The Uromigos Episode 132: Pembro + sEphB4-HAS in Bladder Cancer

Dr. Sarmad Sadeghi discusses exciting data about a novel compound in urothelial cancer with Brian and Tom.

Episode Transcript

Brian:
Everybody welcome to an ESMO 2021 podcast. We’re here with Sarmad Sadeghi from USC, and he has some exciting data about a novel compound in urothelial cancer that he just presented today. Sarmad welcome. If you want to give just a brief introduction of yourself, state just any relevant conflicts, and then maybe just kick off with mechanism of drug which I think is not well known by the listeners.

Sarmad Sadeghi:
Hi, thank you, Tom. Thank you, Brian, for inviting me for your podcast. I’m a medical oncologist. I was mentored by Brian during my fellowship, and I’m very happy to be able be here today. Yeah, so this is a clinical trial that we started a few years ago.

This compound was developed by scientists, clinician at USC. The mechanism of action has some interesting aspects to it. Originally it was thought of as being something involved in angiogenesis, but as the studies and experiments went on, it became clear that it is involved in cell death, and it is involved in recruitment of immune cells and traffic of immune cells across vascular spaces to the tumor marker environment.

Brian:
Sorry to interrupt. It’s an FB2 targeting agent. Do I have that right?

Sarmad Sadeghi:
Yes. So, there is there are 2 ends to this, 1 is EphrinB2 and there is another molecule FB 4. These are both transmembrane molecules, proteins and when they attach there’s bidirectional signal link, and once you block this, you disrupt that angiogenesis and inhibition of the migration of immune cells into the tumor microenvironment and you promote cell death, tumor cell death to be more specific.

So, the way this drug is set up is that it’s a decoy FB4 molecule attached to an albumin to make it soluble and make it stick around in the circulation longer. And once it attaches to EphrinB2, it prevents the usual interaction between native FB4 and EphrinB2 present in the tumor cells. And I have to say these are embryonic pathways and proteins and the experiments show that if you knock down these molecules, the embryo dies.

And interestingly, later in life, these disappear, but on tumor cells, on many tumor cells and tumor environments, they are expressed again. And that’s why we thought that this could be an interesting target.

Tom:
Sarmad, so you investigated this in combination with pembrolizumab in platinum refractory urothelial cancer. You’ve recruited 70 patients to the study. You’ve shown response rates in platinum refractory disease in the mid 35% and response rates of about 60% in the biomarker high group and with PFS and OS, which looks impressive.

14 months OS, hard to make indirect comparisons, but there’s clear activity. Are you confident there’s more activity than pembrolizumab alone? And just talk to me a little bit about the biomarker and why you think that has a role.

Sarmad Sadeghi:
Okay, so to just clarify the response rate among all 70 patients was 37% and we had 15% CR rate among those, which was more than expected. And then in the biomarker expressing group, which we had 46 patients, the response rate was 52.2% with almost 24, 25% complete response rate.

So, 70 patients is a decent sample size and the expectation for pembro alone in that population would be about 21% response rate. And what we see is 37% and expectation for complete responses, about 5% or less with pembro alone. And what we see is 15%. And so just looking globally at all of these patients, it exceeds expectation of pembro alone. But when you look at the biomarker selected group, the ones that EphrinB2, that is even more pronounced.

Tom:
And how do you know the biomarker is not prognostic?

Sarmad Sadeghi:
So, we do know that the biomarker is prognostic, but it is a negative prognostic marker. Patients that express EphrinB2, they do worse than patients that do not, and this is based on TCGA data. Both EphrinB2 and FB4 in urothelial carcinoma are associated with negative prognosis. And that is based on RNA expression and of course during the development of the biomarker, we have looked at IHC and RNA expression for the biomarker.

Brian:
And Sarmad, for this study, the expression was by IHC, correct?

Sarmad Sadeghi:
So, for all of the patients on this study, both in C2O and OHC was conducted and because there was virtually 100% concordance, we have defined EphrinB2 positivity as 1% or more expression by IHC to just develop it as a companion assay that could be done at other places.

Brian:
And is that tumor cells or stromal cells or both, or some combination?

Sarmad Sadeghi:
So that’s a very good question. By our experiments and the way, we have envisioned this mechanism of action based on our correlative studies, it seems like the expression in the endothelium is the best signal. But for the moment we have defined it as expression anywhere in tumor marker environment, including cell membranes of the tumors and the endothelial cells.

Brian:
Do you know for this trial’s biomarker positive patients where it was, or maybe for the responders where it was? I wonder if you’ve dug down to that depth.

Sarmad Sadeghi:
So, we have done it, but the numbers get smaller, so we are not ready to just discuss it or put too much weight on it. But those are very interesting questions.

Tom:
The data received accelerated approval by the FDA, which allows you to develop the drug and discuss with them quickly, but it doesn’t mean that you’re going to get access yet in the U.S. What are the development plans for the future?

Sarmad Sadeghi:
So, this got breakthrough therapy designation of September 1. It’s not accelerated approval but that …

Tom:
I apologize. I apologize. That’s quite different, isn’t it? It’s very different.

Brian:
Big difference.

Sarmad Sadeghi:
It is. Very different. But it facilitates interactions with the FDA, and we were very happy to have those channels with the FDA. This was the grant of breakthrough designation was for patients expressing EphrinB2, so FDA recognized this as the most appropriate patient population for this combination. And the current plans are of course, to pursue accelerated approval.

And it’s going to be done through an expansion cohort for the biomarker expressing patients in platinum refractory setting. And then, of course, once accelerated approval is granted, there has to be a phase 3 study confirming the effectiveness of the combination and those plans are also in the works.

Brian:
And Sarmad, do you want to talk about toxicity? Any signal there for what’s it’s adding to pembro monotherapy?

Sarmad Sadeghi:
So, we have the same range of toxicities that you expect with pembro, not very different with 1 exception, and that is hypertension. So, this is a drug that shares some overlap with drugs like VEGF targeting agents and hypertension is a consequence of that.

But in our experience, hypertension, we have significant number of grade 3 hypertension patients, but once it’s recognized, it’s easily managed, and those grade 3 events were just transitory until patients were able to get on anti-hypertensive medications and they have done really well after that.

Tom:
I think this has been fantastic. I guess one of the exciting things about this is, is we don’t know too much about how this works, but it does seem to have multiple potential mechanisms of action. And I think that angiogenic signal with hypertension makes sense to me. And Brian, you said previously to me you felt this was in line with what you’d expect a VEGF target agent to be. Is that something you still feel about?

Brian:
Yeah, no I think the hypertensive signal means it’s clearly targeting vessels and yeah, I think it was something like 50% grade three. So, it’s in line with of our more VEGF selective agents, like [inaudible 00:11:00] and the like. So, there’s clearly a vascular effect. I think the immune effect is something that’s suggested by this study, but probably needs more clinical and preclinical study.

Tom:
Brian, any more questions from you?

Brian:
No, I’m good. This is great. Sarmad, congrats on the data. This is an investigative initiated study and it’s a lot of work to get off the ground, so congrats.

Sarmad Sadeghi:
Thank you.