Case 1: Novel Agents in Superficial Bladder Cancer

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Arlene O. Siefker-Radtke, MD:Given our ability to better interpret data, I’m sure the new and novel agents coming through the urology clinics are very exciting to the field. What do you think is going to be the next great advance in the treatment of superficial bladder cancer?

Gordon Brown, MD:Well, I think there have been a couple of promising trials that we’ve been engaged in, and certainly I think have been reported out on recently—one being the KEYNOTE-057 data, which looked at the use of pembrolizumab in patients who had high-risk non-muscle invasive disease. They recently reported their data at about 15.8 months follow-up. This was a phase II single-arm trial that looked at pembrolizumab at 200 mg Q3 every 3 weeks for up to 2 years. These patients were surveilled with cystoscopy every 3 months initially, for 2 years, then every 6 months for 2 years. If they recurred then they went into a survivorship arm of that trial.

The primary end point of this trial was really to look at CR [complete response] in this patient population. Understand this was a heavily pretreated patient population. On median, these patients had had 12 rounds of BCG [bacillus Calmette-Guerin] intravesically. They recently reported data on the first arm, which was the arm looking at the combination of patients who had CIS [carcinoma in situ] plus/minus a papillary tumor. About 65% of these patients had CIS alone, roughly 25% had CIS and Ta disease, and about 10% had CIS and a T1 lesion.

And when they reported on their data, they see their complete response rates at 12 months of follow-up of about 40%. This trial was predicated based on the results from the PURE-01 trial, the neoadjuvant trial. And as we’ve seen in other disease states in oncology, we’re seeing some of these successes potentially move a little further, more proximal in the disease state. And the toxicity in this trial seemed to be pretty manageable, which is going to be important to us in the clinic. For the most part, these patients are asymptomatic to begin with. I think the grade 3 immune issues in this trial were about 3%, and the overall AEs [adverse events] were somewhere in about the 28% range for grade 3/4 of treatment-related AEs.

The real question becomes what’s the durability of a treatment like this in this patient population? And we’ve seen recurrence rates, we see about 53% of those patients still having persistent CRs at their recent report. So that holds a lot of promise in terms of potentially changing the landscape of the management of patients with high-risk superficial disease.

Arlene O. Siefker-Radtke, MD:Do you think we’re going to see an FDA approval of pembrolizumab based on these data, or do we have to wait for larger studies?

Gordon Brown, MD:I think you’re probably going to see an FDA approval of this because we juxtaposed these results to what’s currently available for the same patient population. There’s a paucity of treatment options, short of cystectomy, in this patient population. And it appears that based on the preliminary data we’re seeing, that the results are potentially disease changing and paradigm changing in terms of how we approach this patient population. So I do think it will become approved, yes.

Arlene O. Siefker-Radtke, MD:OK. So we can perhaps anticipate that in our medical oncology clinics, or do you think the urologists are going to prefer to give pembrolizumab?

Gordon Brown, MD:I think that that’s an interesting discussion. We know that a handful of us are giving it on trial. I think if we’re going to choose to do this from a urology perspective, certainly outside of an academic medical center, we’re going to have to make sure we have the infrastructure available to support that endeavor. Although, for the most part, these are well tolerated drugs with minimal toxicity profiles. The toxicities that do occur are not insignificant and can be life-threatening. So I think this is not a space that I would want to see anybody dabble in but rather have confidence in what they’re doing. And if they’re not going to be doing it, I would advise them to get the patient to somebody who is going to be able to do it well.

Arlene O. Siefker-Radtke, MD:How about agents outside of immunotherapy, is there anything else coming down that’s looking good?

Gordon Brown, MD:There is one other exciting piece of information that was recently reported in the high-risk superficial bladder cancer space. It was the results of the INSTILADRIN trial, which was just updated. Initially, this was a trial which was reported out in 2017 by Neal Shore, MD, FACS, who looked at the use of basically an adenovirus vector that harbors recombinant human gene for interferon.

This process or concept was really built out of the bladder cancer support work that you guys are doing at MD Anderson Cancer Center. And this was a phase II trial that looked at 40 patients. Their updates to that trial were just recently delivered at the SUO [Society of Urologic Oncology] section of the AUA [American Urological Association] 2019 annual meeting. What we see there is that we have 14 patients who are complete responders on that trial. Of those, 10 were still alive and around to be evaluated at 3 years of follow-up. And 6 of those patients remained NED [no evidence of disease] or CRs out at 36 months of follow-up.

Again, that’s compelling. That’s something that from a urologist’s perspective we might be a little bit more comfortable delivering on a consistent basis in the clinic, this intravesical therapy. The response rates seem to again dwarf anything that’s available in the clinic setting to manage this high-risk patient population. So that’s very promising. They have now just completed accrual of a phase III trial with the same therapy, again looking at primary end points of complete response in that patient population.

Arlene O. Siefker-Radtke, MD:It sounds like we have several promising options coming through that our urologists are going to be interested in giving, and also our medical oncologists will be perhaps pulled in to help and assist, especially with pembrolizumab. Any of your thoughts? Are you getting referrals yet, Betsy or Tian, for pembrolizumab?

Elizabeth R. Plimack, MD:So far we, as a group, only really advocate giving this as part of a clinical trial. I think, Gordon, some of the points you raised are really critical to reemphasize. One is this is a curable patient population, so we have to, in my mind, be curing them with this or at least some of them, if it’s going to be relevant and approvable and come into practice. Maybe we are. I agree, the data are encouraging, but long-term follow-up is really important, especially for that end point. So we’ll have to see. As we can show, there are a number of trials for patients looking at immunotherapy, and I think right now our role is to populate those trials so we can learn the best combination, whether it works with BCG, in what setting, and how many rounds of BCG they need before we should switch to and achieve benefit. And the more we emphasize populating those trials, the better we’ll be positioned to use it in the most relevant way.

Tian Zhang, MD:I absolutely agree, Betsy. There are multiple cooperative group trials as well as industry-sponsored trials of atezolizumab, pembrolizumab, and durvalumab in this space. I think it’s really important to populate those trials and learn from our patients. And it really highlights the multidisciplinary approach to our bladder cancer patients that we take in clinic. And so I do think we work side by side with our urologists, particularly in muscle invasive disease, but now maybe we’ll be seeing some of our non-muscle invasive disease patients, too, going on study.

Arlene O. Siefker-Radtke, MD:Great. I think this is a fantastic case regarding the multidisciplinary approach that we use for bladder cancer and how we’re using this to make these advances. I encourage everyone who’s listening, please refer your patients for these clinical trials because there are so many promising new agents being studied.

Transcript edited for clarity.