Eugene Pietzak: Nice to be here.
Ashish Kamat: So, there's a lot going on on bladder cancer, and of course there's a lot going on as far as the readouts of different trials in bladder cancer, but I'm always excited when we have an investigator-initiated study that makes it to the grand stage. So, first of all, congratulations.
Eugene Pietzak: Thank you very much.
Ashish Kamat: And I heard your presentation, very well presented, I'm sure folks in the audience were able to get all the nuggets, but for our wider audience at UroToday that's listening from different parts of the world, could you summarize your study and the key critical findings, and what people can take from it in their practice?
Eugene Pietzak: Sure. So, we had conducted an investigator-initiated trial as you mentioned at Memorial Sloan Kettering, of patients where we felt were most likely to potentially benefit from treatment intensification over BCG alone. So, the BCG-naive space, as you know, and your audience is probably familiar with, there's been several randomized controlled trials at this point, CREST, POTOMAC, which were statistically positive, with potential benefit in reducing the risk of, or I should say a statistically significant reduction in non-invasive recurrences, but not yet an appearance in reducing the risk of progression, but at the cost of significant amounts of treatment-related adverse events. And then we have the ALBIN study, which was statistically negative, and saw no real difference between that, and of course KEYNOTE-676, which is pembrolizumab plus BCG is reading out.
But that population is very much like the CRESTON, POTOMAC studies. So I would anticipate potentially going to have similar results. But if you look at the subsets enrolled in those studies, very few patients actually had very high-risk T1 bladder cancer. So, we intentionally enriched for a cohort with high-grade T1 with a carcinoma in situ component, and they needed at least one additional risk factor for progression. So, large T1, large tumors, multifocal T1 tumors, T1B, variant histology, prosthetic urethral involvement, vascular invasion.
Ashish Kamat: So, exactly the kind of patient that you and I would probably want to counsel on a radical cystectomy-
Eugene Pietzak: Exactly.
Ashish Kamat: ... and maybe not enroll in a study where we don't know what-
Eugene Pietzak: Yeah. Yeah, the type of patients you definitely feel uncomfortable with BCG alone, you would recommend cystectomy. And as you know, most patients have grown very fond of their bladder, and looking for an approach where they could do that. So, that's basically who we enrolled. And in fact, the criteria for enrollment was that they needed to be recommended for radical cystectomy and decline surgery. So, we enrolled those patients, it was a 37 patient study, our primary endpoint was the complete response rate at six months, and we did not do biopsies on protocol, it was only for cause. So, this is based off the clinical complete response, which is definitely a limitation of the study. So, it was based off office cystoscopy and cytology, but the top line results was basically we saw a 92% clinical complete response rate. The follow-up is still ongoing, but at a median follow-up of 22 months, we saw no patients that had progression to muscle-invasive disease or metastasis.
There were only four high grade recurrences, and there was only two cystectomies that were performed. But we did see the expected side effect profile by adding immune checkpoint blockade. So, we saw a 21% rate of immune-related adverse event, and many of those are autoimmune-related and life-changing really.
Ashish Kamat: Yeah. No, so when you look at the data that came out from the larger studies that you mentioned, and you saw yours, again, with the small numbers, the conference intervals could be similar. So, let's just say 25%. So, based on this data that you have, have you changed how you think about counseling patients when it comes to the very high risk NMIBC patients that are saying, hey, Dr. Pietzak, what is the best treatment I can do for my bladder short of a radical cystectomy?
Eugene Pietzak: Yeah, I think as you know at this point, none of those treatments are FDA approved for BCG naive disease at this point. So, I think our data is going to be very informative if one of them does make it over the finish line with FDA approval, and potentially provide a little bit more confidence that for the patients that I think are most likely to benefit for treatment intensification, they may potentially benefit. Of course, the caveat is ours was not randomized. BCG, as you know, performs very well when it's given with induction and maintenance. So, there are a little caveats, but in terms of counseling patients at this point in time, I often feel very uncomfortable giving BCG alone. But since we started running the study, we see more and more of these patients and they're definitely out there, and I think there's an opportunity to try to provide better treatments for them.
Ashish Kamat: Yeah. I think one of the good things about having these large studies read out is that we have shown, and when I say we, it's the community has shown to people that might have been non-believers that BCG when done appropriately still is the best immunotherapy we have for any cancer, and especially bladder cancer, but it's not perfect, and we can certainly raise the bar and address these very, very high risk patient populations by adding an agent, but it comes at the cost of toxicity. So, again, just not to put you on the spot necessarily, but if you have a young patient, let's just say he's in his 50s and has T1 high grade, T1B, CIS, multifocal, and is asking you, short of taking my bladder out, I would like to get the best treatment option, would you, now knowing what you know, feel comfortable... Full caveat, small number of patients on your study, et cetera. But would you be comfortable offering this combination off protocol to such a patient, or you're still looking at the toxicity data?
Eugene Pietzak: Yeah, I think that's difficult because as you highlighted, they're young, right? We're talking decades, and our follow-up is only for 22 months, and although the larger randomized trials have longer follow-up, they're still only about three to four years out at best. So, when I'm counseling patients, their urothelium is at risk for recurrence for the rest of their life. So, I'm definitely very hesitant, those are the patients I definitely counsel more towards radical cystectomy. But for the patients that are adamant and refusing it, I think one of the nice things that being centers like ours is we have outstanding colleagues in geomedical oncology. So, I would potentially refer the patient to meet with one of the medical oncologists, and have that conversation, and then have probably a more of a multidisciplinary type of conversation. I do think it is potentially going to be an option for patients in the future, but again, as you said, the risk-benefit trade-offs really, that calculus needs to make a lot of sense.
Ashish Kamat: And again, I know with such high CR rates, it's going to be hard to come up with a dichotomy of biomarkers, but any clues as to biomarkers that might suggest who may or may not do well with this combination?
Eugene Pietzak: Yeah. So, we're just now starting to get into the correlatives studies for that. So, we're going to be looking at blood and urine because in part, many of these patients may potentially have some circulating tumor DNA. So, we'll be analyzing that as well as tissue level, and as I mentioned, ours is non-randomized. So, we have a non-randomized comparison group of patients with T1 getting treated with BCG alone. So, we'll hopefully be able to parse some of that information out, but for the time being, the best biomarkers we have is really just the clinical grading stage. And I think we're very fortunate to have outstanding pathologists, who when they report the extent of lamina propria invasion, or those particular details, really could signal whether there's a variant present or not, and guide you one way or another at this point in time. But I think towards the future, we're looking for molecular or an AI-based type of approach.
Ashish Kamat: Yeah. No, so I think we know with CREST and POTOMAC and with KEYNOTE-[inaudible 00:08:10], I think which will read out similarly, that's going to be a good large patient cohort, and then we'll have data such as yours to help us on the clinical side feel good about selecting certain patients for these therapies, right? Because the way I look at it is if somebody comes and tells me, hey, listen, I don't want my bladder out, but I have this very high risk disease, what do you think? I would look at POTOMAC, and I'd say, "Okay, I'll look at that," and I look at your study, and I say, "Okay, I have data to suggest that adding an IO for you might be better than BCG alone." Caveats are small numbers, obviously toxicity factors in. So, congratulations, and thank you for taking the time.
Eugene Pietzak: No, thank you very much, I appreciate the opportunity, both at the AUA for highlighting an investigator-initiated study, but also for you and UroToday as well for giving me this opportunity to speak.