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Alicia Morgans: Hi. I'm so excited to be here with Dr. Michiel Van der Heijden, who is joining me to talk about the NABUCCO trial. Thank you so much for talking with me today. I think importantly, this study was just published in Nature Medicine, and I'd love for you to tell us a little bit about which kind of patients you enrolled and what was the study schema.

Michiel Van der Heijden: Yeah, so it's great to be here and to talk about this study. So the NABUCCO study actually has been going on already for a couple of years, and the first part of the NABUCCO of study was published two years ago in Nature Medicine as well. So in this study, we wanted to use immunotherapy and a powerful schedule of immunotherapy to also have patients who have more high risk disease and response to autoimmune therapy. So what we did in the first trial was that we started with ipilimumab, 3 mg/kg, then a combination of ipilimumab, 3 mg/kg with nivolumab, and then a third dose of nivolumab. And in that study, cohort 1 of NABUCCO trial, we already saw a very high rate of pathological complete response in Stage 3. So in a very high risk group of bladder cancer patients.

So after this study, we had several other studies at our institute, and also other places where they used lower doses of ipilimumab that also seemed to induce responses in other cancer types. So we reasoned maybe in the new adjuvant setting, we need less ipilimumab to still reach the same effect. So in cohort 2 of this study, we actually had randomized between two groups, cohort 2a, which has still IPI 3 and NIVO 1. But in this case, we started with IPI 3 and NIVO 1. And in cohort 2b, we gave IPI 1 and NIVO 3 just to see what the difference would be in this dosing schedule.

We were really surprised, or maybe from the metastatic setting it was not so surprising, but we at least found that that indeed, IPI 3 was giving the same results as in our first cohort, so a very high rate of pathological complete response. But the cohort of patients who received IPI 1 actually had much lower pathological complete response; only 7%. So we think this suggests that also in the preoperative setting, if you want to increase response rate by adding anti-CTLA-4, you have to dose it in the right way.

Alicia Morgans: Well, that is definitely so important. And I think the other important thing is to really characterize this patient population, which is, of course, a muscle invasive bladder cancer population. It's a neoadjuvant treatment. But can you tell me a little bit about were these cisplatin eligible patients or not? And then tell me about their nodal status. Were some of these patients locally advanced, or was this all a really non-nodal involvement type of a population?

Michiel Van der Heijden: Yeah, so the inclusion criteria was Stage 3. So all patients were at least clinically at T3. And I think about 40% of the patients were actually node-positive. So the other patients were T3, T4 N0, and the other patients were node-positives. All patients were either cisplatin ineligible or refused cisplatin chemotherapy.

Alicia Morgans: So I think that's so important, because as we think about the potential to move immunotherapy into this neoadjuvant setting, really the competitor here is going to be cisplatin. And the opportunity to potentially use a cisplatin sparing regimen, and potentially treat patients who appear to be, at least clinically, locally advanced into the nodes is really, really important I think, for our patients. Now, let me know a little bit about how they tolerated it. What was the toxicity profile in those patients, especially the difference maybe between the IPI 3 and the lower dose IPI?

Michiel Van der Heijden: Yeah, so indeed, this is an important point, that ipilimumab, at this dose, has quite some toxicity. And that's indeed what we saw, especially in cohort 1, interestingly. This could be just statistics of small numbers, but it seemed that the schedule where we started with the combination of ipi/nivo had a little bit less toxicity. But of course, statistically we couldn't prove that. And indeed we did see that the toxicity went down in the IPI 1 group, so these patients had much less toxicity.

Alicia Morgans: And did all patients make it to surgery?

Michiel Van der Heijden: All patients made it to at least the choice for surgery, except one patient in the IPI 1 group, who already had an M-3 disease at baseline. This patient progressed on that dose, and didn't make it to surgery because he had a new metastasis just at evaluation. All other patients could have made it to surgery, have made it to surgery, or could have made it to surgery. A few patients after already knowing the results of cohort 1 elected to have a bladder-sparing treatment or no further treatment at all. And actually, these patients are still doing really well.

Alicia Morgans: Well, that's encouraging. And I know you're going to be studying a chemoradiation approach maybe for some of those patients in the future, but just to dig in a little bit more to some of the exploratory work that your group has also done. I know you looked into ctDNA, can you tell me a little bit about that?

Michiel Van der Heijden: Yeah, besides the dosing part of the study, I think this was not a really exciting result that we had. So we've been working in the past, already met with a group from Cambridge, the group of Nitzan Rosenfeld, to determine ctDNA in bladder cancer patients. And over the years, this technique has really evolved tremendously, so it's now an incredibly sensitive technique. So in this study, what we did is we collected urine and plasma, and looked at ctDNA. What we found is that in urine, could track with the bladder response to some extent. But for example, non-invasive types of bladder cancer would still lead to urinary ctDNA, whereas it seemed that plasma was much better at predicting a complete response. And for these translational endpoints, we defined complete response as down staging. So superficial bladder cancers would still be seen as a response.

So we saw that clearance of ctDNA tracked really well with response. But I think what was really amazing is that there were of course a couple of patients who didn't have surgery. There were some patients who had a response, but maybe still a little bit of cancer in their bladders, or a little bit of remaining residual tumor, but cleared their ctDNA. And when we looked at actually outcome, we saw also an enormous difference between the patients who had cleared their ctDNA and patients who didn't clear their ctDNA. So the hazard ratio was about 10 for those groups. And of course, there's other work that has looked at ctDNA as well, and found similar results, but hopefully in the future we can use this technique to see which patients we can offer bladder-sparing treatment, which patients may need additional systemic therapy or at least surgery.

Alicia Morgans: That is so exciting, because to your point, if patients can clear their ctDNA and appear to have no residual disease, at least clinically for those who'd never go to surgery, perhaps they could be followed, and perhaps they could be retreated with an immunotherapy approach in the future, given that exquisite sensitivity to this new adjuvant approach. So it's very, very exciting, and I feel like this data, while it has so many answers, leaves me with many more trials that I would like to do. And I really, really commend you in your group for putting it all together. So if you had a final message to sum this work up, what would you tell us?

Michiel Van der Heijden: Well, I think to sum this up, we found that combination immunotherapy can be very powerful, especially in a preoperative setting with complete clearance in a very short period of time. We now have the tools to track this and to see if patients are responding. And I think this gives us tremendous opportunities, especially to offer patients a personalized approach, and also to offer the right group of patients, even with high-risk disease bladder-sparing option.

Alicia Morgans: Well, that's fantastic. Thank you again, and thank you for sharing your expertise today.

Michiel Van der Heijden: Thank you for having me.