Raj Satkunasivam: Thanks for having me.
Ashish Kamat: So Raj, you're doing a bunch of stuff here at GU26, but we have you here today to talk about a couple of things. So let's start with the RAD VACCINE. Tell us a little bit about what you're presenting, what was the idea, and what's the data?
Raj Satkunasivam: Great. Well, thank you first of all for having me. The RAD VACCINE MIBC trial really came out in an era when we were looking at cisplatin-ineligible muscle-invasive bladder cancer, and as the audience is very well aware, there are limited options at that point. And obviously the field is rapidly changing. Essentially at that time, we saw a lot of studies that looked at single-agent immune checkpoint inhibition, and we saw response rates as measured by complete response at the time of cystectomy in the range of 10 to 30%. And as a field, we were starting to rationally combine other agents with immune checkpoint, chemotherapy, for example, or oncolytic viruses. And we saw perhaps the needle change a little bit, but not significantly. So around this time, we were really interested in some of the work that had been done in the non-small cell lung literature and the concept of in situ vaccination, which is really manipulating the tumor without removing it. And that can be done in a variety of ways. And we were very interested in a concept of using eight gray by three radiation, which has some very interesting preclinical data. Specifically, it turns out the dose matters and the specific fraction that was given here was really related to driving a type I interferon response.
So when you have high levels of radiation, there was upregulation of an exonuclease called TREX1, which eats up double-strand breaks and doesn't lead to the same activation you want. So therefore, there was a possibility that this could really synergize with immune checkpoint. And really what we used was some neoadjuvant data that existed in lung, actually. So giving eight gray by three prior to lobectomy in the context of durvalumab. So when we sort of extrapolated this into bladder cancer, our goal was to really test the hypothesis. Can this immune-modulating radiation potentially improve the response to immune checkpoint? So to sort of address this question, we carried out a phase two trial. We used an immune checkpoint inhibitor which is not yet commercialized called sasanlimab, it's a PD-1 inhibitor. And what we did was we gave the first cycle, which is about four-week dose. And then at the time of the second cycle, we brought in the radiation. We gave the radiation to the tumor or the tumor bed, and it was really stereotactic radiation. The nodes were not radiated. And this started at the time of cycle two.
Ashish Kamat: So just to clarify, the radiation was not curative intent. It was priming intent. So how many gray do you recall?
Raj Satkunasivam: Eight gray was given in three fractions. So for example, it'd be Monday, Wednesday, and Friday that the tumor or tumor bed would've received radiation. And on Monday, they would've received the second cycle of sasanlimab. So the population that we were interested in was the really T2 to T4 N0 negative population. And we were targeting cisplatin-ineligible population per Galsky criteria, but we also allowed patients that refused platinum-based therapy or cisplatin-based therapy to come on board. So the study was powered to accrue 33 patients, and we intentionally were very careful about how we collected tissues beforehand and blood throughout the process, really to try to examine and tease out the immune checkpoint versus radiation effects serially. So with the treatment, what we planned on was that within one to two weeks of completing treatment, we'd go to cystectomy. So what we did was we enrolled 33 patients. We did have a safety lead-in which we cleared. And of those patients, those were typical muscle-invasive bladder patients, it turns out about 70% plus of them were locally advanced, so T3 and higher, and actually the majority of them turned out to be cisplatin-eligible. So these were patients that were actually refusing cisplatin-based therapy.
Ashish Kamat: And that's what we see nowadays anyways, right? And you have to always factor that in when you look at these trials. So far, not surprising, right?
Raj Satkunasivam: Correct. So after we treated these patients, our first and primary endpoint was pathologic complete response. So we had unfortunately four patients progress that could not go to cystectomy. So we had a population of 29 patients that are evaluable. And the top line result here is that we saw a complete response rate of about 46%, and we saw downstaging to non-muscle-invasive bladder cancer or complete response rate of about 76%. So the cohort is early in follow-up, it's about 20 years, sorry, 20 months median follow-up, and we do see a clear separation of these two. I think the other important aspect is thinking about safety in this unique population because we-
Ashish Kamat: But before we go to safety, let me ask you, did these PAT-CR and downstaging numbers surprise you? Did they meet what you were expecting?
Raj Satkunasivam: Yes. So the trial did meet its primary endpoint. 46% in a single-arm trial, it's difficult to compare and across trials, but for us, this does represent a positive signal, something that's worth further studying.
Ashish Kamat: Sure. So where are you headed as far as next steps with this?
Raj Satkunasivam: Yeah, I think it's important to note the safety signals here, and I'll just point here that when you're doing this before cystectomy, it's important to know that we can get these patients to cystectomy in a timely fashion. So everyone underwent cystectomy within two weeks of finishing the second cycle. The side effects that we saw, the toxicity that we saw was consistent with the drug. So we saw a 9% Grade-3-or-higher immune-related adverse event profile. So where do we go from here? I think there's two pathways for us. The field has rapidly changed, as everyone's aware, with the EV303 and 304 trials, which is about to be presented here, and clearly enfortumab vedotin and pembro are going to be likely the standard of care. And the question then is, how do we improve the outcome of patients that don't have a great outcome or response to EV pembrolizumab? And I think this is where we start thinking about adjuncts and additives, whether it be other systemic therapy or potentially therapies to the bladder. And I think radiation, in such an example as stereotactic radiation given an immune-modulatory dose, could potentially be examined in this context. The other aspect to this is the really interesting translational data that came out of it. A lot of work was related to really dissecting the tumor microenvironment and better understanding how the effector T-cells really change and how the dendritic cell populations change during treatment, and that's going to lead to potential hypotheses that could be examined both retrospectively and prospectively. So I think there's two fronts that we would want to pursue afterwards.
Ashish Kamat: Right, no, and again, kudos to you for coming up with this sort of a concept because clearly priming and focusing on the predominant T3, T4, like you said, yes, we might have a new standard of care, we all expect the standard of care to change, but not everyone's going to respond. And then for many years, we and others have used preoperative radiation to help with the resection in patients that were T4B, for example. And using your paradigm, could we bring that in? I know other folks are looking at the same thing. Can we combine systemic therapy with intravesical therapy? So work such as what you've done and the correlative data that's going to be really, really useful. So congratulations and thank you for taking the time.
Raj Satkunasivam: Thank you, Ashish.