Melanie Cole, MS (Host): Today, we're exploring the implications of the FDA's recent approval of TAR-200 or Inlexzo, a novel therapy for bladder cancer as the first and only intravesical drug-releasing system to provide extended local delivery of a cancer medication directly into the bladder. We're taking an in-depth look at this new potentially practice changing approach as a breakthrough with the potential to transform patient care, especially for those with BCG-unresponsive bladder cancer.

Welcome to Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole. And joining me today is my guest, Dr. Joshua Meeks. He's the Edward M. Schaeffer, Professor of Urology, Associate Professor of Urology, Biochemistry, and Molecular Genetics at Northwestern Medicine.

Dr. Meeks, it's such a pleasure to have you join us today for this exciting new development. Give us a little bit of a brief overview of TAR-200 or Inlexzo, the novel therapy that's recently been approved by the FDA for bladder cancer.

Joshua J. Meeks, MD, PhD: Thanks, Melanie. It's great to be back, and super excited time for those of us who take care of patients with bladder cancer, because I really think that this is one of those times when you could potentially mark this day as a sea change in how we treat patients.

If you look back to the history of how we've treated patients with bladder cancer, you know that the bladder is so close to the outside world that, as urologists, it's just made sense for us to put therapy into the bladder in order to address superficial or non-muscle-invasive bladder cancer. And you know, most of the time those are just washes. The best comparison is, you know, it's kind of a mouthwash for the bladder and that makes a lot of sense to treat a superficial tumor.

But, you know, the bladder has a number of barriers that go down to, you know, the superficial layers where the cancer is. And so, those washes, those are very temporary. Probably the longest we ask a patient to hold a therapy is two hours. A lot of folks can't hold the therapy longer than 20 to 30 minutes. So, the ability to put therapy into the bladder while feasible often has practical limitations. And so, it's not uncommon for someone to come in once a week, every week for, say, for example, six weeks to get a treatment to try and keep their cancer away.

Now, what's novel about Inlexzo is that it is a device that is placed into the bladder, and it's a tube that has gemcitabine, which is a chemotherapy that we've used as a wash, but those are in pellet form. And once the device is placed into the bladder, it folds on itself like a Bavarian pretzel. And that shape allows it to be retained in the bladder. So, we place that device into the bladder and it sits there for three weeks and gives off continuous therapy over that time. And then, at three weeks, we remove the device. And depending on where the patient is in their treatment course, another device is replaced.

So, we're here today really to talk about their major paper, which was just published less than a month ago,  SunRISe-1 was the clinical trial. And the way that that device is delivered and the way that we plan to give it to patients is that, in the first six months, the patients will get devices every three weeks. So, those are eight devices. Once they achieve that induction phase, then they go into maintenance where they receive a device every three months. So, you know, in the beginning, it is a fair number of device exchanges, but you can imagine the bladder is receiving six months of continuous therapy. And the benefit from a cancer perspective is that the tumor is always being exposed or the lining is always being exposed to treatment. It's a much longer duration of therapy. And again, that's why in our study that's been published in  SunRISe-1, the response rate was so high. So, 82% of patients achieved a response. And then, 53% maintain that over 12 months.

The exciting thing to our patients is that when you look how fast that works, 96% of people who got a complete response had that by the first cystoscopy. So, that's quick action. That's high rates of response. And then, that's durability. So, that's going to be a game-changer for how we treat patients with bladder cancer. And again, this is in the setting of BCG-unresponsive bladder cancer. Those are particularly hard to treat. But that's the first trial. That's why it's  SunRISe-1.

You know, if you look at the next stage, which is a trial we had open at Northwestern, that  SunRISe-3, that's in the BCG-naïve setting. Those are people that were just diagnosed with high-grade bladder cancer. Comparing it to BCG, that trial, we put patients on that they enrolled here in Chicago. That trial's closed. I think we're excited to see the results of that.

Another setting that was just published last weekend was actually  SunRISe-4. That's muscle-invasive, such stage II to III, IV bladder cancer. Patients receive the same Inlexso device, plus a checkpoint inhibitor cetrelimab, and actually had an impressive response, a 42% complete response. There is some sense that not only is this a treatment for superficial cancer, that there's actually some penetration to the deeper layers of the bladder. So, we see this playing a role basically through all stages of bladder cancer.

Melanie Cole, MS: Wow, that's really amazing and very exciting. Dr. Meeks, what was your involvement in the research and how did Northwestern Medicine contribute to the FDA approval process?

Joshua J. Meeks, MD, PhD: So, this trial actually began a long time ago. And the beginning of it was like all trials on the slower end. You know, I think we've really contributed to multiple other  SunRISe trials that have come from this, because it was very clear from the beginning that this was a new way to approach this, that the engineering was there, that from a patient perspective, this is something that our patients would want. So, you know, we've had multiple other  SunRISe trials open  SunRISe-3,  SunRISe-5. Believe it or not, this is not the only pretzel-shaped device that Janssen or Johnson & Johnson have created. They have another device that's targeting FGF receptor 3, that's the TAR-210. We have multiple of those trials open. So, those are the MoonRISe trials, MoonRISe-1 and 2, again, a change in how we deliver therapies now. So, our patients have been very happy to be involved in this and, honestly, have done a great job, because we think this is sort of the next horizon of therapy for patients with bladder cancer.

Melanie Cole, MS: Dr. Meeks, what specific contributions did you make during the clinical development and trials of this therapy? How did your expertise, which we know is significant, influence the direction of this that increases the quality of life of patients going through this treatment in the first place?

Joshua J. Meeks, MD, PhD: Again, it's been a huge international study. The things that we've been specifically involved with, number one, was device insertion and removal. There's some patient and physician-related reported outcomes coming out about how urologists put this device in. What patients think about it, what are the challenges. Because with this new therapy comes a lot of new potential obstacles. So, you know, urologists who are very used to putting catheters in are not used to putting therapies in. So, like all people who do sort of things at the cutting edge, you have to go through a learning curve. So, we did that probably three to four years ago and sort of tried to figure out when we couldn't put a device in what was the cause. So, we've contributed on that end. I think on the other part of it, we're now involved in some of the translational work, trying to understand at the tumor level those very few patients that don't respond, is there any genetic targets, is there anything that could explain why they didn't respond? Or when they develop resistance, what are those next strategies? So, that's work, that's ongoing and, we're, we're sort of looking forward to getting those reports out.

I think those have been sort of the major contributions to this  SunRISe-1 or the Inlexzo studies in early BCG-unresponsive bladder cancer.

Melanie Cole, MS: Speak about patient selection, Dr. Meeks, and what providers should consider as they implement this new treatment and discuss it with their patients in their practices to ensure that optimal patient care. Speak a little bit about the patient selection for this.

Joshua J. Meeks, MD, PhD: Yeah. So, one of the things that we learned early on with. This specific cohort of patients, the BCG-unresponsive cohort, is that their bladders are not the same as other patients, meaning they've already seen a fair amount of therapy. They already come in with a good bit of urgency. And in fact, you know, if you look at  SunRISe-1, this study, the first cohort was cetrelimab plus TAR-200.

And the reason that that was largely discontinued was that there was a high degree of adverse events that that stopped people from putting the device in. Interestingly, we don't see that in the earlier stage bladder cancer before people have gotten BCG. So, I take that all the way back to say that people who have bladders that have a fair bit of urgency already, you know, there is some coaxing a lot of back and forth that we kind of have to do. For some patients, it's not that many. But still in the beginning when they first receive a device, I think there is some healing that needs to occur in the bladder that patients have to kind of get over that BCG cystitis. There's some tricks from our end that we can do to sort of make that a more comfortable experience. But I would say that trying to work through the bladder-related symptoms of patients until they get to the point where their bladders have healed some more. That's probably the biggest thing.

Otherwise, the Inlexzo is really a great option for many patients right now for BCG-unresponsive bladder cancer. And I think when you look at our options, we've gone from almost none to multiple options. My sense is that this is going to sort of move to the front as far as what urologists are providing for patients.

Melanie Cole, MS: Can you expand on what you just said, Dr. Meeks, about speaking with the patients, about device insertion and living with it and getting used to it? Are there some strategies? Can you give us a few of those that you recommend for other urologists? Because this is something now you were so involved in and know so much about. Educate other urologists here on how they can help to inform their patients.

Joshua J. Meeks, MD, PhD: I think that the biggest thing for patients when we start talking about having a sort of a retained device in their bladder, the biggest thing is hydration. The more people drink fluids in the beginning, the more the device is able to move around and the less they sort of feel it. There's some patients who don't even know the device is there. They have almost no symptoms whatsoever. And then, alternatively, there's other people who can really sometimes feel it moving around. And I'm not sure what the difference is, if you look at the rate of discontinuation, it's under 3%. So in general, it's incredibly well-tolerated.

I think, for the most part, people are pretty resilient, especially as they start seeing, you know, their bladder's looking more and more normal. But, you know, there's medications we can give patients to calm the urgency of their bladder down. We've tried different medicines to alter the pH, a little bit of their bladder. But the biggest thing is hydration and discussions of what you're feeling is not abnormal. I think the only thing else that we've really tried to work on is trying to do device insertion and removal in a sterile way as possible. Because if you look at sort of the more higher risk adverse events, those are patients that potentially get infections and having a device in for three weeks, that's a foreign body, if that gets infected, we usually try to treat with antibiotics through that. But sometimes, maybe this isn't the right therapy for patients or they just need a break to clear their infection. And we certainly have had people who've needed a bit of a break. And then, upon resuming therapy, they're sort of in a better place. Their bladder's healed a little bit, and they actually do quite well.

Melanie Cole, MS: This is really just so exciting. Dr. Meeks, how do you envision this therapy influencing the future treatment landscape for bladder cancer? Explain a little bit about how this therapy will specifically impact the care and outcomes for patients with BCG-unresponsive bladder cancer and where you see it going in the future. Give us a little blueprint for further research.

Joshua J. Meeks, MD, PhD: In general, 25-30% of patients will not respond to BCG, now we have a therapy that has an 82% response rate. We're probably moving to this relatively soon after we get a sense that the cancer is not responding to BCG. It wouldn't surprise me if this becomes a very early option for patients.

I think, downstream, the main question will be, is this a therapy that we're using instead of BCG. And when we look at the muscle-invasive side of the bladder cancer portfolio, does this become a therapy that we're using to treat the cancer to prevent or instead of bladder removal? I really see it as a novel treatment that's going to have widespread impact. And, you know, the sky's a limit on what this can do to really improve both the quality of our patient's life, the length of their life, as well as their ability to retain their bladder that works.

Melanie Cole, MS: Thank you so much, Dr. Meeks. What a great guest you always are. Thank you again for joining us. And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/urology to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole.