Individualized Decision-Making According to Disease Characterization

In the second part of this roundtable series, Drs. Chang, Qin, Jayram, and Bourlon expand on their individual approaches to different disease characterizations, like EGFR+ disease, as well as their thoughts on applying systemic therapy in the intravesical setting as detailed in the SUNRISE-1 trial of TAR-200. The panelists discuss other clinical trials and their impact on community-setting practice.

The NMIBC panelists include Sam Chang, MD, MBA, Vanderbilt University Medical Center; Qian Janie Qin, MD, UT Southwestern Medical Center; Gautam Jayram, MD, Urology Associates of Nashville; and María Teresa Bourlon, MD, MS, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán.

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Sam Chang, MD, MBA:
So let’s go nitty-gritty. Let’s actually drill down into specific patients. All right? Specific situations, scenarios. And we’ll start off with a low-grade bladder cancer, a few small tumors. Dr. Qin, Dr. Bourlon, you guys won’t see those patients, correct?

Maria Teresa Bourlon, MD, MS:
Not usually. I mean, those are patients that are usually diagnosed and seen by urologists and as Dr. Qin explained, they usually get to us whenever they’re looking for additional options. They have gone through many intravesical therapies, they have failed those therapies, and they’re looking for something else that’s not cystectomy and that’s how they get into systemic therapy options, mainly immunotherapy, that’s what we have. There’s no role for chemotherapy or targeted therapies in this scenario, or they’re looking for innovative intravesical therapies most of the time. So they go for us looking for another option different than intravesical or a cystectomy.

Dr. Chang:
Got it. So all right, low-grade patient papillary. Right now we have trials that are opening, that are starting. Anything exciting for you, Tom, in that, let’s call that group of patients the intermediate risk patients. So those are patients that tend to have recurrent disease, that tend to have low-grade disease, tend to have papillary disease. Anything exciting in that space for you?

Gautam Jayram, MD:
Yeah, there’s a lot of interesting things, and specifically when you think about the fact that we didn’t really have much at all a few years ago, and a lot of us in the community still don’t do much for these patients. We use perioperative chemotherapy, a single dose of gemcitabine or mitomycin after the resection. But we know these patients still recur at a pretty high clip over the next two to three years. And so there’s a lot of trials with intravesical agents. I think one of the really interesting things that’s emerging in this group of patients is their incidence of EGFR alterations in their tumors. We’re seeing up to about 60% of patients in this group have EGFR alterations and now we’re starting to be able to target those. And specifically, there are some trials that are targeting these both with the pretzel, with putting Erdafitinib into the pretzel and targeting these patients who are EGFR positive. And then actually there are oral EGFR inhibitors now that are being developed to try to see if that can make a difference. So that’s a really exciting, I think biomarker-driven personalized approach.

And then with a lot of these other interesting agents that are being developed in the higher risk space, we’re seeing, and we know this from BCG gemcitabine docetaxel, we’re seeing that those are very effective also in intermediate risk patients. So I think in that group of patients, it’s a special consideration because a very, very small percentage of patients are going to progress to high-grade disease. Very small. But quality of life is really important. Freedom from major interventions is really important. We don’t want to be taking these patients for TURBTs with general anesthesia every four months. And so I think the calculus is a little bit different. We’re not looking at, okay, well we don’t want you to die from bladder cancer. We’re looking at, we really don’t want you to be bothered by this at all. We really want to maximize quality of life and so it’s kind of a different mindset.

Dr. Chang:
So with many of the disease processes, obviously the more advanced disease, the more aggressive disease we tend to study those individuals first, and that was the case with kidney cancer. That was the case with prostate cancer. That’s been the case with urothelial carcinoma. And so now we’ve gone from advanced disease to invasive disease and we have a lot of trials now focusing on that patient population that is BCG unresponsive. That’s where the pembrolizumab systemic therapy obviously has gotten an FDA approval in the US and that’s where a lot of intravesical therapies have really started, not only to get approval, but also being studied and also being reported.

So let’s talk about some of those exciting BCG unresponsive. Dr. Qin. You talked a little bit about pembrolizumab and the data associated with that. Anything that you and your colleagues at UT Southwestern then consider? Let’s talk about available medications now for those patients who are BCG unresponsive.

Qian Janie Qin, MD:
Yeah, I think for available therapies, it seems most of them are still in the intravesical stage, right? We’re talking about chemotherapy or one of the newer agents, I think N-803 I’ve heard of. Another one with a very long name that’s adenovirus-

Dr. Bourlon:
[laughing].

Dr. Qin:
Thank you. Yes. I just can’t say. So I’ve heard of that utilized in the BCG refractory setting. In terms of clinical trials or kind of exciting things on the horizon from a medical oncology perspective of course, our role is more in that systemic therapy. So I think there’s two folds to that. One is, can we bring systemic therapy into the intravesical setting as you’ve discussed? So what that means is systemic therapy has systemic therapy side effects, Erdafitinib, very terrible side effects in a certain cohort of patients that have started on Erdafitinib. But can we do it intravesically, right? And can we do it with potentially some of the newer sustained delivery systems like TAR? I think TAR-210 was the Erdafitinib kind of version, the intravesical sustained release version for Erdafitinib.

And then I think what would be most interesting is there’s studies looking at immunotherapy combined with intravesical therapy. So those trials are ongoing, but can we move other things into this space? Enfortumab vedotin, as you’ve said in advanced setting, has really changed the landscape of how we treat advanced bladder cancer in combination with pembrolizumab. So can we move EV into the intravesical setting, which I think there has been studies looking at it, but then again, can we incorporate that into TAR or our novel delivery systems? So I think it’d be very interesting to see how some of these advanced therapies can then move into the intravesical setting. Can we use novel ADTs? Now we have bispecifics and such. So can we move these into the earlier setting, not by introducing systemic toxicities, but utilizing and kind of more the localized space.

Dr. Chang:
So Dr. Bourlon in Mexico City, in the US, these intravesical therapies are 99%, or I would say a hundred percent, maybe 110%. I mean basically all those patients that get intravesical therapies, they’re placed within the urologist office, either by MDs or advanced practice providers. In Mexico is that also the case or do medical oncologists also start engaging in placement of these intravesical devices?

Dr. Bourlon:
Mostly the pattern is these patients are seen by urologists. They are seen for diagnosis, intravesical BCG, then intravesical chemotherapy as an option that’s something that we’ve used for years. And nowadays, they’re getting trained in autophagy and also in these interleukin-15 agonies, which is also approved. But that’s a therapy mainly delivered by urologists, right? It’s intravesical therapy. So mostly they’re seen at urologist offices, but sometimes they might not have available neither of these intravesical options other than BCG or chemotherapy and the only other alternative, as we’ve mentioned, is systemic pembrolizumab. So that’s why we see those patients and they usually refer to us because urologists wanted another option or the patient didn’t want cystectomy or didn’t have any other intravesical treatments available and that’s why we see those patients. But they mainly go to the urologist’s office or they’re look into clinical trials or try to look for other options. And they get into do because they have done the research in the website, but usually they’re seen by urologists.

And there’s another challenge because now we need urologists to get trained in all these new therapies. It’s not the same thing as BCG. They might be slightly different. You need to place a device inside the bladder and you need some training and not all urologists are well-trained in treating non-muscle-invasive bladder cancer.

Dr. Chang:
Yeah, no, actually a very good point. The nuances as part of our original discussion regarding risk stratification of these patients who we formerly used to have a dearth of options and now we have a significant number of options other than BCG or single peri-optic chemotherapy in terms of what we do for these patients with higher-risk disease.