乌鸦传媒

Pembrolizumab (Keytruda) demonstrated antitumor activity in patients with bacillus Calmette-Guérin (BCG)-unresponsive, high-risk non-muscle-invasive bladder cancer (NMIBC) with non-carcinoma in situ (CIS) papillary tumors, according to findings from the phase II , presented at the American Urological Association (AUA) annual meeting.

乌鸦传媒 brought together three expert leaders in the field. Moderator Alexander Kutikov, MD, is joined by Adam Reese, MD, and Laura Bukavina, MD, MPH, all part of the , for a virtual roundtable discussion. This first of four exclusive episodes covers their reactions to results from the KEYNOTE-057 study.

Following is a transcript of their remarks:

Kutikov: Hello and welcome everybody to the 乌鸦传媒 AUA roundtable. I'd like to welcome my friends and colleagues, Dr. Adam Reese. Dr. Reese is a member of the Fox Chase-Temple Urologic Institute and is chief of urologic oncology at Temple University Hospital. He's an associate professor at the Lewis Katz School of Medicine at Temple University, and it's a privilege and a pleasure to work with Adam and to have him here at the roundtable. I'd also like to welcome Laura Bukavina, a young force in urologic oncology. She's currently at Fox Chase Cancer Center, a Society of Urologic Oncology fellow, and soon to join the faculty at Case Western Reserve University. Welcome, Laura.

Bukavina: Thank you.

Kutikov: So, today we're going to go through four key abstracts that were presented at the American Urological Association meeting in Chicago just a few weeks ago. We'll cover KEYNOTE-057, this is the pembrolizumab in unresponsive non-muscle-invasive bladder cancer study; we will cover the CORE1 trial, which is CG0070 combined with pembro; the exciting TAR-200 gemcitabine-eluting pretzel, the SunRISe-1 trial; and the CheckMate 274 trial.

So let's kick it off. Laura, you want to tell us a little bit about the KEYNOTE-057 results?

Bukavina: Yep, sure, thank you for having me. So, first of all, I think most of us are aware what KEYNOTE-057 is, but just as a reminder it's pembrolizumab in non-muscle-invasive bladder cancer that's BCG-refractory/recurrent. So per FDA criteria, pembrolizumab was given to patients who underwent BCG therapy, which is defined as five plus two, so minimum of five induction therapies plus two within 6 months of BCG.

And then they defined the recurrence as any persistence of disease or any new recurrences in disease or any progression of disease. So pembrolizumab KEYNOTE-057 trial was actually 57 multiple institutions worldwide, so a huge effort on the part of the investigators -- unfortunately, only able to recruit about 120 patients for the study.

BCG studies, as many of us know, are single-arm studies. They don't need to have a comparison group. So pembrolizumab was a single-arm study looking at two different populations, two cohorts, one which was presented last year, I believe at GU ASCO, was papillary disease plus CIS, which we know has a complete response rate of about 70% at three months and about 19% at 12 months.

Now, this was updated results on the non-CIS, so just papillary disease, Ta/T1, high-grade non-CIS patients. And we can see the similar response overall in terms of complete response; however, slightly higher rate in terms of 12-month disease-free recurrence and complete response rate at about 30% to 45%, depending on how you look population-wise.

As I said, incredible effort from many of the investigators and patients with this trial. However, we do have to consider how pembrolizumab is given. So it's Q3 weeks infusion therapy in patients for 2 years. This was the inclusion criteria. If you look at their actual breakdown of patients that were able to tolerate therapy, only about 22 patients actually went through the complete therapy. There were multiple reasons, people either progressing through therapy because of progressive disease. There were patients who are not able to tolerate because of complications. We know grade 3 complications were about 15%, many of them including lifelong complications such as hyperthyroidism and colitis.

So it is a therapy that's available. However, I think we need to have a discussion in terms of the right patient, the right timing, and really whether we should be pursuing pembrolizumab in our patients for this disease.

Kutikov: Perfect. Thank you, Laura. So, Adam, given the 1-year disease-free survival of approximately 40-plus percent, do you consider these results practice changing? I mean, again, this data that was presented here was for papillary disease, non-CIS, so slightly different cohort than what the FDA approval was for.

Reese: Correct. Yeah, thanks, Alex. I'm excited to be here today and participate. So I think these results are certainly clinically significant and potentially practice changing. I mean, we're all aware this is a notoriously difficult population of patients to treat, the standard of care for these patients for many years has been radical cystectomy, but clearly many of these patients are either medically unfit for surgery or refused surgery due to the significant morbidity associated with it.

So, as Laura kind of mentioned, this report reported about a 43.5% 12-month complete response rate, which really compares quite favorably to response rates that have previously been reported in similar immunotherapy studies in this space. Going back to cohort A of this same KEYNOTE study, that was the cohort that looked at BCG-unresponsive CIS, the initial complete response rate at 3 months for those patients was about 41%, and disease-free survival at 12 months was only about 20%. So here in this cohort reporting a 43.5% disease-free survival at 12 months, it actually compares quite favorably and it is actually quite impressive.

So if nothing else, this study provides us with some great data that we could use to counsel patients, and it suggests that about four out of 10 patients are going to be disease free when treated with this regimen at 1 year.

Kutikov: So, Adam, let me ask you also, 20% went on to cystectomy and 11% I believe were upstaged to muscle-invasive disease. Thoughts? Thoughts on those data?

Reese: Yeah, I think the 11% upstaging rate is reasonably low and is to be expected. And I think this speaks somewhat to the inaccuracies of clinical staging in bladder cancer. I know this is something that both you and I have looked at in the past, albeit in a different setting, after neoadjuvant chemotherapy. But there we found that patients who are thought to be non-muscle-invasive after neoadjuvant chemotherapy, who then go on to cystectomy, the upstaging rates are on the order of 20 to 30% or even higher. So, here an upstaging rate of about 11% is reasonably low. And I think it suggests that most patients, there was not a significant progression of disease while they were undergoing treatment.

The other thing about the cystectomy data that I thought was interesting is that all of the patients that were upstaged to muscle-invasive disease never achieved an initial complete response to pembro therapy. And the other way of looking at that is, so of all the patients who achieved an initial complete response to pembro and ultimately went on to cystectomy, none of those patients were found to have muscle-invasive disease at the time of cystectomy. So I think taken together these data suggest that at least a trial of pembrolizumab in these patients doesn't appear to delay treatment, such that we're missing a potential window of cure in these patients.

Kutikov: Yeah, great. All great points.

Bukavina: Can I make a comment? So I think in these patients, if you actually look at some of their plots, if you look at the progressive disease within 6 months on pembrolizumab, which is a great litmus test for our patients, right, so if you go from Ta to T1 high grade within 6 months, that population has no overall benefit from pembrolizumab down the line. So if you have a patient who's going from Ta to T1 6 months on pembro, I think that's pretty much a guarantee that they should not continue therapy and then go straight to either clinical trial or cystectomy.

Kutikov: Yep, hard to disagree with that. Good points.

So, Laura, let's pivot a little bit to the side effects. So 73-74% of patients had treatment-related side effects, with almost 15% experiencing grade 3 or 4. Given this side effect profile, how do you evaluate this risk/benefit of pembro in this setting?

Bukavina: I think, for me, I have to respectfully disagree about the utility of pembrolizumab and sort of our therapy approach for non-muscle-invasive. I think the complications and the adverse events that are happening with pembrolizumab are far above and beyond what intravesical therapy is currently providing us, right? So we have a lot of alternative therapy available for patients for BCG-refractory disease that fares equivocally and potentially even better in terms of disease-free survival, in addition to having significantly less side effects profile.

So, do we really need to push pembrolizumab as our primary therapy in BCG-refractory disease considering these adverse events that we're seeing? And we have to consider that this is continuous infusion and a lot of these side effects, although they do happen about 14% of patients are lifelong, meaning lifelong therapy will be required for these patients. Diabetes, hypothyroidism, colitis, and death, and sometimes sepsis in these patients.

Kutikov: Yeah, I mean there's definitely hesitation in the urology community to sort of dive into the immunotherapy pool and I think you bring up great points here.

Adam, barring that, if we do sort of give our patients immunotherapy, these immune-related symptoms, do you feel like they're in the wheelhouse of urologic oncology? I think that's the big debate out there. Or do we need to send every patient to our medical oncology colleagues?

Reese: Yeah, I guess I would say that management and identification of these symptoms is something that wouldn't traditionally be considered in a urologist wheelhouse, but I certainly think it's something that we really need to take the time to educate ourselves on and become more familiar with. These agents are still relatively new, they weren't around when most of us underwent training, and they do have, as Laura mentioned, fairly significant and somewhat novel toxicity profiles that we're not too familiar with.

So certainly we need to familiarize ourselves with these types of complications in both identifying them and then basic management strategies for these toxicities. But I do think it kind of stresses the importance of a close interdisciplinary relationship between urology and medical oncology. As a medical oncologist, at least for now, probably have more experience in this realm and can certainly help us in managing a lot of these adverse events.

Kutikov: So perhaps call to action for our society is to provide urologists with resources to acquire these skills if certain practices choose to pursue these therapies in-house.

Bukavina: Yeah. One last comment, Alex, is that this trial, because it started several years ago and compared to the new trials that we're going to discuss later on in terms of intravesical therapy, this trial, particularly how they defined CR [complete response] is very different to how the new trials are defining CR.

So the new trials define CR as actually biopsy proven. Random biopsy or targeted biopsy, no evidence of disease. However, this trial was based only on cystoscopy, as well as cytology, which we all know is not 100% in terms of diagnosing disease. So can we actually trust these numbers in terms of disease-free recurrence rate? If you compare one trial to another and there's such heterogeneity in terms of how they define the recurrence of disease, I don't necessarily know if we're looking at the same sort of percentage of CR.

Kutikov: Yeah, very challenging. That's a great nuance. And, as you know, the work that we've done here at Temple, showing that under-staging even in bladders that looked perfectly normal is up to 25% in patients with muscle-invasive disease. So to your point, Laura, what may look normal or somebody may brush it off, may actually be a undetected recurrence.

I think for the young generation that's listening to this now, non-muscle-invasive bladder cancer is just a huge opportunity. There's so many unanswered questions and it's great to see all the interest that this disease is now receiving because there's just so many opportunities to improve our patients' lives and improve the treatments that we provide for them.

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