ESMO 2020: Combination Therapies in Locally Advanced or Metastatic Urothelial Carcinoma Bladder Cancer - Josh Meeks

September 28, 2020

In this clinical conversation with Alicia Morgans, MD, MPH, and Joshua Meeks, MD, PhD we hear their clinical perspective combination therapies when treating metastatic urothelial carcinoma. They discuss several studies with recent data from the European Society for Medical Oncology Virtual Congress, (ESMO) 2020 including the KEYNOTE-361 the DANUBE trial, and the IMvigor130 data presented at earlier conferences. 

Biographies:

Josh J. Meeks, MD, Ph.D., 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.

Read the Full Video Transcript

Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today, a friend and good colleague. Dr. Josh Meeks, who is a urologist here at Northwestern, as well as being an assistant professor of urology has a lab of his own, is a surgeon-scientist and a wonderful sort of student of the data. Thank you so much for talking with us today about the data from ESMO.

Josh Meeks: Thanks Alicia, it's great to be here.

Alicia Morgans: Thank you, Josh. So Josh, as you think about the data from ESMO 2020. Where do you go first? How do you start dealing with and thinking through that data?

Josh Meeks: Yeah, I think it was a really great meeting. I'm excited to be able to, take the data in over the course of last Saturday. All the bladder work was mostly presented on Saturday and the two major trials that I think kind of kicked everything off were KEYNOTE-361 and the DANUBE trial. Again, those two pieces can sort of go together with the ESMO 2019 data from the IMvigor130 sort of putting all three of those trials together. Again, all first-line trials, all a thousand patients, all really looking about the question of... They all had arms of chemo versus I-O monotherapy plus... And so again, for IMvigor130 it was atezolizumab at plus chemo for KEYNOTE-361 it was pembro plus chemo and then obviously for DANUBE was sort of the one-off trial.

It was durvalumab and tremelimumab. So, really interesting trials. Let's start with KEYNOTE-361. Again, that data read out with both PFS and OS not reaching their primary end point of showing a survival benefit. There was a PFS benefit that was very close and it looked good. Doesn't really fit in with what we see from IMvigor130, which has not read out the OS endpoint at this point. But I think, in general, we all were incredibly optimistic that adding chemotherapy to immunotherapy would really increase our survival for our patients in the first-line setting. But I'd say, unfortunately, we're still stuck at that 14 month time point and so I think overall, we kind of anticipated that obviously based on the press releases.

But I'm intrigued to find that. Again, we're not really able to push further than chemotherapy. I guess it tells us that, for better or for worse chemotherapy is still very, very good. Which is kind of, at least been our experience here that, that's kind of the standard that we begin with for many patients. Are you... I ask you Alicia... Again, as a surgeon, I'm more of a spectator in this arena. What's your thoughts on the combination data? Again, when we started these trials and I'm impressed that the community has so quickly been able to go through the data, the trials have started, finished, accrued and resulted. But what is your thoughts as a medical oncologist here?
Alicia Morgans:

Alicia Morgans: I completely agree with you. I think unfortunately, the data was a little underwhelming. But I would say that it is clear from what we can see that cisplatin-based combination chemotherapy is actually the way to go. That's the way that we've been going since the FDA mandate or warning, I should say, suggested that combination chemotherapy for any fit patient is actually probably the most efficacious. So for all patients, when I see them in the metastatic setting, or in the non-operable setting. We think about, can we give this patient chemotherapy? And if we can, can we try to get cisplatin into this patient? And again, if we can then move forward with cisplatin-based combination chemotherapy.

If we can't, then it's a little more nuanced because we're thinking about carboplatin and whether we need to use a carbo platinum combination, or whether these patients may be high standing for something like PD-L1 or tumor mutational burden TMB. But we don't have great data to suggest that TMB high or a PD-L1 high, for example, is really going to suggest that these patients are better off receiving a checkpoint inhibitor. So I guess the bottom line is we always try to get chemotherapy into patients who can tolerate it. We cannot always do that, but these trials seem to support that approach.

Josh Meeks: Yeah, I mean, other than the lack of efficacy of the chemo I-O combinations here, I was really impressed, just kind of really being able to pull out the checkpoint alone data. That, I mean, even when Biomarker Enriched wasn't as robust as we potentially thought. But I will say that, it's interesting all arms had, chemotherapy winning in the very beginning and then sort of the reverse as far as stabilization of those curves of immunotherapy, which seem to take over and those curves crossed. I mean, the curves definitely show that there's a benefit and I know that the numbers don't hit statistical significance. But clearly, there's stability that you just didn't really see with the chemotherapy as part of it. But again, the chemotherapy wins in the beginning and the immunotherapy win while it's termed. Which, coincident to Saturday was the release of JAVELIN 100 in the New England Journal.

So it was kind of funny that you had two trials that weren't successful, whereas what we thought is being successful and then you follow that up with a very successful press paper in the New England Journal. I guess, over the past year and a half, we've heard a lot about the label change and that there's patients with a poor performance status than medical oncologists don't necessarily feel they could get chemotherapy. Again, I think that field comes back to, it seems to come back to a comfort as far as how comfortable people are trying to push to get chemotherapy in patients. Certainly, I have a bunch of patients that saw me for a cystectomy. They progress by the time of the first scan and they couldn't get chemotherapy and they got single agent they've done well. So that suggests immunotherapy doesn't work in that frontline setting. But, what's your take-home now Alicia? Are there really patients that you think should be getting immunotherapy as first line?

Alicia Morgans: So my take on that is that the patients who really should be getting immunotherapy first-line are the patients who can't tolerate chemotherapy. I think what we saw from these trials is that chemotherapy is, as I said, very effective and I wonder in the JAVELIN trial, if we're really selecting out those patients who are going to respond and I think we've heard this from others, Elizabeth (Betsy) Plimack, for example, back at ASCO. We're selecting patients who are going to respond to treatment by saying in the JAVELIN trial, for example. You had to have stable disease or better in that trial in order to go on to maintenance avelumab. So we are really pulling out those patients who are going to respond and we're saying, Hey we're going to give you something extra. So it's wonderful that they then had a survival benefit as compared to their alternative, which was just monitoring.

But are these patients who will do well anyway? And what can we do for those patients who aren't able to have that stable disease or better in the chemotherapy setting? In practice, as we've talked about, in practice, if you have progressive disease during chemotherapy, what is your next line of treatment? Well, it's probably immunotherapy. And will that work? In many cases no. Of course we have things that are looking at NGS to identify patients who may have FGFR mutations or alterations that we can act upon through clinical trials. But these are probably bad actors and luckily we do have enfortumab vedotin which is not going to be a selected population.

But really after immunotherapy, that's where we end up. So, it's hard to know how much we're moving the needle, but I do appreciate that we know that if we have stable disease in the metastatic setting with chemotherapy, we can move right into I-O with avelumab and we can have pretty substantial benefit. So that's what I think, it's all chemotherapy and then this addition for those responders and we really are still trying to work out the heterogeneity of those patients who are not responders said initial chemotherapy.

Josh Meeks: Do you think those are about, what do you say 10 to 15% of patients that have progression on chemotherapy?

Alicia Morgans: It is and then I failed to mention of course, the patients who are not eligible for chemotherapy. So that's another saying 30% of patients when they're in the metastatic setting at least. That's about my population that I think when we get into other community practices, for example, that may be even a greater population. If those patients are presenting later or are afflicted with more comorbidities at the time of presentation. So it is a sizable percentage of patients that either don't respond to initial chemotherapy or are not actually eligible in the first place.

Josh Meeks: So your thought then is the JAVELIN population is the best that they can go on to get better. The population that I see similar to that, are those patients that get neoadjuvant chemotherapy and you rarely see progression. I think I've seen progression maybe a handful of times from a scan. They get neoadjuvant and then another scan before surgery. But, I would say that, the data is probably about 40% or so have significant residual disease after neoadjuvant chemotherapy and they do really poor long-term. I think worse, I don't know if it's worse per say, that the chemotherapy is selected out those worst population. Maybe, that's what our IMvigor010 population was that got, adjuvant immunotherapy. Those are already a chemotherapy resistant group.

To me that really is where we need to be focusing our attention is, how do we go after those tumors that are platinum-resistant? Because whether you're treating them in the neoadjuvant setting or the metastatic setting, getting over that lack of response ultimately probably decides a lot of their fate and we've got nothing for them. Again, I think I look at the neoadjuvant setting. I think that, really trying to figure that biology out is important. Do you think that, again the IMvigor130, KEYNOTE-361 data has any implication for a number of these trials in the neoadjuvant setting that are combining chemotherapy and I-O. Do you think it's the same disease? Do you think it's a smaller burden of disease and maybe less heterogeneous? Do you think that we'll see the same thing there? Do you have any thoughts on what we're going to see with those trials?

Alicia Morgans: Yeah. I mean, I really think that it's all about patient selection and this helps us select those patients who are going to be responders versus non-responders. But I don't know. I think that ultimately we still have trials that are ongoing, that will help us understand this better. So the AMBASSADOR trial through the Alliance that is being supported by all of the cooperative groups is trying to understand this. Andrea Apolo is really leading that charge for patients who have any residual disease after neoadjuvant chemotherapy and the new agiment setting. Then they go through their surgical procedures and then we understand how or we randomize them of course, to surveillance or to pembrolizumab So what is the answer going to be? I don't know. I am a little-

Josh Meeks: That's the opposite of JAVELIN, right? I mean, and so-

Alicia Morgans: Of course! I think he was thinking about the neoadjuvant setting and sort of selecting out these populations. But absolutely different than JAVELIN.

Josh Meeks: I mean, so like Niagra, for example. Is a big trial internationally, chemo plus I-O in the neoadjuvant setting, followed by adjuvant durvalumab. It'll be very interesting to see how these multiple drug, neoadjuvant trials compare to what we're seeing again with the first-line metastatic setting.

Alicia Morgans: I think that the data's still out there and we have to see, I certainly don't have any ethical reasons to not put patients on trial and if I knew the answer, I would have those concerns. I think that we still need to figure it out and I do think that things like what you're doing in your laboratory to understand the heterogeneity of these tumors is going to be really critical and understanding which patients are going to respond to these combination therapies in which patients are really going to need something else. My hope is that on the horizon, we are going to have that something else that we can use when these options don't work.

Josh Meeks: I agree, obviously totally that there's probably subsets of these cohorts that have responded very well. People cured and then there's subsets that just do very poorly and maybe looking at the extremes are what we should be doing to see what's going on there. When do we get people on drugs, different drugs sooner, or, what's really working in that group, that's responding well and how do we try to get mimic that in the others that are having less of a response? So I hope that, these big trials are an opportunity for, industry as well as for, people interested in this to figure out. To sort of delve into that and do some really nice translational work.

Alicia Morgans:  I agree and just, of course a shout out to your lab, as you're trying to do some of this work, because I think that we need to have many minds, many patients engaged to try to answer the question and as you're thinking about the data from ESMO this year. Is there any change that you're going to make in your practice based on these studies?

Josh Meeks: Well, again, I take care of patients at a much earlier setting. It makes me really think again about, for example, how we take care of carcinoma in situ. The argument that we're having with for the KEYNOTE-57 data or the SWOG 1605, single-agent immunotherapy with responses that are very similar, of anywhere from 20 to 27% at, three to six months. That's not too different than what you're seeing here and it makes me wonder if this thought of local control followed by, long-term maintenance therapy may, not being an unreasonable way to go. When we think about carcinoma in situ for example.

Alicia Morgans: I think that I agree with you completely and I look forward to Pharma and to others sort of supporting you as you move forward and hopefully start some of those trials because the paradigm, the JAVELIN paradigm. What we saw from Matt Galsky's were really in the metastatic setting. If we could move that earlier, if we have these refractory settings, can we do some sort of maintenance I-O? Can we get more of a response? That would be wonderful. Then if you and your lab could figure out for us, which patients may actually benefit from that, we would be even happier. So lots of work to do, lots of exciting stuff. What would your take-home message be from ESMO this year?

Josh Meeks: Again, I'm really impressed by how well the meeting went. I'm impressed by everyone's thoughts on how to interpret the data. I thought that was a very.... All the presentations were done quite well. Again, my take home from this is that immunotherapy works, chemo I-O together is additive, not synergistic and we need to continue trying. So looking forward to, sort of the next phase of a big trials that will be coming forward.

Alicia Morgans: Great. Well, I thank you and I thank you for your time, for your urologist perspective on this data. Which is not underwhelming, but could be perceived as so and it's really exciting if we think about it and sort of tease it out. So thank you so much and I appreciate it.

Josh Meeks:
Thank you Alicia
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