Advances in Bladder Cancer Beyond Immunotherapy and Checkpoint Inhibitors - Evan Yu

(Length of Discussion: 9 min)

Evan Yu and Alicia Morgans have a diverse conversation highlighting the advances in the field of bladder cancer beyond IO and Checkpoint inhibition.   They introduce a variety of therapy options being studied such as FGFR inhibition, antibody-drug conjugates, HER-2 and DNA repair.     

Biographies:

Evan Yu, MD 

Alicia Morgans, MD

Read the Full Video Transcirpt:

Dr. Alicia Morgans: Hi and welcome to continued coverage of ASCO 2018. I am thrilled to have with us here today Dr. Evan Yu, who is a professor of medicine at the Seattle Cancer Care Alliance at the University of Washington. He's also the Director of GU Medical Oncology as well as the Director of Clinical Research Services. So thank you so much for being here with us today, Evan. 

Dr. Evan Yu: Yeah, thanks for having me here. It's always fun. 

Dr. Alicia Morgans: Great. Well we've talked at this meeting and in other conversations and you and I have talked a lot about the advances in bladder cancer. There's a lot beyond IOs actually and I'd love to hear your thoughts on some of the latest and greatest in therapies that are not immunotherapy-based or checkpoint inhibitor-based, at least for bladder cancer

Dr. Evan Yu: Yeah there's a lot of great things happening right now. So multiple different areas, the anti-androgenics. Obviously there are FDA approvals for different anti-androgenics in many different diseases. In urothelial carcinoma, we're still waiting and there's data ongoing or trials ongoing with platinum combined with Bevacizumab. We will wait to see the results of that cooperative group trial. 

There's also recently a Phase 3 trial with ramucirumab when added to docetaxel in patients who had received prior platinum and they were allowed to receive prior IO therapy. That showed an improvement in radiographic progression-free survival but unfortunately there was a press release saying that overall survival had not been met. So we'll have to wait to see that data and we'll have to wait to see what the regulators think about it since the primary endpoint was met with progression-free survival. 

Another area that's pretty exciting is FGFR inhibition. There are multiple pan tyrosine kinase inhibitors out there but there are also some monoclonal antibodies that are specific to FGFR3. I think that's an interesting field. Most of the trials are enriched with assays that test for translocations, mutations, etc., and we're seeing response rates with multiple different agents for instance like erdafitinib in the approximately 40% range. Erdafitinib does have breakthrough designation there so we'll be excited to see the results of that and multiple other FGFR inhibitors that are being tested. 

Antibody drug conjugates are another exciting field. This is really cool because you're targeting a protein that's highly expressed. It really doesn't matter what the purpose or the function of the protein is. It's just you need expression so you can go after it with an antibody, with a linker and a payload. The payload can be multiple things, MMAE, microtubule disruptors, SN-38, topoisomerase-1 inhibitors. There's a lot of different interesting payloads that are being looked at. 

Enfortumab Vedotin is an agent that actually FDA breakthrough designation because in the early Phase 1 studies, we really saw depending upon which subset, 40% to 60% response rates. And the interesting thing is with IO, we worry about patients that have liver metastases because there may be immune exclusion. The micro-environment may not allow good penetration and utilization there. However, what we're seeing with ADCs is we're seeing really good response rates in patients with liver metastases. So that may be an interesting unique niche. But we'll wait to see Phase 2 results of enfortumab. Their combination trials and a Phase 3 study starting. 

I think another area that's pretty interesting is actually HER-2. We've been there before. There have been platinum plus trastuzumab combinations that look pretty promising but there were some cardiotoxicity. There's some newer data with combinations with trastuzumab and pertuzumab out there. It looks promising. It's very early and there's even antibody drug conjugates that target HER-2 that are probably coming in urothelial carcinoma. There's more mature data in gastric cancer and breast cancer in very heavily pretreated populations but you know, we'll look forward to see that. 

I think the last area is DNA repair. So, we've seen some interesting data from Maria Carlo, she's going to be showing some data here. Abstracts already released, looks like close to 200 patient population. They have a 29% germline DNA repair hit rate, I mean, and 13% in bladder primary. So that seems really, really high but I think it just opens our eyes to the fact that, there are these patients that have inherited DNA repair abnormalities and that portends potentially to response with PARP inhibitors. There's trials with olaparib, rucaparib, all ongoing in that setting as well. So those are kind of the things that I think are coming. It's really exciting because there's a lot of things.

Dr. Alicia Morgans: There are. And you know, I have been involved in a number of these studies with you actually and have been really impressed both with the response rates, but for example, with some of the antibody-drug conjugates, the tolerance is actually really good. So you know, patients for clinical trials are selected to be strong enough and hardy enough to be on trial. But once they're on, if the drug is really toxic, they experience the same side effects everyone would experience and you know, may make us take them off agent because they certainly just can't stay with certain levels of toxicity. 

But I have seen a number of patients who, especially those who are borderline in terms of their performance status, really improve and thrive with some of these agents, both because they were responding to the drugs, but also because they were highly tolerable. That's not true of all of these agents of course, but can you speak to that particularly in the setting of an antibody drug conjugate where we can target chemotherapy or that payload and really augment the power of the chemotherapy in that particular area where the target is? In the area of the tumor. 

Dr. Evan Yu: Yeah, I think that's a really good point. I mean these agents do have pretty good tolerability because the whole idea is, you have an antibody that's targeting a protein with a linker that's bringing a payload that if you were just an infused it in a patient will be way too toxic, but it's totally inert and inactive until it reaches the target, gets internalized and then the lysosomal cleavage with a low pH, cleaves it and then it's released intracellularly. 

So it's super cool how it works and it also makes sense that it's not as toxic. Now there are classic toxicities we have to think about with antibody drug conjugates. It's a class effect. We'll see potentially neuropathy. We'll see potential corneal changes, depositions, but that's always reversible. 

We haven't seen a ton of that in their early trials with ADCs in bladder cancer, which is good. So I think that as far as I'm concerned, the toxicities have been quite manageable and quite minor. 

Dr. Alicia Morgans: I agree. And I think some of the targeted agents, like the FGF agents really seem to have some impressive responses too. And these are quite common mutations in our bladder cancer patients, especially in my setting at least when they're heavily pretreated. So have you had personal experience with any of these agents and success? 

Dr. Evan Yu: Yeah, I can say that these agents, again, I'm very excited about them, but I will also point out one fact, that when we're seeing response rates in the 30, 40% range, we have to recognize that they are enriched, selected population. 

They're not all comers. They've been screened and all the different states are using different assays, but they are enriched, selected patient populations. So that's one thing to keep in mind.

We do see impressive responses. Toxicities are pretty minor, but they can be some annoying things. You can get nail changes. You can get taste changes. I think the thing that people talk about the most is the hyperphosphatemia with the FGFR inhibitors.  But that's usually well managed with diet only. I mean, occasionally you have to use binders, but that in, and also studies were in the 5% range and most of the time it was pretty well managed just with diet. So that's reassuring. 

Dr. Alicia Morgans: It is. So I think it seems that in the field of bladder cancer at least, we're making a lot of progress. We've got some targeted agents that will allow us to take what is truly a heterogeneous population of patients and break them down into individual responders to really personalize therapy. And some of the response rates in these selected populations are really, really encouraging. So do you have any final thoughts or words to sort of summarize your feeling about the current bladder cancer landscape? 

Dr. Evan Yu: Yeah, I do. I think that we have hope for molecular stratification in this field. I think in the future we might be moving towards a setting where we are doing testing upfront and if we were found to have an alteration, we're going to go after that alteration whether it's FGFR, HER-2 or something else. And then if you don't, you might fit better under an IO you know, chemotherapy pathway, platinum-chemotherapy pathway. 

This then leads back to some of the TCGA work that kind of points towards different subtypes, luminal, basal subtypes, even greater sub classifications in the recent TCGA updates. It's possible that certain patient populations that are high expressing for let's say FGFR3, might not do as well with IO or chemotherapy. I think that has yet to pan out. 

It might be vice versa. So there's probably a Venn diagram that intersects there, but it's possible that it's a small level of intersection and that we'll be able to select therapies. And you really use molecular stratification to say your best for this therapy, your best for that and then you put patients down different pathways. That's what really, what we're striving to do is to have good biomarkers and predictive markers to really treat patients correctly based on the biology of their cancer.

Dr. Alicia Morgans: Well, given the history of treatment in bladder cancer and these recent advances, I would say that the time has come for bladder cancer and for this molecular stratification. It's really exciting and I appreciate you taking the time today. 

Dr. Evan Yu: Yeah, thanks so much for having me.
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