Alicia Morgans: Hi, I'm so excited to be here with Professor Matt Galsky, who is joining us to talk about the co-primary endpoint analysis of HCRN GU 16-257. This is a phase II trial of gemcitabine, cisplatin, and nivolumab with selective bladder-sparing in patients with muscle-invasive bladder cancer. Dr. Galsky is joining us as a professor of medicine at the Tisch Center Institute at Mount Sinai. So excited to have him here to talk about the work that he presented at GU ASCO 2023. Thank you so much for being here with me today, Dr. Galsky.

Matthew Galsky: Thank you, Dr. Morgans. Always my pleasure.

Alicia Morgans: It's always my pleasure and it's always exciting to talk with you. I just love how the work that you're doing really shifts our thinking around some of the conventional standards that are, really, decades old when it comes to bladder cancer. And in this particular trial, you're not just looking at this combination to understand the clinical complete response, but you're helping us to think about how we actually judge the response to neoadjuvant treatment and whether we can potentially spare patients from definitive treatments like cystectomy when they don't necessarily need it. I think the whole thing is really thought-provoking. So, would you mind setting up the trial for us? Tell us what you studied.

Matthew Galsky: Sure. Of course we know that with cisplatin-based neoadjuvant chemotherapy, a subset of our patients will have a pathological complete response, 30-40% depending on the study that you read. And we know that that's associated with a highly favorable prognosis, of course, not because what's happening in the bladder, because the bladder comes up, but because of that representing probably a surrogate for eradication of micrometastatic disease. I think we've all had the experience where we tell our patients that they've had a pathological complete response, we're very excited for them, and that they look at us a little bit like we're crazy, that we're telling them that there was no cancer in their bladder after their bladder was removed.

And so, clearly, this is not a new concept whether or not a subset of patients can be treated definitively with TURBT followed by systemic therapy and not need definitive local therapy. This dates back decades. Harry Herr published on this decades ago with MVAC, demonstrating that a subset of patients can retain their bladder with this approach.

I think one of the limitations with a lot of these types of paradigms though in medicine are that they're studied and they're sometimes studied in single centers and written up as retrospective series, but not a whole lot of prospective investigation of this topic. I think one of the reasons for that is because there's been a lot of concern about the disconnect between clinical and pathologic staging, and that's really been the barrier to advancing this paradigm. That individuals will argue that you really can't determine who has a path CR with just clinical staging. I think a lot of that data is certainly important to acknowledge, but the limitation with that is that when we talk about a response assessment, of course we have to define it very rigorously and consistently, and we have to approach it as rigorously as we do any biomarkers. So that's really what we sought to do.

We sought to accomplish two goals. One, to see if we could add immune checkpoint blockade to chemotherapy to even increase the benefit more. And we designed the study in 2016, so this was a strategy that was really attractive at the time. And the other was, could we rigorously assess and consistently define clinical complete response as you would with any biomarker to establish the performance characteristics, such that we could trust clinical complete response to guide treatment decisions in the future?

Alicia Morgans: I think that's what is so forward-thinking about this, because, to your point, clinical staging is something that can be challenging with muscle-invasive disease. And of course there are those among us, probably even including myself, who have argued that we don't want to lose the opportunity for cure for those patients who may be under-staged by the clinical assessments.

One thing that I think is so interesting in this particular study is that you, as you mentioned, were extremely rigorous about how you defined clinical complete response. This was standardized for all patients, mandating biopsies and other assessments. Can you tell us, of course, you gave the treatment, you can explain maybe what the treatment was, what are the schedule for the neoadjuvant treatment, and then how did you judge clinical complete response?

Matthew Galsky: The eligibility was pretty standard eligibility for a neoadjuvant study. Patients who were cisplatin eligible with muscle-invasive bladder cancer, T2 to T4a N0 disease. Patients received four cycles of gemcitabine, cisplatin, plus nivolumab, and after the fourth cycle, they underwent clinical restaging, which included an MRI in all patients, unless contraindicated. I could come back to the MRI issue because I think it's important. And then cystoscopy with biopsy of any visible tumor. If there wasn't visible tumor, then biopsies in a template in the bladder, and urine cytology. All of those assessments were combined to define clinical response in all of those assessments had to be normal for a patient to be judged to have a clinical complete response.

Alicia Morgans: And then you also assessed for progression-free survival and other disease control endpoints. How frequently did you do these assessments to understand if the patients may have had recurrence, and what did that follow up look like?

Matthew Galsky: The way that the trial was designed is that patients who had a clinical complete response based on those assessments were offered the option to have a cystectomy, which, of course, would still be standard of care, or not have a cystectomy and proceed with an additional 4 months of single-agent immune checkpoint blockade and then just surveillance after that. Patients who didn't have a clinical complete response, we recommended that they proceed with cystectomy.

So we weren't sure, at the time that the study was designed, how many patients with a clinical CR would choose cystectomy versus not, and so the trial endpoints were two-fold, there were co-primary endpoints. The first primary endpoint was just to define the clinical complete response rate because it hadn't been assessed formally before, and the second was to determine the positive predictive value of complete clinical response for a composite outcome measure. The reason we had to use a composite outcome measure, of course, was because we weren't sure if patients would have cystectomy or not. And so we didn't want to use a bladder intact survival endpoint, because that would be biased if patients opted for cystectomy. You can't really fault the response assessment for that.

The composite outcome measure was 2-year metastases-free survival in patients who had a complete clinical response and opted for no immediate cystectomy or pathologic response less than T1 disease in the bladder if they opted for immediate cystectomy. Of course, the reason for 2-year metastases-free survival in patients who opted to retain their bladder is the point that you made before, that, really, our priority was demonstrating that this was safe in that patients who opted to retain their bladder immediately, that we weren't going to compromise long-term outcomes.

Alicia Morgans: Great. And so, what did you find, Dr. Galsky?

Matthew Galsky: The complete clinical response rate was 43%, and it turns out that aligned really closely with our assumptions. I should mention, 76 patients enrolled, 33 patients had a complete clinical response. 32 out of 33 opted for no immediate cystectomy. So I think patients certainly were voting with their feet, as they say, in terms of the approach that they preferred to pursue in that setting. The positive predictive value of clinical complete response for 2-year metastases-free survival was 0.96.

We had designed the study seeking a lower bound of the confidence interval above 80% for the positive predictive value, which was achieved. And so we think that clinical complete response, as assessed and defined in the study with this treatment regimen, is associated with highly favorable prognosis and could potentially identify patients who can safely avoid immediate cystectomy. And I think that the key thing there is immediate cystectomy because of the 33 patients who opted for no immediate cystectomy, 8 had local recurrences and subsequently underwent cystectomy, and that survival, of course, that metastases-free survival, is including that potential for, quote-unquote, salvage cystectomy.

Alicia Morgans: Among those patients, did any of the patients develop metastatic disease that would then of course render them incurable?

Matthew Galsky: 2 patients of those 33 developed metastatic disease. 1 patient who did have a local recurrence ended up having a cystectomy, and then about a year after cystectomy, developed metastatic disease. The other patient, somewhat curiously, had no evidence of local recurrence even on cystoscopic reassessment at the time that they were found to have malignant ascites as the sole presentation of metastatic disease. So it's a little bit of an unusual situation, but, yes, that occurred in those 2 patients.

Alicia Morgans: But I think, to the initial point regarding patients making these decisions about whether they proceed with their bladder intact or whether they move on to cystectomy, it's really interesting that that patients were very clear in that decision making process. And so, I wonder, from my perspective, this doesn't necessarily suggest that adding nivolumab is going to get us a higher complete response rate, although I'd love to hear your perspective on that. But it does, from my view, set a potential standard for prospective trials in terms of bladder-sparing opportunities that don't even necessarily involve radiation as a consolidative treatment. I would love to hear your thoughts on both of those.

Matthew Galsky: Yeah, I think there are a couple take home lessons. I think, one, I'm not completely sure what concurrent Nivo adds based on the study. But what I will say is that, I think, sequential Nivo added something. And remember that in the metastatic setting, concurrent chemotherapy plus immune checkpoint blockade, not necessarily a home-run yet, although there are questions about Cis versus Carbo, but switch maintenance therapy has really changed management. And this is essentially switch maintenance therapy in the muscle-invasive bladder cancer setting. Only patients who had a good response to upfront chemo were able to get single-agent immune checkpoint blockade. So that's one reason why I think the Nivo added something.

The other thing reason I think it might have added something is that there was a study that was presented at ASCO GU as well, the RETAIN study, which is a little bit of a different design, but there are similarities there. The metastases-free survival was much lower for patients who opted for no cystectomy in that study, and I think one of the differences in that study versus ours was the use of maintenance immune checkpoint blockhead.

I think, to your point, the other potential interesting finding of the study is, even if the community isn't ready to fully embrace no definitive local therapy, and I think one could argue that, but even if that's the case, I think this establishes that clinical response is an incredibly important prognostic marker, in that we're enamored with pre-treatment genomic biomarkers and others, rightly so, but we ignore in situ to response to treatment as a means to proceed with risk-adapted personalized treatment strategies. And so, one could envision patients undergoing clinical response assessment and then concurrent chemoradiation or bladder-sparing for those who've had a complete clinical response in an effort to identify the patients who will do most well with that approach based on in situ to assessment of treatment with systemic therapy.

Alicia Morgans: Well, certainly something that is exciting for patients and I think a bit paradigm-shifting, at least in the ways that we have considered clinical response in the past. So, really excited to hear that. Now, you did make a mention of commenting further on MRI and I'd love to hear what you were thinking about there.

Matthew Galsky: Yeah. In the study, MRI was recommended and we got MRIs in 50 of the 76 patients that were enrolled. Those underwent blind central review and VI-RADS scoring was applied. VI-RADS, of course, a system that was developed for initial staging of bladder cancer, but one could apply that situation to restaging imaging as well. And what we found is that if the restaging imaging was VI-RADS 1 or 2, then that was highly significant for its association with metastases-free survival. So then there's this extra element that perhaps using uniform imaging, we could identify patients to triage for bladder-sparing after initial systemic treatment in personalized treatment decisions, even more.

Alicia Morgans: Really exciting and I look forward to seeing where things go. To that end, where do things go from here, Dr. Galsky?

Matthew Galsky: We have version two of this study that's ongoing, and then version three, which has been approved for funding but has not opened yet. Version two is based on the concept that the complete pathological response rates with single-agent immune checkpoint blockade really do rival that's achieved with supply based chemotherapy. And so, could we extend this approach to an even larger subset of patients by using a treatment that could be applied to a larger subset of patients?

So we have a study with single-agent Pembro. Patients get two doses at the 6-week dosing interval and then undergo clinical restaging. If there's not a complete clinical response, then they're offered the opportunity to either have concurrent chemoradiation or cystectomy. So, more approaches integrated into that study for bladder sparing. And if there is a complete clinical response, then a maintenance immune checkpoint blockhead. This study's been ongoing for about 6 months now.

Alicia Morgans: Fantastic. Well, I appreciate your time, your expertise as always. If you had a message for listeners or for patients summing this up, what would it be?

Matthew Galsky: I would say that, with all of the new drugs that have become available for the treatment of bladder cancer and the drugs in development, I think, as clinical investigators, we really have to think about developing treatment paradigms rather than necessarily developing drugs. I think our pharmaceutical partners, of course, develop drugs very well and really what I think what clinical investigators in academia have done well in the past is really developed new treatment paradigms, and we should keep revisiting our old treatment paradigms and think about how we might be able to make things better for patients and ultimately integrate these new tools that we have in a different way.

Alicia Morgans: Well, no one seems to do that quite as well as you and your team. Congratulations on this work, and thank you for taking the time to share it today.

Matthew Galsky: Thank you.