Brendan Guercio: Thank you. Thank you very much for having me.
Zachary Klaassen: We've seen a ton of therapeutics in this disease space over the last five to 10 years or so. Just at a very high level for the listeners, what's these PCR rates from a general range that we're looking at now?
Brendan Guercio: Yeah. So we've seen a lot of significant improvements, thankfully, for our patients. With the gemcitabine, cisplatin, and durvalumab regimen from the NIAGARA trial, we see path CR rates of about 37% now. And with enfortumab vedotin, and pembrolizumab, or EV+P, we're now seeing pathologic complete response rates of 55 or 57%, which is really outstanding given the historical context.
Zachary Klaassen: Yeah, absolutely. From your state-of-the-art lecture, really sort of bringing this all together, just give us a couple of key highlights from the lecture you presented at ASCO.
Brendan Guercio: First, that patients who achieve a pathologic complete response, or path CR, do exceptionally well. It's a very positive prognostic marker. And second, for patients who receive cisplatin-based neoadjuvant chemotherapy alone before cystectomy and achieve a path CR, the standard is still surveillance for those patients because they do well.
But for patients that are receiving the regimens that we use more often now, these perioperative immunotherapy-based sandwich regimens, which are referred to as such because they sandwich surgery between preoperative and postoperative systemic therapy, for those patients in the clinical trials, the standard was to resume systemic therapy after surgery regardless of pathological response.
Zachary Klaassen: I think as a surgeon who takes out bladders, none of these patients want to take their bladder out. And so we're looking for ways to spare bladders, but spare it in a safe manner and really get the oncological benefit from that perioperative treatment and then safely not take the bladder out. Quality of life issues. All these things we know. In your multidisciplinary group, when you're having these discussions, currently, what are the patients where you're thinking, okay, maybe this patient has a path CR? What is your sort of criteria, your guys' multi-D approach?
Brendan Guercio: Yeah. I think it's a really great question that obviously a lot of our patients care a lot about.
Zachary Klaassen: Sure.
Brendan Guercio: Unfortunately, I think our tools for selecting patients in this situation are still a little limited and require further validation.
Zachary Klaassen: Sure.
Brendan Guercio: We know historically that a clinical complete response is defined by cystoscopy, imaging, and urine cytology might misclassify residual muscle-invasive bladder cancer in around 25% of patients. Hopefully, newer technologies like MRI, circulating tumor DNA, urinary tumor DNA, maybe even AI, I think are going to really improve our ability to correlate clinical complete response in pathologic complete response, but we're not quite there yet in terms of prospective validated data for that approach.
Zachary Klaassen: Yeah, absolutely. Speaking of all those things, and that's exactly where I think we're at, what combination of those, or maybe all of them, do you think it's going to take for the medical oncologist, the surgeon, to say, "Hey, you've had a really good response. X percent chance you've got a muscle-invasive disease, we can maybe safely not do a cystectomy."
Brendan Guercio: I think it's really going to take all the data we can get. I think that eventually we're going to be getting MRIs, circulating tumor DNA, urinary tumor DNA on all of these patients, maybe repeat TURBTs to try to identify the patients that really can safely forego both cystectomy and bladder radiation since both come with significant morbidities.
And we're in the process now of generating prospective data to really look at those questions with exciting trials like EV-209, EV-309, work from the Hoosier Cancer Research Network, but we don't have that prospective data yet. We do know that even these exciting tools are not perfect. In the NIAGARA trial, 50% of patients who had negative ctDNA before cystectomy still had residual bladder cancer at the time of surgery. So more investigation is still needed before these are available for primetime clinical use.
Zachary Klaassen: Yeah, it's a great summary. No, I think if we look five years ago, we didn't have very many of these great systemic therapies. We've talked about EV pembrolizumab. We've talked about NIAGARA. We have the tools now to get that path CR. Just figuring out who those patients are is going to be crucial. Would you agree?
Brendan Guercio: Absolutely. Exactly right.
Zachary Klaassen: Fantastic discussion. This is such a hot topic among both med-onc and urologic oncologists. Any parting thoughts for our listeners? Any take-home messages?
Brendan Guercio: Most importantly that systemic therapies for muscle-invasive bladder cancer are now very effective and more tolerable than they used to be. There's very few patients with muscle-invasive bladder cancer that should not get some form of perioperative systemic therapy like enfortumab and pembrolizumab. And hopefully in the future, we'll have better data with ctDNA and other biomarkers to better tailor that perioperative approach for our patients.
Zachary Klaassen: Yeah. Great take-home message. Brendan, thanks so much for joining us on UroToday.
Brendan Guercio: Thank you.