Expert Explores Trials in CIS-Refractory Bladder Cancer

Jason M. Hafron, MD, CMO

Professor of Urology

William Beaumont School of Medicine

Oakland University

Royal Oak, MI

Chief Medical Officer

Medical Director of Clinical Research

Michigan Institute of Urology

Troy, MI

IN THIS INTERVIEW, Jason M. Hafron, MD, CMO, discusses recent approvals in the non–muscle-invasive bladder cancer space and data from several clinical trials evaluating agents for bladder cancer. Hafron is the chief medical officer and medical director of clinical research at Michigan Institute of Urology, and a professor of urology at William Beaumont School of Medicine, Oakland University.

A lot of growth has occurred in the bladder cancer space, specifically with non– muscle-invasive bladder cancer. Could you describe some recent developments?

A: [The field of] bladder cancer is exploding. [It] is exciting, it’s changing, and we’re just at the start of this [in] that we are going to see a tsunami of new treatments and new indications. It’s very exciting. It’s also going to require a lot of education and understanding of how to apply these therapies. With that being said, we’ve seen 2 recent approvals in the CIS [carcinoma in situ] refractory space in patients who are cystectomy ineligible [and] who received adequate BCG.^1,2 And we have an intravesical agent that has been recently approved and is being used in a lot of our LUGPA [Large Urology Group Practice Association] practices.³

You mentioned that one challenge might be knowing when to use these agents or how to sequence them. Can you discuss this further?

A: These agents are very expensive. [They] have been studied in very specific patient populations, and so what we as urologists have to learn about is exactly what these indications are. I think the key is that these are for CIS-refractory disease plus or minus papillary disease. That’s the pathological requirement. And then [patients] also had to have received adequate BCG therapy. They’ve had to [have] received at least 5…of 6 induction therapies and 2…of 3 maintenance therapies for 2…of 6 inductions. So there is definitely some nomenclature and some wonkiness to this to figure out who qualifies for these treatments, but it’s very important that we understand this because these were the patients [who] were studied, and in the real world, this is what the payers are going to be asking for. Overall, all of this–the pathology as well as the BCG requirements[concerns] patients [who] refuse cystectomy or are medically ineligible to get a cystectomy. It’s a little wordy. It’s a little tedious to find these patients, but it’s really critical. Otherwise, you’re not going to get reimbursed for these therapies.

What are some of the agents coming down the pike in this space?

A: I’ve been very lucky to be involved in a lot of clinical trials, and we’re seeing a lot of trial activity. It’s almost comparable to where we were 5 years ago with prostate cancer. We’re really in this bladder cancer revolution.

There are 4 major trials that have completed or nearly completed looking at BCG-naive disease, so [these are] patients [who] are newly diagnosed, [with] highgrade T1 CIS or high-grade Ta, greater than 3 cm, high-risk disease. [The question] is that if we combine them with an immune-oncology checkpoint inhibitor, will that decrease recurrence and decrease progression? These trials will read out maybe next year, and I think that will be very exciting, because that would potentially change the standard of care in bladder cancer for a lot of our patients.

Visual Synopsis

The other trial [ENVISION; NCT05243550] that’s very interesting is for a product called UGN-102.⁴ It’s a reverse thermal gel similar to what we use in upper tract urothelial carcinoma. This gel is going to be indicated, pending approval, for patients with intermediate-risk bladder cancer, and it’s conceptually a cool idea. We’ll see how it [gets taken] up into the space, but it’s a chemo-ablative [agent]. So the thought here is…, can we use this gel to ablate tumors? But would that allow us to do [fewer] TURBTs [transurethral resections of bladder tumor], fewer invasive procedures on these patients? Because if you think about it, intermediate-risk bladder cancer typically is not a life-threatening disease, but it can be a high therapeutic burden and [carries] some risk to the patients that they [will] require repetitive TURBT. We’ll see. But again, it’s innovation. It’s new concepts, new drugs, which we know we need for this disease space, and it’s just exciting for us to see.

What we’re seeing is a significant amount of research being done in [patients with] BCG-naive, high-grade Ta, T1, and CIS. This is like bread-and-butter urology–a large patient population. And there are 4 major trials going on right now. I think all of them have [been] completed. There’s the CREST trial [NCT04165317], which is a subcutaneous checkpoint inhibitor. There’s [KEYNOTE-676; NCT03711032], which is pembrolizumab in combination with BCG. We’re also seeing the ALBAN trial [NCT03799835], which also is a combination trial with BCG and a checkpoint inhibitor. And lastly, the POTOMAC trial [NCT03528694]. The bottom line here is that what we’re critically looking at is, can we improve the recurrence rate of BCG with a checkpoint inhibitor? We all know that BCG is good, but it’s not perfect. There’s a high recurrence rate and even a worrisome progression rate. So if we apply a checkpoint inhibitor, can we improve that recurrence-free rate and prevent a lot of the aggravation…and a lot of the challenges that BCG affords? These are exciting trials, and these will have significant impact on the standard of care, obviously, if they’re positive, but I think we’ll start seeing, hopefully, results [by the] end of next year.