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Alicia Morgans: Hi. I'm delighted to have here with me today Dr. Josh Meeks, who is an Assistant Professor of Urology at Northwestern Feinberg School of Medicine. Thanks so much for coming to speak with me today.

Josh Meeks: Thanks for having me, Alicia.

Alicia Morgans: Great. So you have done a lot of work with the cooperative groups, SWOG in particular. Thinking about bladder sparing, I know we work together to do bladder sparing in our clinic, and I'd love to hear your thoughts on the SWOG study, the 1806, which is about to open, and really, I think, take this space by storm. So can you tell us a little bit about this study?

Josh Meeks: Yeah, we're so excited for our SWOG/NRG 1806, which activates on Friday. This trial has really been in development, I'd say, for about a year and a half, and during that time, I mean, it truly has been a complete multi-cooperative group effort. Obviously, NRG, it's just been at the cutting edge of really, in my opinion, once again, as a surgeon, redefining what a chemo-radiotherapy regimen is that we really should be following across the country, so that's really one of the benefits of this trial, that if you want to ... If you look at the MGH sort of group and NRG, they've really put a beautiful protocol about how to do this.

Very similar, from a surgeon, people doing things differently in different places ... They've really made a very nice standardization of how to do radiotherapy for treating bladder cancer. So, it's that, and then the trial is randomizing patients 1:1 to get chemo-radiotherapy and then chemotherapy is a little bit of dealer's choice is going to be sort of chosen based on patient comorbidities, and then obviously, the treatment arm is going to receive atezolizumab. You know, I was involved at the TM part of this, with Felix, Petros, and Bishoy and really, just the TM was a ton of work and incredibly exciting, trying to figure out what these biomarkers would be that we could potentially look at their predictive of response in the atezolizumab arm. We're incredibly excited to do this.

Once this is done, this will be the largest trial in chemo-radiotherapy in North America. So, over 400 patients, it's got a ton of energy and enthusiasm and could really change how we look at this disease.

Alicia Morgans: I completely agree and I want to emphasize my appreciation for the group because it has been NRG, SWOG, Alliance, ECOG. I've participated through the ECOG arm. And they've been able to come together around the radiation schedule but also around the systemic therapy because there's been a lot of challenge actually as a medical oncologist to sort through all these Phase 2 studies. None of them are really head-to-head or regimen against regimen. They all have different radiation schedules. How do we think about the best treatments to give? I think for the non-cisplatin eligible population that's easier, you know, we have a nice study that tells us about 5-FU/mitomycin and that benefit, but for the cisplatin eligible patients, it's hard. So that's really been standardized. Yes, it's dealer's choice but it gives us a backbone on which to build as a field, which is hugely important. It has helped our clinic, I think, as well.

Josh Meeks: Yeah, the option for single-agent gemcitabine as well.

Alicia Morgans: Yeah

Josh Meeks: What are your thoughts about the PRO involved in this trial?

Alicia Morgans: So, I am really appreciative that we were able to incorporate that. You know, that can be something that is forgotten sometimes, but just as correlatives are so important in understanding which patients are going to respond to therapy, I think it's important to understand what the patient experiences, and actually right before we recorded you mentioned that there really hasn't been an involved assessment of quality of life for patients who have undergone bladder sparing, and we make assumptions about what these patients like, what they prefer, what they're experiencing, but we don't know. So in this trial, there's a really nicely designed multi-cooperative group assessment of quality of life and I really think we're gonna get some better understanding of what the patient experience is like on a broad scale in this large trial, rather than just the physician's interpretation of some CTCAE toxicity data, for example.

Josh Meeks: Right, and that's actually part of the primary outcome of bladder intact disease free survival, so part of that is having a good, functional, healthy bladder that people are happy with as opposed to undergoing a cystectomy for symptoms. I think we'll get a lot of important data from the control as well as from the therapeutic part of it. I'm really excited about this one.

Alicia Morgans: Yeah. You know it's really interesting though, too, that there are other protocols going forward looking at bladder sparing. A lot of enthusiasm in the field, certainly with our group and with others, and I think some of these are really built on understanding which populations may be best served, and where can we de-escalate therapies to try to avoid over-treatment, avoid the toxicities, and I would say that there is sort of, we've had our own discussions in our clinical trials group about what's safe, what's not, and I appreciate it that everyone's trying to really push the envelope here. Can you tell us about some of those trials?

Josh Meeks: Yeah, I mean I think all of this really starts with basic questions of looking at patients that have gotten chemotherapy in a neoadjuvant setting. So we're lucky if we have that paradigm, and then are there biomarkers in their tumor that can help us predict response or not response. Do multiple trials, the Sloan Kettering group, the Fox Chase group, both showing that DNA damage repair, specifically the ERCC2 mutations, other DNA damage repair pathways, RB, ATM. If you have those certainly you're in a much greater chance of having a zero, a T0, and as a surgeon when I take a bladder out that's a T0, I'm curing the patient, but you always wonder how that patient will do long-term. So this trial is asking that in a prospective fashion. So there's two of them at least we know that, the one through Alliance that the patient gets genotyped, and then they'll go on to get chemotherapy and if they're a complete responder and they have the DNA damage signature they have the ERCC2 mutations that are functional, they get the opportunity to keep their bladder completely. So, you know -

Alicia Morgans: Without radiation.

Josh Meeks: Without radiation, right. So that's outstanding. So, if they're able to show that that is successful, then that's a huge benefit both for bio-marker driven research in bladder cancer and then from a patient perspective. That's amazing, right? So, because you've taken local therapy out of the equation. I think then the next question is what else can we do to figure out how to obviously improve that and not just be that very small percentage of patients. But I love the fact that we're asking those questions and certainly the fact that it's all stemmed from important biologic questions that people have been really working on for the past several years.

Alicia Morgans: Absolutely. I do want to mention one little bit of hiccup in all of, at least, you know, from our discussion, the complete response is based on a pathologic response just on a TUR -

Josh Meeks: A clinical response, right?

Alicia Morgans: A clinical response, to be very, very clearly a clinical response, based on the TUR, so it's not taking out the bladder and then looking for that pathologic CR, which is what we kind of benchmark as a success, it's a clinical response on a TUR.

Josh Meeks: So you think a cystectomy should be done for the first few folks just to make sure that -

Alicia Morgans: So, I don't know what the right answer is, but that is my concern that clinical staging in bladder cancer can be a problem, and I'd love to hear your thoughts because we go back and forth on this in our clinical trials meetings and you're always very clear about your thoughts and I always love your enthusiasm, so just would love to hear your thoughts about, you know, how this can work. Because I think it's possible, you just have to help us get over our fears.

Josh Meeks: Well I think there's a lot of ways you can do it, one imaging is so much better, so if you look at some of the imaging that's been done very recently, for example in the PURE-01 Study, you know you have before and after, and very good visualization comparison of imaging to pathology. So, I think that's gonna help us a huge amount, that we didn't have before.

The second potentially would be more biomarkers we can see. Ultimately it's gonna be patients that will tell us say, whether they're gonna have to take a risk or not, unless there's some lead-in where people would get a cystectomy and say, see a clinical response equals pathologic response, but I think there'll be a lot more, in the future, of trials that will have the opportunity for avoiding local therapy and then for many of those, some of those folks that don't have a complete response, that's where the trial enrollment would come in.

Alicia Morgans: Absolutely. And like you said, I think a lot of this is gonna be driven by patients. Because patients don't want to be over-treated. They ask me, and I know they ask you over and over, how can I avoid losing my bladder and if I don't have to undergo radiation and have all of those, sort of lower urinary tract symptoms, how can I avoid that, so they need to drive this at the end of the day, and that patient and investigator clinician partnership I think is really key and is really a fantastic thing that I've seen in bladder cancer recently, so thank you for playing such a big role.

Josh Meeks: Oh, it's been my pleasure.

Alicia Morgans: Thanks.