Jan-Jaap Mellema: Thank you for having me.
Leslie Ballas: Dr. Mellema, can you just describe the Indi-Blade study?
Jan-Jaap Mellema: In the Indi-Blade study, we offered combination ipilimumab and nivolumab, followed by a consolidative chemoradiotherapy, to a clinical T2 to 4A and N0 to 2 muscle-invasive bladder cancer patients in an effort to try and broaden the population of patients that were now able to receive chemoradiotherapy and bladder-sparing treatment.
Leslie Ballas: And tell me, I saw in the abstract that you also collected ctDNA data. Is that correct?
Jan-Jaap Mellema: Correct, yes.
Leslie Ballas: And can you tell me at which time points you collected them?
Jan-Jaap Mellema: We collected them throughout the study for up to a year of follow-up. The baseline for this collection was at the first immunotherapy cycle, and then afterwards, the second and third cycle as well. Then at the response evaluations after the immunotherapy and after chemoradiotherapy, and then up to a year of follow-up.
Leslie Ballas: And patients prior to immunotherapy had TURBT. Was it a complete TURBT or just a biopsy?
Jan-Jaap Mellema: Correct. It was a complete visible TURBT, yes.
Leslie Ballas: Okay. How many node-positive patients did you have on the study?
Jan-Jaap Mellema: A total of seven, so 14%.
Leslie Ballas: Tell me about what you found.
Jan-Jaap Mellema: We found that patients treated thusly achieved a two-year bladder-intact event-free survival of 78%, by which the trial met its primary endpoint of a target of 70% bladder-intact event-free survival. And overall survival was 96%, which of course, is premature at two years, but very encouraging nonetheless. Most patients were able to receive all three cycles, though there was quite a portion of patients that was not able to receive mostly the third cycle of nivolumab, three milligrams per kilogram.
Leslie Ballas: And what did you find with the ctDNA data?
Jan-Jaap Mellema: ctDNA analyses showed that if we look at longitudinal ctDNA dynamics, patients that would eventually experience an event usually remained ctDNA positive throughout the treatment or became ctDNA positive at the time of recurrence. Conversely, in patients that were ctDNA negative at baseline, they remained negative throughout the course of the study. And those that were positive but would not experience an event eventually became ctDNA negative at either the first or second response evaluation.
Leslie Ballas: Did you look specifically at the node-positive patients? Did they clear their ctDNA after the ipi/nivo?
Jan-Jaap Mellema: We don't have that specific data available. We do know that of these seven patients included with clinically positive lymph nodes, four remained without an event and five still remained with a bladder in check at this moment yet.
Leslie Ballas: Dr. Van der Heijden, as the PI of the study, I wanted to ask you, the ctDNA negative patients at baseline, I think there were 88 or something percent that were negative at baseline, does that represent a more favorable population that was evaluated in this trial?
Michiel Van Der Heijden: Actually, at baseline, the percentage of ctDNA positive was about 35%, which is indeed a bit lower than what we've seen, for example, in NIAGARA. Also, there's some data not in a prospective study, but there's some data in chemoradiation where it's also lower than that 55% we've seen in NIAGARA. I think what we were trying to do in this study is to include a broader population because we saw really good activity in very high-risk patients, so stage three patients, in the NABUCCO trial, which had surgery, of course, including in patients who were at baseline node-positive. We felt that with this regimen, because it was so effective, we could actually extend the population to a broader population.
We did manage to include stage-wise a population of patients who had higher stage than we'd usually refer for chemotherapy, but still these patients at baseline were selected that, in principle, they should be able to receive a bladder-sparing treatment. If they had a dysfunctional bladder or a very bulky tumor, they would not be candidates. I think there is a bit of a difference, that you have the difference between TNM staging, and really is a patient suitable for chemoradiotherapy. I think that the ctDNA data might be reflected. Another point, which I think is also important in the Netherlands, all hospitals for their diagnosis do a thorough TUR, so they try to be as complete as possible. I think this may have been different also from other international trials where, in some places, they don't do such a thorough TURB.
Leslie Ballas: And was TURBT done after ipi/nivo as well prior to chemoradiation?
Michiel Van Der Heijden: No. The TURBT was done before ipi/nivo. Then it's a short course, of course, of immunotherapy. Then we actually staged quite thoroughly with a cystoscopy MRI CT scan, and we did not do another TUR at that point. Actually, patients who had signs of progression, so if we suspected a progressive disease or a really residual disease, then we would refer to a TUR.
Leslie Ballas: And did any patients need that?
Michiel Van Der Heijden: Actually, only very few.
Leslie Ballas: Okay. As you very well know, there's a lot of discussion about whether or not patients need local therapy after some form of induction, chemo-immunotherapy, or EV/pembrolizumab. How do you integrate this into that debate?
Michiel Van Der Heijden: Yeah, and I think that's really the debate that we should be having at this time. It's a very important question. What we're seeing now is that we have very active in systemic therapy, so induction therapy becomes very good. In the first neoadjuvant study with EV/P, we see a 55% path CR rate. A lot of patients will be thinking, "Why do I still need to have this cystectomy?" There's, I think, two general schools of thinking. One is that we want to select those patients who have a path CR and really not do any consolidative treatments. Another way of thinking could be, well, with modern techniques of radiotherapy, it's not as toxic as we maybe remember from the past. It seems that the patients generally tolerate it very well. Why would we risk it and just give a good consolidative treatment with limited toxicity? I think that those are the two directions. I think where we'll end up is basically a mix of those approaches. I think we'll also be presenting urinary tumor DNA work on this meeting from NIAGARA.
I think that's also very interesting and exciting work where we show that actually urinary tumor DNA could give a better assessment of the primary tumor. We also did multiparametric MRIs, which I think could also have value here in assessing the primary tumor. If you combine those assessments, you may be able to really select the patients who have a very high chance of having a path CR, and perhaps they don't need any further treatment. But for the other patients, they may still respond well, maybe not have a clinical complete response, but still respond well. Those patients would still be good candidates for some form of consolidated treatment, but I don't think they all need a cystectomy. And the last point I wanted to make here, I think we also need to have the voice of the patient in here because it's very exciting for us, as research and academics, to really find this small population of patients who doesn't need any consolidative treatments. But I think a lot of patients just want to keep their bladder. The patients I've been seeing and following for now already multiple years in this Indi-Blade study are very happy with the results to their bladder, so I think we have to incorporate that perspective as well.
Leslie Ballas: Absolutely. I think that's a really important point. Did you guys collect urine on these patients?
Michiel Van Der Heijden: Yes, we did collect urine on these patients, and we're still hoping to do analysis of urinary tumor DNA as well. We've done that in the past in NABUCCO as well. We saw actually similar findings with that analysis, which was published along with the NABUCCO trial results as what we're seeing now in NIAGARA. I think this could still be an interesting thing to do.
Leslie Ballas: And I think you bring up a really important point, which is that a clinical CR is not necessarily a pathologic CR, and that local therapy is important in patients, the chemoradiation component to this study. We know from SWOG-0219 that of the patients who had a clinical CR, that 60% of them still had disease on cystectomy, and so adding local therapy I think is important. Because you did not do a TUR on most patients after immunotherapy, do you know what percentage looked like they had a clinical CR?
Michiel Van Der Heijden: That's a very tough question. We're still analyzing, for example, our MRIs. I think those would be really important. We're also collaborating with other studies that have done MP MRIs. We've done those also in NABUCCO, so it's a very broad program to study multiparametric MRIs. We want to use AI-based methods to also assess response. All of that will come later because it takes time, of course, to do this properly, but we will have results of that in the future. But at this point, I think it's a bit difficult. We didn't specifically assess patients who would be clinical complete response.
Leslie Ballas: Yeah. Well, congratulations to you and Dr. Mellema on this wonderful abstract. It was really a pleasure to discuss it with you.
Michiel Van Der Heijden: Thanks a lot.