What is New on Bladder Cancer Treatment: ASCO GU 2019? - Josh Meeks

April 18, 2019

Josh Meeks discusses the bladder cancer data from the ASCO GU 2019 meeting that is compelling from the perspective of urologists in this conversation with Alicia Morgans.  


Josh J. Meeks, MD, PhD, Assistant Professor of Urology and Biochemistry and Molecular Genetics at Northwestern University Feinberg School of Medicine, Chicago Illinois

Alicia Morgans, MD, MPH, Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi. My name is Alicia Morgans and I'm a Medical Oncologist at Northwestern University. I am pleased to have here with me today Dr. Josh Meeks who is an Assistant Professor of Urology at the Northwestern University Feinberg School of Medicine, who is here to talk with us about the urologist's view of the work presented in bladder at GU ASCO 2019. Thanks so much for being here with us, Josh.

Josh Meeks: Thanks for having me, Alicia.

Alicia Morgans: Of course. So, take us through the information that was discussed at GU ASCO, starting maybe from a non-muscle invasive kind of angle, and let's think through these from a urologist's perspective. It was a really busy meeting so lots to cover.

Josh Meeks: Yeah. There was a ton of data at GU ASCO in 2019 and I think, yeah, you'd have to start with KEYNOTE-57 as sort of a really important trial. Most of us have been waiting to see this data now for at least the last two years. So, KEYNOTE-57 was a Phase 2 trial of patients that were BCG unresponsive and it's not the entire cohort that was really up for evaluation in this interim analysis. It was really just what they called Cohort A which was around 130 patients. Now, once again, these were all BCG unresponsive patients, and so most of them had already been highly exposed to BCG. We define that as having seven or more treatments of BCG, but in this case, this group had over 12. 

Now, what's neat about Cohort A is that they're all CIS so in the neighborhood of, you know, 65% or so were CIS alone, and then the rest had either some high-grade Ta or T1 tumors. And so, these are patients that we see and, once again, many folks thought that checkpoint therapy would have just as an important role in this disease state as it did in the more advanced states so this is really an unmet need. I think if you compare it to the intravesical therapies that we give, you know, probably the best thing that we offer folks is gemcitabine-docetaxel, which has around a 40% or so disease response rate at two years. But, it's slowly sort of moving along, and sort of giving these, you know, that requires a lot of weekly installation so if this could be effective, very well tolerated, given every three weeks, you know, could provide a very new avenue of therapy for these people that largely, you know, some of them could have a cystectomy, but many of them are relatively unwell patients and really couldn't tolerate a radical cystectomy.

Alicia Morgans: Yeah, agreed, and it seems like this was well tolerated with sort of minimal toxicity, nice response rates. Where do you think this stands in the pathway moving forward getting into, you know, later phase trials and looking at this I guess more in-depth because these kinds of immunotherapy approaches for the non-muscle invasive BCG refractory population are definitely an area of interest for patients for sure?

Josh Meeks: Well, I mean, my take on it's a little different. I tell you, looking at the CR rate, they only had a 40% CR rate at three months which, I tell you, I think a lot of us had anticipated a much larger complete response rate in this population to something as strong as a checkpoint therapy. So, I have to admit, and I don't think I'm the only one who has this opinion that we're a little underwhelmed by a 40% CR rate, you know, I think the good news is that of those people who responded, they seemed to have somewhat of a durable response. They talk about over half of those patients having ongoing clinical response which is outstanding. 

I think probably the thing that I'm the most impressed about this trial is that they have a zero rate of progression and so, you know, it's not the carcinoma in situ that these patients die from. It's their progression to invasive disease, muscle invasive disease, and metastatic disease, essentially why you're looking at the lining of their bladder, their cancer is progressing in a way that you really can't measure. So, this suggests to me that you may lose the war in the bladder to CIS, but that's not really the battle. The battle is survival. So, if we can treat... If this continues and if these patients really don't have progression to muscle invasion or metastases, then the local battle you can keep fighting with intravesical agents, which may win the battle in the bladder but may lose to progression.

So, I do think that this is going to play a role in the future. What's interesting is going to be the combinations going forward. So, for example, if you challenge these patients, in one of the trials, what's going to come from this is, I believe it's Keynote-676 that's going to be combining BCG plus pembro.  So, the BCG could bring immune cells to the bladder and then you're getting the benefit of a checkpoint, but I think this is an important first study. Once again, this is only the first cohort, which was CIS only in a very strong population. I think if you contrast this to what you guys take care of in the metastatic setting where you're looking at lesions on imaging and you're watching them get smaller, you know, it's a different bar when you have actual cells that you can sample in the bladder and the patient starts with those carcinoma cells and they have to go away.

So, what you're looking at is a complete resolution of disease down to the cellular level by three months, which is a pretty high bar. I'm just not sure that's the same as having, you know if you're looking at like a, you know, a swimmer's curve, having disease get smaller. I mean, you're talking about the absence of disease. True, they're probably starting with less disease in the metastatic setting, but I think it's kind of a population that has a very high sensitivity for failure and really I like the fact that they're looking at progression as a, you know, potentially as a secondary endpoint. That really could affect people's survival long term.

Alicia Morgans: I completely agree. But I wonder if there might be a way to, similar to the way that you do installations with BCG or, you know, recurrent treatments over time, if there might be a way to boost, you know, X month to try to continue those responses a little bit longer because I worry, even in patients who only have recurrent CIS, that at some point that CIS is going to become more aggressive with continued time and mutation to become something that's going to ultimately become muscle-invasive. So, I do wonder about recurrent instillations or recurrent treatments and to see if that might be something that could make this a little bit longer lasting.

Josh Meeks: So, I agree completely, yeah. I think though the other thing that we have to look at is the toxicity. And BCG is pretty well tolerated. Nearly everyone has some kind of side-effects but you're comparing the side-effects with an IV therapy. Now, they had two deaths in Cohort A. None of those they think are related to therapy itself, but you look at the AE profile. It's very comparable to what you guys have reported from metastatic disease with anywhere from 12% for treatment-related AEs, I just think this is probably reasonable for a population that is cystectomy ineligible. But, when these start moving up to BCG naïve kind of patients that are high risk, I'm not sure that's going to be tolerated as well. I just think that's a lot of toxicity for people that could potentially get BCG alone.

Alicia Morgans: I agree. And I appreciate your conservative optimism in this because it's easy to get carried away with some of these IO approaches. So, great explanation and great thoughts around this KEYNOTE study. What else did you find particularly compelling from a urologist's perspective?

Josh Meeks: Well, I think that there are other trials that were in the metastatic space but using therapies that I think are very unique and I think the good news is that those will probably quickly play a role in earlier stages, the muscle invasive and one that I'm particularly interested in in the, honestly the non-muscle invasive space was the FIERCE-21 vofatamab trial. That was Andrea Necchi's trial, the Phase 2 study. I thought that was very interesting because it was an FGF receptor-targeting therapy and we know that in the non-muscle invasive space, particularly in the Ta high-grade patients, 80% of tumors have a mutation in FGF receptor three. So, those tumors seem to be driven much more by the FGF receptor three driver than by an overall high total mutation burden.

So, even though that study was really done in the metastatic space, when patients that for the most part had already received, you know, honestly platinum and checkpoint therapy, I think if you look at the activity of that therapy and how well it was tolerated, you know, to me it's a very promising therapy that could move to the muscle invasive space and then once again, particularly targeting the luminal kind of urothelial cancers that don't really respond incredibly well to chemotherapy. We know that they probably don't respond well to checkpoint therapy, but is sort of a third branch of therapy targeting those more luminal kind of tumors and looking at the TCGA that could be anywhere from 25 to 30% of bladder cancers that you could target with an FGF receptor targeting tumor. And so, like I said, I think that it's very interesting, very well tolerated, that don't have the hyperphosphatemia and skin changes that you have with some of the other targeted therapies. 

This, once again, is an antibody that's targeting FGF receptor three both wild type and mutated FGF receptor three, so overall very promising response in patients that were, you know, already failed multiple lines of therapy. So, anywhere from in the monotherapy arm 21%, in the dual therapy arm up to a size 27%. So, I think that's a very promising therapy that I hope will have a role, sort of, once again, getting towards more of a precision based therapy for bladder cancer.

Alicia Morgans: I love this study as well and want to emphasize the pretreatment or prior treatments that these patients had had, you know, over half in both of the treatment arms had had at least two regimens. Over half in both arms had had checkpoint inhibitors. So, these were patients who had definitely been exposed to therapies. I mean, a lot of them even had visceral, including liver metastases so patients who had really aggressive and advanced disease, who seemed to actually tolerate this therapy, even when combined with docetaxel, not just the single agent. So, that I thought was really compelling and I also thought it did seem like there was a little bit of a, maybe a little bit of a better response rate and change from baseline in terms of decrease in size of lesions with the combination. But there was also a pretty decent response for the monotherapy which is encouraging as well, particularly if the patients have contraindications to chemotherapies so really an interesting study that I hope and I'm sure is already moving onto next steps. A good way to target this particular driver of FGF.

Josh Meeks: But you can imagine, for example, there are some particularly refractory papillary tumors that we don't know a lot, don't really know how to tolerate, how to manage very well. Once again, you can give docetaxel intravesically. You can give vofatamab IV, but not incredibly frequently. So, you could figure out some combination potentially of targeting these tumors with an intravesical IV combination for, particularly challenging tumors. Once again, all this based on toxicity and how well it's tolerated. Only 5% in the combination arm stopped therapy due to AEs, so all of that's very promising.

Alicia Morgans: Absolutely. So, what else did you think was interesting? I know there were some antibody-drug conjugates that were presented as well.

Josh Meeks: Yeah. I was really impressed with the sacituzumab, the IMMU-132 trial. So, what's really kind of neat about that is that it targets this TROP-2 cell-surface antigen which seems to be somewhat enriched in bladder cancer, but then it's delivering this SN-38 payload, so I like this fact that you're trying to target a tumor and getting really high doses of cytotoxic therapy to the tumor and once again, this was a Phase 1 going into a Phase 2 that was only about 45 patients but heavily pretreated and well tolerated despite the fact that these folks had already been heavily treated. So, the response rate, I think they saw somewhere around 30 to 33% and as you guys always point out to us the folks deliver metastases have the worst prognosis.

And in this case they seem to do even a little bit better so I'm impressed by sort of the creative nature of these therapies and, you know, will those play a role in an earlier setting? Hard to say, but it's great that we have more options for people when they sort of progress through platinum and progress through checkpoint.

Alicia Morgans: Yeah. I think one of the most exciting things from my perspective as a medical oncologist in the world of bladder cancer is that we are tackling this disease from so many angles at this point and I was involved in the Phase 1 and then progression to Phase 2 for this study and had, I put some patients on this trial for the Phase 1 portion in particular that had had multiple prior agents. They were heavily, heavily pretreated and that happens in phase one where we're really just trying to find the dose. Certainly interested in early efficacy and giving our patients access to therapies to which they would otherwise not have access. But the restrictions are usually less than a Phase 2, for example. And these patients seemed to respond and they tolerated it pretty well.

And TROP-2 is expressed pretty highly on these cancers which also gives us hope that a larger number of patients may receive benefit from something like this where when we think about targeting things like FGF or other targeted approaches the population becomes smaller and smaller as you become more and more specific with what your target's going to be, but this, I think, has a broader appeal because it could treat a larger population. So, pretty well tolerated. We saw some interesting results and I am really eager to see this continue to move forward, probably more for late-stage disease, just given, you know, the earlier stage, especially refractory non-muscle invasive disease. I don't know that something like this is ever going to get there, but who knows? In a heavily pretreated population, there was toxicity, but these were patients who already had a lot of medical issues going on anyway because of their disease and prior therapies so perhaps it is better tolerated earlier, but I see this probably moving forward in the more advanced setting.

Josh Meeks: Yeah. Once again, the more therapies we have for folks, the more options they have.

Alicia Morgans: Absolutely. So, any other studies that you would want to recognize or mention before we start to wrap up?

Josh Meeks: Yeah. I mean, I still think that there's two that we just, that just kind of got, that also had podiums that were very interesting. You know, the COACH trial, which was a Phase 2 trial looking at gemcitabine-oxaliplatin. Once again, there's some early data that gem-ox would be better tolerated with less side effects than gem-carbo and the big challenge, for example, when we see these patients that come in with trigonal disease that have renal failure and just can't get cis and they go to surgery knowing that, you know, they're probably not going to do well long term. Any agent that could be given in patients with poor renal function could give a benefit to patients. So, they had very impressive response rates that were similar to gem-carbo, but there was one subgroup where they sort of did a sliding comparison of renal failure and those with the worst creatinine clearance under 30 have potentially the best response to the gem-ox at like 60%.

So, I thought that was impressive because we have, once again, another bullet in the arsenal to treat these tumors, especially considering that most patients, you know, 30 to 50% of patients won't get platinum so at least we have something else to give them that seems to be more tolerated and even do better in patients that have poor kidney function.

Alicia Morgans: I completely agree, and I would love to see this study done in a little bit of a larger scale with a particular focus on those patients with the lowest creatinine clearance because as you mentioned to me just a few moments before we started, it's really those patients who seem to have maybe a poor response to gem-carbo and a more robust response to gem-ox and anything we can do to target the right treatment to the right patient is, I think, going to be beneficial. And this data makes me want to see a much larger scale study so that I can appropriately treat these patients. It's not uncommon that people don't have good kidney function and we really do need to have effective options for them as they reach that point.

Josh Meeks: The last paper that I thought was interesting and honestly was more thought-provoking than anything was this randomized trial of adjuvant chemotherapy combined with radiation therapy after radical cystectomy. This was originally reported kind of a while ago. Once again, it was from the Cairo area so they had a very squamous enriched population. This was just the urothelial patients and only around 150 of them, but these were people with high-risk disease, stage three or higher, node positive, almost half of them were node positive. And they got either 45 gray versus two cycles of gem-cis 45 gray, followed by two more cycles of gem-cis so it was really comparing this adding adjuvant chemotherapy add to response in the adjuvant setting compared to radiation alone. And they do show an improvement in disease-free survival of around 60% for disease-free survival of two years.

So, if you think about that enriched population, for example, node-positive disease, it's not surprising that chemotherapy helps, but I think it's surprising that you can have such a high disease control rate in patients that have pretty aggressive disease, so we don't routinely use radiotherapy here, but I think considering that in people with high-risk tumors may sort of enter into our adjuvant therapy treatments.

Alicia Morgans: So, I agree and actually was just speaking with one of our radiation oncologists about a patient who would have met criteria to enroll in this trial just a few days ago. The Egyptians are really raised, sort of leading the charge in this from what I can tell, at least in terms of published data. Does this study sort of give you pause and make you think about using radiation with or without chemotherapy in those patients who have positive nodes and maybe big tumors after cystectomy?

Josh Meeks: Yes. I think, you know, certainly in people that don't qualify for adjuvant trials to evaluate checkpoint. I mean, I think, realistically offering folks access to those trials is going to not only potentially help them, but move our field along to figure out if this is something we should be doing. But there are some people who just can't get on those trials or, you know, you just don't, you're, you know, are not really qualified for them. So, I think this is another possibility. A lot of radiation oncologists are, don't feel comfortable giving adjuvant radiotherapy after cystectomy because of potential bowel toxicity. But this clearly shows it can be done and done safely and sort of adds to the potential therapy options we give people.

Alicia Morgans: True. But it is important, as you mentioned, to make sure that we're not doing these things just off trial without, or without experience, to kind of approach this in a systematic way and to make sure that we are conscious and aware of that and that we limit toxicity as we try to improve disease control. So, I really appreciate you taking the time to go through all of these presentations from GU ASCO, would love to hear some final thoughts, overarching messages of what do take home from GU ASCO 2019?

Josh Meeks: Well, I think GU ASCO 2019 gave us a real sense of where the field's going, you know, checkpoint used to be the horizon that we thought was going to be the end-all of how we care for patients and clearly it's become used and used liberally, but probably going to be used with other agents. And so then finding, you know, after checkpoint what's the next best thing in sort of applying novel technologies is going to have a big impact on metastatic urothelial carcinoma, but also in the earlier stages long term.

Alicia Morgans: I agree, and I look forward to continuing to treat patients with you and to hear your thoughts on these exciting developments, and I really appreciate your time today. Thanks so much, Dr. Meeks.

Josh Meeks: Thanks, Alicia.