Nicholas James: Yeah.
Elizabeth Plimack: Dual trained from the Royal Marsden. So Nick, thank you so much for joining us.
Nicholas James: Pleasure.
Elizabeth Plimack: Great presentation this morning.
Nicholas James: Thank you very much.
Elizabeth Plimack: Really compelling story of the trial, right?
Nicholas James: Yeah, yeah.
Elizabeth Plimack: Which was started, conceived as a randomized trial, ended up being a single arm trial. Pandemic obviously hit it hard. Congratulations for completing it and sharing the results today.
Nicholas James: Thank you.
Elizabeth Plimack: So tell us a little bit about the study, what we learned, and then we'll talk a little bit about what questions it leaves remaining.
Nicholas James: Yeah. So the key takeaways were chemo radiation is already a standard of care as an alternative to cystectomy, and there's a growing interest in bladder preservation driven by the new highly active drugs that we have rattling around in GU oncology and bladder cancer in particular. And in all settings, pretty much apart from the chemo RT bladder preservation setting, we've got a lot of data showing that if you add a checkpoint inhibitor to the package, you get much better outcomes. And so, patients now having bladder preservation, they're at a bit of a disadvantage, because there's no evidence to support giving them checkpoints inhibitors. You predict they should work. But-
Elizabeth Plimack: With the radiation part.
Nicholas James: With the radiation part.
Elizabeth Plimack: Yeah, yeah.
Nicholas James: So what we designed actually quite some while ago pre-pandemic was a trial where we were taking our standard chemo RT regimen, not trial modality therapy, by the way. We don't-
Elizabeth Plimack: Right. Right. I like you made that point. Yeah.
Nicholas James: Yeah. And added a single shot of neoadjuvant durva, a shot of synchronous durva, and then 11 adjuvant shots of durvalumab. So pretty much the same schedule as NIAGARA's. Well, slightly different but similar, except that the synchronous bit is with the radiation instead of with the gem, cis, and there's no surgery.
And so we started it out as a randomized feasibility and safety study because we were concerned, and there was some trials that had this as a problem that if you radiosensitize the normal tissues as well, of course. And then of course you're very concerned that you cause excess damage. So we were very concerned in particular about bowel sensitization because that has been reported in other trials. And we're using a schedule with quite big doses per fraction, certainly compared to North American studies. They tend to use more protracted lower dose per fraction. And we know that impacts on your risk of late radiation side effects in particular.
We had an initial feasibility and safety where we added the durvalumab and had safety at the first six patients, first six patients who'd had neoadjuvant, first six patients who had not had neoadjuvant who, although they've had less treatment, they're usually less fit. So those were the ones we were actually most concerned about.
Elizabeth Plimack: Right.
Nicholas James: And actually all of that was fine, and that was randomized and the plan... And in fact we were so happy with it, we added in another cohort which was node-positive patients. And they were also fine.
Elizabeth Plimack: Right. I saw that, yeah.
Nicholas James: So treating the whole nodal field on top of the bladder only field and that was all fine. And we presented the toxicity data at GU ASCO last year. So what we were showing here was the efficacy data in addition. So the thing that we were disappointed about was that the COVID pandemic stopped recruitment completely, all cancer trials were stopped during it. And then when we tried to restart it, the NHS had been messaging heavily, "Stay home, save lives, protect the NHS, i.e. hospitals are dangerous," which they are of course. But particularly, if you're an elderly cancer patient, they are not safe.
The patients just did not want to come for the extra treatments. We really found it tough to recruit to. And so in the end we thought, "Well, we must get something out of this." So we turned it into a single arm trial. We used our previous chemo RT trial-
Elizabeth Plimack: That's a great move, yeah.
Nicholas James: ... as a baseline. What we'd seen in BC2001, which was one of my precursor trials, was that patients at 12 months, about 60% were disease-free, 40% had had some sort of relapse, either non-invasive level-
Elizabeth Plimack: Of course, that's before any neoadjuvant was being used with radiotherapy and before the checkpoint era.
Nicholas James: Yeah, this is a pre-checkpoint era. Yeah. So this is a trial we first published in 2012. We updated in 2016 with 10 year outcomes. So basically the control arm was still that same treatment. It was chemo RT with 5FU mitomycin using a four-week schedule. So we had a pretty robust benchmark. And in truth, we had the control patients from the initial randomized part, which actually performed very similarly. I wasn't allowed to show the data, but we will at some point show that data.
So I think it was a reasonable thing. And so, we picked 60% as disease free at one year as being a reasonable benchmark that we had to beat. And so, anything less than 60% we said, "Definitely not interesting." And we said, "In order to be really interesting, it has to be above 75%."
Elizabeth Plimack: And?
Nicholas James: And we actually hit 80%. We were very pleased with that. And when we looked at the confidence intervals, they exclude 60% with a very significant P value. We were very happy with that. But also bladder preservation being such a hot topic, we wanted to look at what the bladder preservation rate was, 100% for 12 months. So this is 12 months post-treatment actually, not 12 months. It's 12 months post-treatment.
If you look at the relapse rate, about half the relapses were metastatic, the other half were in the bladder. I haven't got the breakdown as to whether they were non-invasive or invasive, but they did not lead to a cystectomy. So I'm assuming they were all non-invasive and just treated with local... But I have to confess, I don't know that and this is further analysis that we'll do. And all of the AEs were basically in line with what you expect from the components. There was no worrying signal. In particular, there was no suggestion we were radiosensitizing either normal tissue-
Elizabeth Plimack: We learned a lot from just that, right, understanding which is great.
Nicholas James: So the frustration is, is that what they had wanted to do was do the randomized thing all the way through to a proper phase 3 given that interim signal, but that's been-
Elizabeth Plimack: Well, maybe it's better you didn't, because the control arm now, it would probably be something with a sandwich of EV+P.
Nicholas James: Yeah.
Elizabeth Plimack: So, along those lines, I noticed 75% of the patients in the single arm of your study had neoadjuvant therapy.
Nicholas James: Yes, they did, yeah.
Elizabeth Plimack: And that would be a differentiator from the BC 2001 study, right?
Nicholas James: Yeah. About a third had neoadjuvant in that. So this is-
Elizabeth Plimack: Chemotherapy.
Nicholas James: Neoadjuvant gem, cis.
Elizabeth Plimack: Gem, cis specifically.
Nicholas James: Yeah. But yeah, these new, highly active therapies-
Elizabeth Plimack: Did anyone in your study get EV+P as their neoadjuvant?
Nicholas James: No, no. It wasn't yet-
Elizabeth Plimack: It wasn't available, right? The timing didn't, wasn't, like that. So...
Nicholas James: But yes, if we were thinking what trial would we do next? Yeah, we'd do neoadjuvant EV+P. And we've got a trial application in, and the proposal being that you would just observe the patients who get a deep CR defined on urinary DNA, MRI, ctDNA, as well as cystoscopy and stuff. And randomized them to, well, dealer's choice of surgery or radiotherapy. We would be very surprised if anybody picked surgery in that setting.
Elizabeth Plimack: Well, actually the randomized study now looking at EV+P and bladder preservation has radiation as the control arm, not cystectomy. So to your point, I do think that's felt to be the alternative at this point.
Nicholas James: Because I think it's very striking looking at the quality of life data from the EV+P data that presented alongside my data this morning. And there was no decrement in quality of life for EV+P compared to the standard of care.
Elizabeth Plimack: Yeah, right.
Nicholas James: But your quality of life went down-
Elizabeth Plimack: With cystectomy.
Nicholas James: ... with cystectomy.
Elizabeth Plimack: Yeah. We were just talking about that.
Nicholas James: Two thirds of the patients in BC 2001, their quality of life went up. Even during treatment, it went up overall.
Elizabeth Plimack: And that doesn't surprise us, right?
Nicholas James: Yeah.
Elizabeth Plimack: Because clinically, we see the urinary symptoms improve with treatment.
Nicholas James: Exactly, exactly. And particularly if you've got a setting where as we... Yeah, they'll have had a TURBT, but there's no particular requirement they're debulked because that's how they're diagnosed. But we're not sending people back for re-resection. So we're treating people where we know they have residual disease. And of course, as you say, it gets better. So their bladder function improves, even with the side effects of the radiation.
Elizabeth Plimack: There's one last question that came up actually in the online questions that I don't think they asked you yet. Was the staging to qualify for the study after neoadjuvant?
Nicholas James: No, it was before.
Elizabeth Plimack: So did you have to have... Okay. So you were potentially treating some people who did get those deep responses from their neoadjuvant?
Nicholas James: I guess a third of them would have had CRs, yes. But we did do an assessment. They had to have some sort of assessment to check they hadn't progressed. Because our practice is if they progress on neoadjuvant therapy, DNA damaging treatment, they don't do very well with another DNA damaging treatment.
Elizabeth Plimack: Oh, okay, so those weren't included, right.
Nicholas James: So the neoadjuvant patients will, you've got a bit of a selection for better patients in there.
Elizabeth Plimack: Sure, sure. Well, you did have amazing results. I guess that makes sense that you did some selection there. That's great. Well, this sets us up. I think we learned a lot of things. We learned that durvalumab doesn't increase radiation side effects, safe to give throughout, that with this approach, patients can keep their bladder and live a long time.
Nicholas James: We hope so, yeah.
Elizabeth Plimack: We can get great results, and that maybe the next iteration does involve EV+P in one way or another and that's being tested in trials, which is great.
Nicholas James: Yeah. No, it's super exciting period to be in working in bladder cancer.
Elizabeth Plimack: It's great. Well, thank you so much for sharing your research this morning.
Nicholas James: Pleasure, yeah.
Elizabeth Plimack: And today on UroToday. It was great having you. Thanks.
Nicholas James: Thank you very much.