currently in development for LA/m UC, including ongoing trials and challenges. We are joined today by a leading expert in urothelial cancer, Dr Thomas Powles from the St Bartholomew’s Cancer Centre, London, UK.
Hello and welcome to this Expert Interview entitled "Clinical Insights on the Treatment Algorithm in Unresectable Locally Advanced or Metastatic Urothelial Cancer". My name is Delyth Eickermann. I am delighted to be joined today by a leading expert in urothelial cancer, Professor Thomas Powles from the St Bartholomew’s Hospital Cancer Centre in London, United Kingdom. Welcome and thank you for joining me today, Dr. Powles. During this Expert Interview, we will be discussing the novel drugs currently in development for locally advanced or metastatic urothelial cancer, including ongoing trials and challenges. Dr. Powles, the treatment landscape is evolving rapidly in 2023, with more treatment options being introduced as first-line choices. How do you anticipate the evolution of first-line treatment strategy in the coming years and can you share with us the "where next" in this setting? Firstly, thank you for inviting me. I'm very grateful to be here. You know, I think it's... taken a long time for us to make a big change in the treatment of patients with advanced urothelial cancer. Essentially, patients with advanced disease have been treated with platinum-based chemotherapy, Gem/Cis or Gem/Carbo, for a generation. In fact, as long as I've been an oncologist, and I'm feeling older every year. We've tried multiple times to beat Gem/Cis and Gem/Carbo. Maybe 20... I don't know how many times. We've not been successful. There are two reasons that we've not been successful. The obvious reason is we haven't had good enough drugs. Some people in the past have said we haven't invested enough time and effort into urothelial cancer, and we haven't done enough trials. There was a time, perhaps ten years ago, when I think that was true, but the introduction of the immune checkpoint inhibitors changed all of that. And since then, there have been a plethora of randomized trials in urothelial cancer. The more recent developments with the antibody-drug conjugates have resulted in a second group of studies that have come through. And so essentially, we have drugs like atezolizumab and pembrolizumab, which are used after platinum-based chemotherapy. And of course, avelumab, which was the standard of care for first-line maintenance avelumab. But these immune checkpoint inhibitors as single agents didn't fulfill their potential. And they never beat front-line chemotherapy. The antibody-drug conjugates (ADCs) such as enfortumab vedotin (EV) and sacituzumab govitecan (SG), both FDA-approved in those patients who previously had progressed after platinum-based chemotherapy. So we had a series of drugs or two groups of drugs, essentially, for those patients whose cancers had progressed after platinum-based chemotherapy. We combined those two drugs together, enfortumab vedotin and pembrolizumab. And we took on front-line chemotherapy, Gem/Cis or Gem/Carbo in a prospective randomized Phase III study. And in that 880-patient trial, one-to-one randomization with progression-free survival and overall survival as the primary endpoints, we showed approximately a 50% reduction in the risk of progression, a 15% reduction in the risk of death. We showed much higher response rates associated with the combination. We showed a CR rate of 30%. We showed lower Grade 3 or Grade 4 toxicity. We had infrequent, less than 1% treatment-related deaths. And so essentially in the last three months, there's been a seismic change in the way we perceive this disease. And indeed, very recently, it achieved FDA approval in first-line urothelial cancer patients. And this, in my opinion, now supersedes Gem/Cis or indeed Gem/Carbo. The question for the future around this combination. How many cycles do we need to give? At the moment, we continue to progression. I think many patients, when they get to ten cycles, many patients are beginning to reduce dose or discontinue therapy, particularly the enfortumab vedotin. We need to address those questions in more details. That's the first thing. The second thing with this combination is we're going to move it into the perioperative, the neoadjuvant setting, and try to cure more patients. And then, the second question, which I think you've asked, which is really important, is how do we progress. What do we do next with this combination? And this is an important issue. There are some data out there with two or three different groups of drugs. Different antibody-drug conjugates, and that's what I'm going to talk about first, targeted therapies with things like erdafitinib, and then, the third group of drugs, the novel immunotherapies. If I can start first with the new antibody-drug conjugates, there are other antibody-drug conjugates, of course. In breast cancer, you've got T-DXd and T-DM1. You've got new ADCs in lung cancer. There was some nice data on HER3 ADCs in lung cancer. And of course, you've got the TROP-2 ADCs, Sacituzumab govitecan, being the most prominent of which. Sacituzumab govitecan is being explored in prospective randomized Phase III studies. It already has FDA approval. But it's not being widely used currently. The most exciting study is probably TROPiCS-04, which explores sacituzumab govitecan versus chemotherapy in platinum-refractory disease. And that's exciting because it would establish a standard of care. But if enfortumab vedotin and pembrolizumab is the new standard of care in first-line setting, what does that mean for those patients who previously had different therapies? And that becomes very confusing. And actually it's possible, in my opinion, probable, the triplet combinations are going to be really important in the future. And there are two combinations which I think are really exciting. The first is sacituzumab govitecan and enfortumab vedotin together, with an immune checkpoint inhibitor. We've got Phase I data at the United States, showing you can combine enfortumab vedotin and sacituzumab govitecan together. That combination has response rates of 70%. If you put an antibody-drug conjugate or two antibody conjugates with pembrolizumab or a different immune checkpoint inhibitor. My feeling is we could get even higher responses than we saw with EV/Pembro and durability of response. So I think that's a really exciting avenue. And the second exciting avenue with antibody drug conjugate combinations, in my opinion, is there's also a study called the VOLGA trial, which looks at enfortumab vedotin with a PD-1 inhibitor or PD-L1 inhibitor, durvalumab and tremelimumab, a CTLA-4 inhibitor. CTLA-4 has got a patchy history in urothelial cancer, but it looks like it increases response rates by about 10%. So again, that's a neoadjuvant trial. The VOLGA trial, it's ongoing. It's enrolling. It's a really important study. And I think the triplet combination is a really important question in urothelial cancer. There are other ADCs that we need to explore in urothelial cancer. There are some data on HER2 ADCs with disitamab vedotin and indeed they're being used widely in China. I think that data is exciting. I'd like to see combinations. And there's a combination of disitamab vedotin and pembrolizumab in randomized Phase III trial. I'm excited about that. I'm also excited about the HER3 ADCs, which is a different group again. So I've talked to you about four different ADCs just in the last few minutes in urothelial cancer. When you look back in time, where we only had Gem/Cis or Gem/Carbo, this makes things very exciting. I've also talked about triplet therapy. If I park the antibody-drug conjugate issue for a second, and move on to what I think are other areas of exploration. We've seen some data with targeted therapy with erdafitinib. We've seen the THOR trial, looking at personalized therapy for those patients with FGFR3 alterations. We've seen better outcomes compared to chemotherapy. In the NORSE trial at ASCO 2023, Arlene (Dr. Arlene Siefker-Radtke) presented data showing the combination with PD-1, and she did show quite impressive response rates. And I think we do need to incorporate erdafitinib or other FGFR3 inhibitors into the treatment algorithm, perhaps more aggressively than we're doing at the moment. And again, I'm afraid I think that's with combinations. I don't think as a single agent, it's going to change the field in the same way as enfortumab vedotin and pembrolizumab has. So we need to explore FGFR, we know it's a target and we need to look at that. And then, the third group of drugs I wanted to talk about, the second generation of immunotherapies. We know that the second generation of immunotherapies, dare I say, OX40 as an example or IDO as an example, haven't been particularly successful. We've been exploring them for ten years, but we now have LAG3, and we've got TIGIT as two new targets being explored in prospective randomized Phase II studies, trying to beat a historic standard of care. And it is my hope that we can indeed find the second generation of immune checkpoint inhibitors. And of course, beyond there. There is some exciting work on personalized cancer vaccines, and Moderna and BioNTech getting involved in adjuvant trials in a broad spectrum of areas. I'd like that to include urothelial cancer as well. And then, of course, the last piece which I always talk about, the personalized approach with circulating tumor DNA to identify those patients that really need therapy and monitoring treatment with circulating biomarkers rather than using radiology, is an area of real excitement for the future. So in summary, bladder cancer, in my opinion, has completely changed in the last three or four months. Antibody-drug conjugates with immune checkpoint inhibitors, specifically EV/Pembro, I think has changed the landscape. I think there is more work to be done with new antibody-drug conjugates, antibody-drug conjugate combinations, immune antibody-drug combinations. But also, let's not forget about second generation of immune checkpoint inhibitors, targeted therapy and personalized therapy with circulating tumor DNA. Thank you for sharing your insights on the "where-next" in first-line treatment strategies. The rapidly changing treatment landscape in the first-line setting has made the subsequent care much more complex, resulting in unmet needs. What are the unresolved issues and challenges that need to be addressed in future clinical research? That's a really good question. What do we do now? While if we've changed first-line therapy with enfortumab vedotin and pembrolizumab, we don't have very much data for patients whose cancers have progressed after that. There are two observations of interest from the EV/Pembro trial. The first is that progression-free survival and overall survival. Progression-free survival. You know, about a year, just over that, but overall survival over 30 months, that means a lot of the patient journeys being spent after first-line therapy. EV/Pembro seems to be generating these long, deep responses and they go on, in my experience, the patients I've treated, longer than I expected. Nevertheless, there is a role and an important role for subsequent therapy, but we don't know how much it adds to overall survival. Currently, we have no data on that and we have no data on which drugs to give. The first question is what do we use in the EV-302 study? And what we used predominantly was platinum-based chemotherapy as the second-line standard of care. Why did we use that? Well, that's all we've really been using for such a long period of time. FGFR inhibitors, also approved in the United States, were actually very infrequently used in that population. My feeling is, the platinum-based chemotherapy is the standard of care after EV/Pembro. If patients have FGFR alterations, erdafitinib may be alternative, but I would personally see it more as a third-line therapy, in my opinion. Sacituzumab govitecan doesn't have positive randomized data yet in urothelial cancer in any setting. And although it has FDA approval, we haven't seen any data post-EV/Pembro. And so it's my feeling that sacituzumab govitecan is not yet the right drug to sequence after EV/Pembro. And then, when you look for other alternatives in urothelial cancer, there are actually few and far between. So, common sense dictates, let's do what happened in the study because those patients do well, that sequence platinum-based chemotherapy. But I'd like to see studies now. And we're going to see studies for that post-EV/Pembro population. And I think sequencing antibody-drug conjugates is a really important question. Number one. Number two is, do we need to continue or should we stop the immune checkpoint inhibitor? And I think that's something that I'd like to see. And if you said to me, what sort of trial do we need to be looking at? I would be looking at novel ADC and novel immune combinations. So there I said it LAG3 or TIGIT with either a HER3 or a HER2 ADC, or a TROP-2 ADC versus platinum-based chemotherapy would be a standard trial which I think we could do, and I think we should do. Recruiting to those trials in the short term is hard, because EV/Pembro has only just started to be used, and patients are going to be on that for 12 months. And so in 12 months' time, we will start being able to recruit to these studies. But it takes six months to start a study anyway. So I think we should be planning those trials now. We should be assuming the landscape is going to change. And we should be learning more about sequencing therapies, which we're not actually doing very much of from a prospective study perspective as it stands. Thank you. Could you share with us the other promising pipeline therapies for locally advanced or metastatic urothelial cancer, and also introduce their mechanisms of action? I think that we've gone through a period and I think the right place to start with is with the antibody-drug conjugates. I think the HER3 and the HER2 antibody-drug conjugates are exciting. Disitamab vedotin is an example of a HER2 antibody-drug conjugate. I think that's relevant. I think there are other antibody drug conjugates in other tumor types which are coming into urothelial cancer. And I think that we haven't seen activity for those drugs yet. We haven't seen data yet, but we look forward to that. I think the TROP-2 ADCs are already established with sacituzumab govitecan. So that's the first group of drugs. I think the second generation of drugs that are exciting is there's a second group of immune checkpoint inhibitors. LAG3 and TIGIT are two of those. There are also the personalized cancer vaccines. And we've tested those before a little bit. But we're now testing them more aggressively. There's data on pancreas cancer. And there's data on some other tumor types as well, including melanoma. The personalized cancer vaccines, TIGIT and LAG3, for me are the three more exciting immune agents which I'm looking at, although I'm sure there'll be someone who would disagree with me and say this is actually much more exciting. And I would bow to their knowledge. Then, the third group of drugs, the targeted therapies, I would say that erdafitinib is now established. It's not yet EMA-approved, but it is FDA-approved. It has positive randomized Phase III data. I'm not sure we've got the biomarker right. And I'm not sure we yet have the best FGFR inhibitor we possibly could. So I'd like to see a second generation of FGFR inhibitors. And there's also ongoing discussion about other targets and other potential targeted therapies. My personal opinion of that is, drugs like cabozantinib, which I know are continuing to be explored, I'm less excited about the targeted therapies in isolation than perhaps other people are. And then, I know I talked about this, I know it's not a drug, but it is very important that we redefine advanced disease. At the moment, we wait until an X-ray shows a lump on it. And by that time, that's too late for many urothelial cancer patients. We need to transform advanced disease by focusing more on minimal or molecular residual disease, which can be identified by blood tests rather than radiology. And the reason why this is important is if we go earlier with minimal residual disease using circulating tumor DNA, we can explore those drugs in a new earlier space. And indeed, Dr. Matthew Galsky is doing that combination of LAG3 plus nivolumab, versus nivolumab alone in ctDNA-positive patients. So what he's doing is super exciting. And then, the last group of drugs which I think is worthwhile talking about, which has been explored but is still ongoing, are the CTLA-4 inhibitors. Tremelimumab is being explored in combination with durvalumab plus the ADC, enfortumab vedotin, as a neoadjuvant triplet. So actually, in urothelial cancer, we've got randomized trials, randomized Phase II and Phase III studies with three antibody-drug conjugates. We've got ADCs in Phase II and in randomized Phase III. We've got some randomized Phase III with targeted therapies. I've said I'm not as excited as other people are around that. But I am excited about trying to refine FGFR inhibition. And I think erdafitinib is a great drug. I'd like to see that move forward, either in combination or the different, better FGFR inhibitor. So the identification of predictive biomarkers of response to chemotherapy, immune checkpoint inhibitors, antibody-drug conjugates and targeted therapy is crucial for treatment decision-making. What are the current developments in this field and what are the future applications? Biomarker development in urothelial cancer has not been as successful as we, as a group, would have liked. We focus heavily on PD-L1 as a biomarker. I'm fairly confident that PD-L1 is not the whole story. In fact, I don't think it's a good biomarker for urothelial cancer. We've tested it many times in prospective randomized Phase III studies as the primary endpoint from the IMvigor211, all the way down to trials like DANUBE. And it's failed. And we need to move on to a second generation of biomarkers, particularly for immunotherapy. We know innate and adaptive immunity are both important, predicting response to immune checkpoint inhibition. We also know the tumor mutational burden is relevant. We also know host factors and host immunity. And potentially, even the microbiome plays a role in response to therapy. I don't think there's an easy solution to predict response to immunotherapy. I think we may be able to generate algorithms with more than one biomarker in the future. I'm excited about some of the RNA signatures, but this is not the TCGA signature. There are potentially RNA signatures for innate and adaptive immunity, which may be better than PD-L1. But RNA signatures are very difficult to translate into biomarkers or convert into biomarkers. They take a long time to do. I think the second group of drugs, the antibody-drug conjugates have a target. Now, enfortumab vedotin is targeting Nectin-4. Nectin-4 is overexpressed in the vast majority of urothelial cancer patients. And so I think, as a single agent therapy, I don't think Nectin-4 is a useful biomarker. I don't think we're going to use that. The same applies for TROP-2, which is widely expressed in urothelial cancer. But the second generation of ADCs, the HER2 and the HER3 ADCs, I think, are going to be biomarker-driven. I'd like to see that. I think disitamab vedotin is a really attractive second generation antibody-drug conjugate. And I think we need to look at that in the HER2 positive population. And then, the last biomarker which I think is relevant is circulating tumor DNA. About 40% of post-surgery patients are ctDNA-positive. Those patients that are positive relapsed in about 90% of the time. Those that are not positive only relapse about 10 to 20% of the time. So that's a quite discriminatory predictive biomarker for relapse. But it also appears to be a predictive biomarker of response for atezolizumab. There's a prospective study called IMvigor011, which randomized ctDNA-positive patients with no evidence of disease or radiologically to atezolizumab or placebo in a randomized Phase III study. And I think that's a really important trial, which is recruiting globally at the moment. So, the first chapter of biomarker development with PD-L1 was unsuccessful. The second chapter for immunotherapy requires work. We still don't have the answer, but we have moved to circulating tumor DNA. And of course I should, before I finish, mention FGFR and those HER2 ADCs, both of which I think we're going to be using biomarkers in the future. So yes, we'll get there. We're not quite there at the moment. Thank you very much, Dr. Powles, for your valuable insights. We look forward to the future development of the treatment landscape, and how biomarker-driven precision medicine could provide more valuable outcomes for patients. Thank you very much for having me.