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Ashish Kamat: Hello everyone, and welcome to UroToday. I'm Ashish Kamat, Professor of Urologic Oncology at M.D. Anderson Cancer Center, and it's a pleasure to welcome to the forum once again someone who's been with us many times, Professor Mark Tyson from Phoenix, Arizona, and also his mentee, a pre-med student, Jacob Moyer. So welcome to the forum, guys.

Mark Tyson: Thank you, Dr. Kamat. Pleasure to be here.

Jacob Moyer: Great to be here. Thanks for having us.

Ashish Kamat: So I'll leave this like an open dialogue, right? Because you guys presented this data at the recently concluded ASCO GU in San Francisco and of course missed the opportunity to have a fireside chat with you. But it's very important for the listening audience to gain your perspective. So, Jacob, if I could ask you first to just present at a high level. In short, what was the data that you presented?

Jacob Moyer: Yeah, I appreciate the opportunity. So the data we presented was the first real-world published data on nadofarogene firadenovec in BCG unresponsive, non-muscle invasive bladder cancer. We presented 43 patients—46 patients received the medication—and this was at all three Mayo Clinic sites, so Arizona, Florida, and Rochester collaborated together with this data.

And what we saw was, in this smaller sample size, we saw 79% complete response in the CIS with or without papillary disease cohort and 68% in the papillary-only cohort at three months. And then we did have some additional follow-up data, but we're reporting that as our primary outcome, since it's what we have the data for all 43 efficacy-evaluable patients.

Ashish Kamat: And Mark, if I could ask you—I mean, you've obviously been familiar with what's been going on in the studies that we've done and so on. How would you put this real-world experience in the context of what we know about the drug in the trials, for example?

Mark Tyson: Well, yeah, one of the concerns we have with these drugs that come through clinical trials is that the populations that they're studied in are not representative of the actual patients who are going to be receiving them. And so we are testing really the efficacy in a real-world population—so-called effectiveness. And as Jacob said, 79% of patients had a complete response at three months.

And this is a traditional BCG unresponsive population. None of these patients did not meet the standard FDA definition, and so historically it’s a difficult-to-treat population. Obviously, you did a lot of work to create that definition and to refine it.

And so we tested this new drug in that population and found that, somewhat paradoxically and maybe somewhat unexpectedly, the complete response rate was better than we found in the phase III trial. Now, I hesitate to say that it’s a lot better. It appears to be no worse, at least. The populations, obviously comparing across them, would be different.

But I would say—just separate from that, and there will be some KM estimates of durability that we'll be publishing soon—but separate from that, 79% really is “what is the durability?” And that’s the data that Jacob presented at ASCO.

And we largely found very similar durability to what was seen in the trial. And about 50% of the intention-to-treat population at around nine to 12 months had recurred, kind of across both cohorts. So I would say it appears to be no worse than the trial. It’s nice to see it in a real-world population. And so those would be my high-level takeaways.

Ashish Kamat: Yeah, no, I think that's an important point to make. Because obviously when we proposed the definition and the FDA adopted it, it was to do single-arm studies because nothing was being done. But as is the caveat with single-arm studies, you never know—are the investigators cherry-picking their patients? And I'm not casting aspersions because I do this too. But are we using our clinical bias to enroll patients in the trial that might have a favorable outcome, right? Or maybe they’ll have a worse outcome. We don’t know this. So having real-world data like you just mentioned is really crucial.

So Jacob, I'm going to ask you this—and Mark, feel free to chime in if you want—but if you, Jacob, have data on what the landmark percentages are at three months, six months, nine months, can you share those actual numerical values with us?

Jacob Moyer: Yeah. So in our CIS population with or without papillary disease, we had a 79% complete response rate at three months. At six months, it was 74% complete response rate. And at nine months, it was 60%. Granted, the six- and nine-month are Kaplan-Meier estimates of complete response.

In the papillary-only cohort without CIS, the high-grade recurrence-free survival percentage at three months was 68%. At six months, it was 57%, and at nine months, it was 40%.

Ashish Kamat: Great, thanks. Mark, a little bit of clinical insight from you: Did any of these patients get retreated?

Mark Tyson: Yes. We retreated two of them: one carcinoma in situ patient who did not have a response and one papillary patient who did and is still in complete response.

Ashish Kamat: And that's something that, of course, we've learned after the trial. And it's being studied. But we thought it was not going to be necessarily safe. So the trial was written so that if you had a recurrence you had to come off. But it’s nice to know in the real world, and it's being studied, that retreatment is certainly safe and feasible, as we've learned.

Mark, a quick question for you, because obviously it comes into play—the skill of the urologist in resecting tumors. And traditionally, we've taught and seen in the published studies that the response rates or the disease-free rates in papillary-only tumors are better than CIS because in CIS, we're not removing all the tumor, in papillary disease you are. Any ideas—and I'm not saying that you guys are bad surgeons, right? So any ideas as to why yours was flipped? Is it a numbers thing—just small numbers—or you think something else going on?

Mark Tyson: Yeah, I think it's probably because of small numbers. And maybe with a larger cohort we would see maybe more parity between the two. Or it may be typically what we see is actually the opposite of what we're reporting. It also could be just because it’s small numbers. It could just be selection—maybe some of those tumors in the papillary cohort are especially onerous biologies.

But we dived into this a little bit because I was also a little perplexed as to why we were showing this. And we kind of did a post-hoc analysis looking at the blue light patients. And about half of the patients underwent blue light TURBT, and the other half had not, as the immediate TURBT prior to study entry. Presumably those patients are especially cleared of disease. And we actually didn't see any variation according to enhanced cystoscopy technique versus white light. I'm not saying that that's because there’s no effect—obviously selection would go into that too, and we would be using blue lights in patients that we were particularly worried about.

But I don't have a good explanation for it. I think this is what happens sometimes in the real world. We see results that don't necessarily reflect what we saw in trials. But the results are so small that I'm hesitant to make any sweeping conclusions from it.

Ashish Kamat: Yeah, and I think that’s a point to be made. And this is encouraging data because it does not deviate from what we saw in the published studies. And people will often come and say, “Well, in the published studies, you guys had numbers in the 50% range, and at 12 months, it’s only 23%. So why should I use it in my patients?” And this sort of at least gives you a sense of confidence that you’re not going to have worse results. So that’s really good.

Mark, a general question to you—not necessarily related to this abstract—but you, I’m sure, see patients just like I do that want to keep trying different rounds of treatments now that they hear there are so many different drugs available. So two questions: Number one, how many rounds of treatment do you think is acceptable for a patient so long as they stay non-invasive before you say, “No, I’m not going to try anything more,” number one. And number two, in the grand scheme of things, assuming you have access to everything that's been approved and will be approved and is off-label, where do you position nadofarogene?

Mark Tyson: Yeah. So with respect to the first question, if somebody is high-grade T1, obviously I'm loath to do anything other than cystectomy. I'm really concerned about those. I know you kind of alluded to that in your question, but I just want to make that really clear for our listeners.

These are patients that probably should not be treated with intravesical therapy, and they probably should go directly to cystectomy. But there are occasionally patients who don't want it or who are ineligible for it. For those patients, I might consider one line of therapy before reevaluating the role for cystectomy. In somebody who has a small amount of CIS or high-grade TA that’s unresponsive to BCG, I'm a little more likely to consider a couple of rounds, assuming that they stay noninvasive. And so one to two clinical trials, maybe a round of Gem/Doce. You have some nice data on rescue BCG.

So I don't typically get through three or four or five rounds. I sometimes do in somebody who’s really not a candidate for surgery. But I think probably that two number is what I would think is probably the average for all comers.

And then the second question about where I would position nadofarogene: Right now, in the BCG unresponsive space for patients who are interested in standard-of-care therapy, FDA-approved therapies, it’s right up there with Gem/Doce. And we’re now just getting the ability to prescribe nogapendekin. So we'll see how that experience evolves.

We've got some patients who are asking for that by name. So right now, the convenience and logistics—once every 90 days—tolerability, and then the real-world efficacy or effectiveness that we showed in Jacob’s study has really kind of—nadofarogene’s been my go-to in somebody who has already failed Gem/Doce or doesn't want to do Gem/Doce or, for whatever reasons, is not interested in cystectomy.

Ashish Kamat: Right. No, excellent point. And I sort of totally agree. I think the convenience and scheduling of nadofarogene is such that when you present it to some patients, especially those that can’t keep coming to your office every week, they’re like, “Let me try this.” And then your numbers are reassuring. Like I said, hopefully they’ll stay in the expanded study the same, but they’re definitely reassuring.

Guys, Dr. Tyson, I want to thank you for taking the time spending with us. Jacob, congratulations. It’s not very often that someone that hasn’t entered medical school has a mentor like Dr. Tyson that allows you to have a presentation at a large international-scale meeting such as ASCO GU. So congratulations.

Jacob Moyer: Well, I do recognize how lucky I am. And I appreciate you also taking the time to talk with us about this study. It’s very exciting for me, as you point out, for obvious reasons. So I appreciate it.

Mark Tyson: Yes. Thank you, Dr. Kamat. We're delighted to do this with you. Thanks for having us.

Ashish Kamat: Thank you.