The State of Immunotherapy in Bladder Cancer - Thomas Powles

Thomas Powles discusses the current state of immunotherapy in the treatment of muscle invasive bladder cancer (MIBC) specifically in second line after cisplatin-based chemotherapy with Chuck Ryan.  He discusses the recent learnings that immunotherapy offers long-term durable response in 10 - 20% of the cisplatin-eligible patient population who are biomarker positive.  They discuss ongoing clinical trials and the opportunities in both muscle-invasive bladder cancer (MIBC), as well as the future of treatments in non-muscle invasive bladder cancer (NMIBC).  

Biographies:

Professor Thomas Powles, MBBS, MRCP, MD Centre: Experimental Cancer Medicine Professor of Genitourinary Oncology, Lead for Solid Tumour Research at Barts Cancer Institute, Director of Barts Cancer Centre

Charles J. Ryan, MD 



Read the Full Video Transcript

Charles Ryan: Hello. I'm joined today by Dr. Thomas Powles from the Bart's Cancer Center where he is the Director and a Professor of Genitourinary Oncology. Dr. Powels does work in both bladder cancer and kidney cancer. We're going to talk about both today. 

And I want to start out by talking about your impression of the state of immunotherapy in bladder cancer.

Thomas Powles: The state of immunotherapy in bladder cancer is super exciting at the moment. We've had this first wave of drugs that's come through. The monotherapies. I won't talk about the detail or the five different drugs available but essentially what we need to know is it's replaced second-line chemotherapy in platinum refractory urothelial cancer so now everyone should, in my opinion, almost everyone should be exposed to immunotherapy with a chance of long-term durable remission, maybe between 10 and 15, 20%, which is not great yet. We need to do better.

The biomarker doesn't seem to work very well at the moment. We've a lot of uncertainty in that area and so we all now have a tranche of front-line trials, metastatic studies that are ongoing. We also have that front-line label which has recently changed to exclude the biomarker negative patients to biomarker positives. That's a very important step-

Charles Ryan: Very important.

Thomas Powles: ... because it tells us the biomarkers change and clinicians shouldn't be treating biomarker negative patients. The FDA and EMA have told us that's a dangerous thing to do. Let's be really clear about that. Until the randomized Phase 3 studies read out, let's focus on that biomarker positive front-line setting.

Charles Ryan: What is the guidance on biomarker negative patients currently?

Thomas Powles:: So, if you have biomarker negative in the front-line settings, cisplatin ineligible, you should not be getting immunotherapy.

Charles Ryan: Cisplatin eligible?

Thomas Powles: Yeah, ineligible.

Charles Ryan: Ineligible.

Thomas Powles: Cisplatin, so, if you're cisplatin eligible you get cisplatin therapy, cisplatin ineligible, you used to be able to get immunotherapy for everybody and now that's changed. You have to be biomarker positive. The FDA and EMA have both told us that. They won't have gotten this wrong and that means that there'll be biomarker negative patients who probably are coming to harm's way if we're giving them immunotherapy so let's not do that. Let's wait for the randomized trials to read out at least, and when they read out, we're just going to have the next two years and two key questions.

Question one: Durva-treme CTLA-4 PD-L1 combination versus chemotherapy. Can we beat chemotherapy with immunotherapy, yes or no?

Key question number two: Pembro plus chemo, atezo plus chemo. Can we reproduce the lung data by combining chemotherapy with the immunotherapy long progressing or improving progression-free and overall survival? 

Those are the two key questions and that's in the next year, 18 months, I would imagine and then not far behind there are the adjuvant studies with the atezolizumab and nivolumab and then we've of course been doing some neoadjuvant work, showing path CR rates and then this fantastic new non-muscle invasive data as well. So, the move has been three key chapters to it.

Chapter one has been this initial chapter. We've established the drugs. Chapter two is refining and improving, particularly in the front-line space. And then chapter three is going to be about moving the drugs early in the disease and really curing a lot of patients. And that's really important. We need to learn more about the biomarker and we probably need to actually get some more effective combinations and that's about as exciting as you can get in cancer right now.

Charles Ryan: Yeah. I mean, to think that when we started, bladder cancer was, there was just nothing new and it was a sad state of affairs where we hadn't improved on platinum in 20 some years or so, so it's just an, you know, we're drinking from the fire hose as we say now and it's all really good and there's all kinds of different combinations and permutations that we need to sort out. So, final thoughts on bladder cancer, then we'll switch and talk about kidney for a little bit.

Thomas Powles: I'm excited by enfortumab vedotin, which is an ADC, an antibody-drug conjugate, sacituzumab govitecan looks really active. Let's combine that too and let's bring that really early in the disease process in the future. That's got to be really important because the drug looks active and it looks different so that's exciting and of course there's FGF with erdafitinib, data looks great. And again, there's work to do there. 

We're doing a study called BISCAY which has got next-generation sequencing, looking for mutations. I think it's foundational. I'm looking for mutations and then you get immunotherapy plus FGF or immunotherapy plus PARP and so there's that targeted story which I'm going to talk about in kidney cancer, targeted therapy being very effective there combining with immunotherapy too. 

So, there is the immunotherapy chapter. There is also the second generation of drugs chapter and we're going to bring those chapters together and I think that it really is a piece where I think in the United States, you're going to have personalized therapy with FGF and PD-L1, you're going to have immune single therapy and combinations. You're going to have immune combinations, you're going to have immune targeted combinations and you're going to have chemotherapy combinations with personalized therapy all moving over into these processes in the next two or three years.

Charles Ryan: Do you know if FGF is mutually exclusive with PD-L1? There's no reason why it would be.

Thomas Powles: Yeah.

Charles Ryan: Are there cancers that, tumors that express both?

Thomas Powles: Yeah.

Charles Ryan: Or is that commonly co-expressed or what's the story there?

Thomas Powles: So there's been a little bit of work on this looking at TCGA analysis there with classic, I mean, it changes a lot but the classic system with the four classifications, one, two, three, and four, luminal basal, luminal 2 over-expressed the FGF group and that group doesn't actually have huge PD-L1 expression, but it does have some immune infiltration associated with it. Actually, when, this data comes from IMvigor210 and so when you look at that, there may be some, or the theory is that they're not overlapping in that particular group. But we don't know enough about that yet and studies like the study I mentioned before, BISCAY, but there will be other trials too looking at FGF plus immunotherapy looking for response rates in those groups, you could treat 30 patients and we're looking for response rates of 50, 60% I'd like.

Charles Ryan: Amazing, yeah.

Thomas Powles: I don't know the results yet but that's what I'm expecting, that's what I'd like to see, and those sort of results obviously practice changing and so I think we have these huge opportunities around the corner. When you look at prostate cancer and kidney cancer, the need to move therapy on is, the bar is high, you have to get survival, and we've recently had ipi/nivo, the bar still remains relatively low, you know, median survival of these patients is still only 12 to 14 months in metastatic disease. Imagine when you look back in kidney cancer back in 2000, survival was only about 12 months then but now we're moved, we've probably tripled that to three years. And so, I think that same transition will happen very quickly in bladder cancer and I think the drugs I've mentioned today will take part in that.

Charles Ryan: Yeah, I agree. It's really an exciting time and thanks for your work on this and thanks for your input and your educational efforts on that behalf.

Thomas Powles: It's a pleasure.
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