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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 discussion that you gave at GU ASCO 2023. You were able to enlighten us on some of the use of immunotherapy and its use in earlier stage bladder cancer. So tell me a little bit about the abstracts that you discussed and what your thoughts were.

Michiel Van Der Heijden: Yeah, thanks for having me here. The first abstract was about non-muscle invasive bladder cancer and pembrolizumab in this disease. So we already know that a couple of years ago the results for CIS, so carcinoma in situ, were published at with pembrolizumab, and this was the second cohort in that same trial where they treated patients who had papillary disease, so high grade TA or T1 disease that is refractory to BCG treatment, with pembrolizumab. The results of this trial showed that about 43% recurrence-free survival was seen at one year. So this met the target that in previous working groups was set for this setting because it's actually a setting where we don't really know what to expect. The standard treatment will be cystectomy, but there's also a couple of other mostly intravesical treatments around. And this recurrence free survival rate more or less falls within the range of those other treatments that have been tested in the past.

There are some treatments that have been not really rigorously tested in phase two trials like radiofrequency hyperthermic intravesical chemotherapy, which have basically higher recurrence free survival rates, but those groups had more heterogeneous population so it's quite difficult now to know which one is better. And it's also quite difficult to know what actually to expect, what is the natural behavior of this type of disease? So I think that's still somewhat an unanswered question. So I think this was a solid trial that was well executed and I think it's the largest of its kind, but it's still a single-arm trial and I think to move forward, we really need to do randomized trials in this space to see what we can safely offer to these patients who are BCG refractory.

Alicia Morgans: And so how would you do that randomization? What would the other arm be? If we're going to use the pembrolizumab as one arm, would the other arm be cystectomy or some intravesical treatment?

Michiel Van Der Heijden: Yeah, I think it would definitely be some sort of intravesical treatment because all the other treatments are basically intravesical treatments. There's not one of them that is really considered the standard of care so I think you can pick either one. What I think would be really exciting to move this field forward is to also combine these treatments because of course it would be very attractive to combine intravesical treatment with systemic therapy, maybe in a three-arm trial, which of course is difficult to do in this type of population but that would be the ideal situation where you can really tease out individual components of all these treatments and what is actually adding efficacy.

Alicia Morgans: That would be great with another recurrence free survival endpoint. And maybe you could even mix in some CT DNA just to add some interest there. That might be interesting as well.

Michiel Van Der Heijden: Absolutely.

Alicia Morgans: Wonderful. And you also discussed, I think, Dr. Galsky's presentation on adjuvant nivolumab. Can you tell me a little bit about that?

Michiel Van Der Heijden: Yeah, so a couple of years ago, the group, the CheckMate 274 trial came out in New England Journal of Medicine showing that nivolumab has a value as adjuvant treatment for high risk bladder cancer. So that's patients who mostly have either residual disease after new adjuvant chemotherapy or have at least T3 disease for patients who did not receive new adjuvant chemotherapy for whatever reason. In these patients in intention to treat, there was already a benefit in disease-free survival, although the benefit was higher in the PD-L1 positive group. So in the US, nivolumab is registered for the whole population, whereas in Europe it's actually only registered for the PD-L1 positives. Now, in that publication, it seemed that in the intention to treat group that the curves were sort of coming together and with this longer follow up for disease free survival, we see that these curves actually seem to stay separated.

Now the big question for this trial is still, is the results in the intention to treat group mainly driven by the PD-L1 positives or is there actually a real effect in the PD-L1 negatives? And that remains a very hard question to answer because where we might expect that DFS benefit immediately translate in OS, that's not necessarily the case. Actually in bladder cancer in the past for chemotherapy trials, there was a bit of a disconnect between these two parameters. So I think what we really need to judge especially these groups where it's not so clear to meet the PD-L1 positive group, the difference is so big that it's quite clear. But there's a couple of groups where the difference is not so clear. And for those groups, we really would need overall survival data. And unfortunately we're not there yet and may actually take some time before we finally get the overall survival data.

Alicia Morgans: But that is good news when we see these overall survival times stretching on and on, certainly good news for our patients. But to your point, it is hard to understand exactly what to make of this given the difficulty around the DFS endpoint. I think it's really interesting to think about this population. Do you think, from your perspective as the discussant, that the label is best as it's written in Europe where it's really only the PD-L1 positive patients or to have that all comers opportunity? And certainly this is your opinion as the discussion and no pressure.

Michiel Van Der Heijden: Yeah, sure. No pressure. US first, Europe. No, I think to be honest, that EMA was right to restrict this label to PD-L1 positives. I think in the PD-L1 positives, the magnitude of the difference was so big that I cannot imagine that OS is going to show a really good difference. I think in the PD-L1 negatives, if you see those curves side by side, then it seems that a lot of its intention to treat is driven by the PD-L1 positive group and I don't know how much there has left for the PD-L1 negative group. So I think for that group, I would like to see overall survival data.

Alicia Morgans: I think that's very fair.

Michiel Van Der Heijden: Of course, this is my opinion, and it's, of course, very different if you're a patient and you'd think the side effects usually are quite limited for a monotherapy checkpoint blockade. So why not just try it? And I can see that perspective as well. But I think from a purely medically scientific point of view, I think we would need to see that overall survival data.

Alicia Morgans: Okay. Well fair. And to your point, this is your discussion, your opinion, and I think that we'll have to just wait and see what the survival data shows and we can look at those subgroups and continue to discuss, I guess, is the best way to say it. So thank you so much for your time. If you had to sum up the use of immunotherapy in these earlier disease states, earlier than metastatic at least, what would that be?

Michiel Van Der Heijden: Well, I think there's enormous opportunity for immunotherapy to go to earlier stages. We see it works well in earlier stages. I think it has always been very difficult if it has been compared directly with chemotherapy. It's not worse. But we couldn't really show that it's better. I think in the end, the new adjuvant setting is the most logical and best place to use this. But of course, we do need randomized trial to prove it.

Alicia Morgans: Wow. We'll have to-

Michiel Van Der Heijden: But for now we have to do adjuvant treatment, but I'm a firm believer in new adjuvant treatment for immunotherapy.

Alicia Morgans: Yes. And I think you've done some great work in the space and we'll continue to figure this out. I think that the most exciting thing for patients with bladder cancer at least, is that we continue to have these developments fast and furious, and we're learning more each day. And I sincerely appreciate the time that you're taking to invest in the research in this space, and certainly to discuss the work that was done and presented at GU ASCO. So thank you so much for your time.

Michiel Van Der Heijden: Thank you.