Mark Tyson: Thank you, Dr. Kamat. Appreciate you having me.
Ashish Kamat: So there's a lot of stuff going on with bladder cancer at the AUA. As always, seems in the last five, eight years, there's always new developments. And this year, the buzz, not just at AUA, but in general, seems to be BCG and IO therapies. And you, of course, here are presenting the PATAPSCO work, the US-based durva plus BCG. So share with us a little bit your insights, your findings.
Mark Tyson: Sure. And thank you again for having me. PATAPSCO is a follow-on study to POTOMAC. And as most of your audience probably already knows, POTOMAC read out last year and was published, showing just really quite how effective BCG really is. BCG plus induction plus maintenance versus induction plus maintenance plus durvalumab was essentially the trial. Large phase three. They tested whether you could replace maintenance with durvalumab in a third arm, but basically showed BCG induction plus maintenance was very effective.
But the question is, can we improve upon that efficacy? And PATAPSCO really doesn't answer that question. That question was answered in POTOMAC, but PATAPSCO answers a question of what the safety profile is in a POTOMAC-like population in the United States. So BCG-naive, high-risk patients, they received BCG induction plus maintenance and a year of durvalumab. And the primary endpoint was incidents of Grade 3 or 4 AEs.
There was 99 patients that participated, 19 sites across the US, and the primary endpoint ran out at 12%. So 12% of patients developed a Grade 3 or 4 AE at six months.
There was an additional four or five Grade 3 AEs that developed after that six-month time point, but overall we didn't really see a lot of difference between what we would've expected in terms of the side effects from BCG and the side effects of durvalumab. We didn't really see a whole lot of additional side effects from the combination.
Probably the most interesting piece for me as an investigator looking at this trial and the data in this space is about 20% of patients developed an immune-related adverse event, which was a little lower than we saw in POTOMAC. POTOMAC was a little closer to 27%. Only 5% of those were Grade 3 or 4, but still interesting because BCG is so effective and the side effect profile is so well tolerated.
Ashish Kamat: Yeah. And thank you for sharing that. And clearly the intent of the trial was more regulatory, get the US experience, the AEs, but are there any clues in the US population? Because clearly the way patients are sometimes managed in the US, and I know you had 19 centers and maybe four or five patients in each center, but any clues from the data as to, something similar to what Dr. Shore presented today, which patients might actually do best in the US population with the combo?
Mark Tyson: Right. Yeah, I watched Dr. Shore's presentation with great interest this morning because it really was trying to dive into just exactly how efficacious is this. The primary endpoint's a primary endpoint. What's two-year EFS or three-year EFS? I think it's DFS for POTOMAC, but still that delta is well defined, but maybe there's some other elements that might be useful like time to cystectomy or development of BCG-unresponsive disease, all those things that Neal presented this morning.
My sense from PATAPSCO is that this was used in a very high-risk population. About half the patients had T1 disease, and that kind of makes sense because, as an investigator, that's who I was putting on this trial. I wasn't putting just high-grade TA patients on there, even just a little bit of CIS, and I don't really think it's appropriate to use this drug for those patients if it were to get approved.
I'm thinking about those patients who have disease that we should really be doing cystectomy in. That 55-year-old patient that you presented this morning in your plenary session that had that ... Let's just say it wasn't a T3 cancer. Let's say it was a T1 cancer where it looked real bad on CT and you resected them, they had some concomitant CIS, and you really want this person to have a cystectomy and they say no. And you want to hedge against that metastatic disease risk, you want to give them the best foot forward, and you're willing to take on some of those side effects because they're younger and healthy and they have good functional status. That's the person I'm thinking about using it in. But I don't know if that's based in the data, per se, to your question. I think it's probably just more of an extrapolation from what I've seen from POTOMAC and PATAPSCO.
Ashish Kamat: Yeah, I think that makes sense. That's where most of us are heading. And when I talk to patients or I talk to other colleagues such as yourself, I think we're going to reserve the discussion of using the IO plus BCG to augment BCG's already high efficacy in the patients that you and I would otherwise be recommending a radical cystectomy to.
But let me ask you since you've obviously done a deep dive in the toxicity part of things, how does the risk-benefit of toxicity in a hypothetical young patient, like you mentioned, where you're trying to throw the kitchen sink at them from a treatment perspective, are you also then throwing the kitchen sink at them from a long-term AE? What's your sense from the toxicity profile?
Mark Tyson: Yeah. So most of the Grade 3 and 4 immune-based AEs that we observed in PATAPSCO were thyroid-related, either hypo or hyperthyroidism. We did see some adrenal insufficiency and those types of immune-related events where steroids are required for a period of time. Like I said, that occurred in about 5%.
In my opinion, that is a really hard thing to present to a patient. When they're coming to you and BCG is so effective and the combination, yes, it has efficacy, that's clear from POTOMAC, but that risk-benefit ratio really has to be weighed. And that's why I think the people that I would consider using this in is the people that I'm worried that they don't have a cystectomy. They're going to be developing or potentially at risk for metastatic disease. And I think that's what maybe justifies the IO therapy in this population, but short of that, just a garden-variety CIS that we clean up with blue light, I don't think it's worth the risk, but it's something that I think is probably going to need to be kind of thought through pretty carefully relative to some of the intravesical therapies that we see in the BCG-unresponsive space.
For example, many of them are well tolerated. They're all about, more or less, about the same in terms of their efficacy. Maybe there are some numerical differences, but this one is a different kettle of fish, and I think it needs to be viewed through that more critical lens.
Ashish Kamat: Yeah. I know those are also good points. For many years, we've always seen sort of a correlation between the adverse events with BCG unresponse. Maybe not the nuances of the adverse events, but the extreme adverse events. And now there's a lot of emerging data, published and not, showing that patients who develop rash on EV tend to have better outcomes in the metastatic bladder setting. Do you have any sense that the patients who develop toxicity with the IO addition have a different response profile?
Mark Tyson: It's a very interesting question, and I don't know the data at the moment for PATAPSCO, only because efficacy data for PATAPSCO hasn't been published and I haven't seen it. So I think that that's coming probably next year, and that would be a really good question to ask our AstraZeneca colleagues to look at because, yeah, I mean, it kind of makes sense. If you're developing side effects, then maybe there's on-target activity as well from the drug. So I don't know the answer to it just yet, but I'm hoping to have an insight to that maybe this time next year, hopefully.
Ashish Kamat: Yeah. And again, full disclosure, every time we, and I mean anyone asks them to pull up some data like this, they actually do. So hopefully they will listen to you asking for it and we'll have something that you can present next year and have you here talking about it, right?
Mark Tyson: Yeah.
Ashish Kamat: As always, pleasure, it's a pleasure, Mark. Thanks for taking the time.
Mark Tyson: Thank you, Dr. Kamat.