Past and Future of Clinical Trials: Stimulating Different Responses, Scheduling Considerations

In the fourth part of this series on NMIBC, Drs. Chang, Qin, Jayram, and Bourlon share what they anticipate for the future of clinical trials as well as the scheduling and logistic considerations of offering clinical trial/academic center treatments in the community setting.

Discussing these past and future landscape considerations for NMIBC are Sam Chang, MD, MBA, Vanderbilt University Medical Centerl Qian Janie Qin, MD, UT Southwestern Medical Center; Gautam Jayram, MD, Urology Associates of Nashville; and MaríaTeresa Bourlon, MD, MS, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán.

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Sam Chang, MD, MBA:
Dr. Qin, any specific kind of highlights that you’d like to hit regarding kind of the SunRISe-1 trial?

Qian Janie Qin, MD:
Yeah, what has already been said, really. I don’t have too much more to add for the trial itself, but what’s on my mind is what’s next. There are other trials looking at IO in combination with TAR-200, the SunRISe-3 trial in the BCG responsive realm.

Dr. Chang:
Yes.

Dr. Qin:
And then there are IO with BCG combinations, right? Again, in the BCG responsive realm. And I’m sure there are other trials with IO combined with something intravesical in the BCG unresponsive realm. So I think with how well TAR-200 monotherapy did, I think my question is how are those going to read out? Those combination therapies, which a lot of them are still going to take a couple years. Are we going to make any changes to those? Are they going to keep accruing? Because you have a very, very effective drug and it gets approved, that really changes the landscape of your trial enrollment because you want to give standard of care better than standard of care. So I think that will be kind of my question is how will this data change one, the standard of care moving forward once the longer readout, the 12-months and longer readouts, the disease-free survivals and all of that readout, is it going to change our standard of care? And if it does, then what happens to the currently ongoing trials? And then what’s your next design of trials? We have to think about any of those things.

Dr. Chang:
Yeah, Dr. Qin I think raises some really important points. When it comes to current trial, past trial kind of development. If you look at the agents that have been FDA approved, they were basically Phase 2 trials. And that was based upon the FDA type of advice regarding the fact that, hey, we were in a space where there were a dearth of options. No really good data, nothing really out there. And as a result, we had approval of a systemic therapy, pembrolizumab, and we had approval of Anktiva as well as Adstiladrin. Two different types of therapy based upon stimulating the immune response, different types of scheduling, but results, and we’ll talk a little bit about comparisons that we shouldn’t do, but we always do, but approved basically on Phase 2 type data. Now, just as you raised, we’ve got these options out there, how are we going to be able to evaluate? How are we going to be able to compare? Et cetera. And so having this data out there in the more advanced setting we’ll look at things as we go earlier in the disease process as well.

In those patients with BCG unresponsive disease, obviously we’ve had this discussion of avoiding cystectomy and being able to respond. Dr. Jayram, you used the term CR quite a bit. For the urologic surgeons, we don’t always use that. It’s like, is it their not. So CR being complete response, basically no evidence of disease. You talked a little bit about the three-month mark and the 12-month mark. And in all honesty, the data is non-comparable, but we’re always going to compare. So the difficulty that I’ve had is people will use different numbers and percentages to make it sound better, but over time, if you look at the overall cohort, I want to know if I start off with 100 people, what happens at a year? What happens at two years? Et cetera.

And so when the systemic therapy first came out, there was, oh, this 40% response rate. And of that 40% more than half, et cetera, et cetera, were at one year. But then if you look at the numbers, the pembrolizumab arm at 12 months was basically 19, 20%. It had a continued complete response out of that initial cohort. So in looking at that data, Tom, what impresses you then about the 12-month mark with the SunRISe data?

Gautam Jayram, MD:
Yeah, I think if you line all of these studies up and irregardless of the agent, you do see it consistent decrement with time. And so we’ve talked about this in urology circles. That’s the natural history of the disease. That’s carcinoma in situ. I’ve heard people say, “Well, I don’t think you’re ever going to cure this disease.” I’ve heard that being said. I think that it’s almost like a virus. You try to kind of suppress it, push it off, put it in remission for as long as possible. But if you follow these patients long enough, it will come back. And I think we both probably have clinical experience with patients who’ve had years of a hiatus from having CIS, and then it comes back.

So I think that’s what you have to look at this, that’s the background here. Is that this isn’t like a measurable lesion on a scan.

Dr. Chang:
Yes, good point.

Dr. Jayram:
This isn’t something that it goes away and it stays away. So with that being said, you’re right. Every study has shown that. And in three months, CR I think has been really valued because it shows that, well, what’s the best it’s going to be?

Dr. Chang:
Yeah.

Dr. Jayram:
And then we know it’s going to kind of come off. But with TAR, we haven’t seen as big of a decrement. We’ve seen a really good initial complete response, and then we’ve seen a really good durability. And so the story, I think is still to be told. I think that the three-year numbers and the five-year numbers are going to be much different. But then the question becomes is does that matter that much if you have a really good initial response and then you have time? Like we’ve talked about, you’re just basically giving patients time. And now in this atmosphere we’re in, we can sequence agents. We can put different agents together and say, “Okay, well, we did gene therapy here. Let’s do chemotherapy here. We will do a cytokine-based therapy here.”

And so I think it’s notably impressive, the CR rates. And I tell people too in this space that you have to be careful because in our world, how you detect the disease is very different based on what institutions you go to and how people do it. Some of these studies required a mandatory biopsy at the end of trial or during the trial, some of these studies are just going by cystoscopy and cytology. And so your detection rates are going to be different based on how you protocol the trial.

So all of those things play into the CR rates, and that’s why in theory, you can’t lean on just CR rates. And in the community, in my setting, I kind of tell… My thought is that the absolute number is not going to be crucial because all of these therapies are good, and they all represent a step up from where we are now. It’s going to be access, it’s going to be logistics, it’s going to be cost, it’s going to be the intangibles I think that help us pick the therapies. It’s not just going to be, okay, the CR rate is so good with this, we have to use this.