A New Class of Immunotherapeutic Molecules for Metastatic Prostate Cancer in Development - Karim Fizazi

November 5, 2020

There is an urgency to develop therapies to treat prostate cancers resistant to chemohormonal and radiation therapies. Unfortunately, immune therapies have offered limited efficacy in patients with metastatic castration-resistant prostate cancer.  At the 2020 European Society for Medical Oncology (ESMO) Annual Meeting, interim results from a phase 1 study of AMG 160, a targeted half-life extended, bispecific T-cell engager (BiTE®) immune therapy that engages a patient’s own T cells to kill prostate cancer cells via binding of CD3 on T cells and PSMA on cancer cells, in heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) patients was presented. Of great interest, convincing early signs of efficacy (eg, PSA drop, symptom abatement) were observed.

Join this discussion between lead investigator Dr. Karim Fizazi, Professor of Oncology and GU Medical Oncologist at Gustave Roussy, University of Paris Saclay, Villejuif, France, and Dr. Alicia Morgans, Associate Professor of Medicine and GU Medical Oncologist at Northwestern University, Chicago, Illinois, USA for a background of the mechanisms behind this novel treatment, side effects, and main findings, and a view on the future of this treatment. 

Official study title: A phase 1 study evaluating the safety, tolerability, pharmacokinetics, and efficacy of prostate-specific membrane antigen half-life extended bispecific T-cell engager AMG 160 in subjects with metastatic castration-resistant prostate cancer - NCT03792841


Karim Fizazi, MD, Ph.D., Head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France and Professor of Oncology at the University of Paris

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Read the Full Video Transcript

Alicia Morgans:  Hi, my name is Alicia Morgans. I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago, in the United States. I'm so excited to have here with me today, Dr. Karim Fizazi, who's a GU medical oncologist and a professor of oncology at Gustave Roussy in Paris, France. Thank you so much for being here with me today, Karim.

Karim Fizazi:  Thank you, Alicia. Always a pleasure.

Alicia Morgans:  Wonderful. So I wanted to speak with you a little bit about the AMG 160 presentation that was recently made at ESMO. And you are the anchor author on that presentation and certainly a lead investigator in the work. Can you tell us a little bit, before we get into the trial itself, what the BiTE platform is? So that folks from the GU oncology world can start to become more familiar.

Karim Fizazi:  Sure. So BiTEs are indeed, new compounds, with basically two hands, if you will. For example, the AMG 160 has a hand that can bind to a target here, that is PSMA for prostate cancer, but obviously, it can be in something different. They are free for small cell lung cancers and perhaps in the future prostate cancers with neuroendocrine differentiation, but it can be very different targets. So that's one hand of the drug and the other drug is actually bindings to CD3 which is an important protein in the lymphocyte T surface. So basically you're breaking, you're making sure a lymphocyte T is going to bind to a cancer cell and hopefully, it will recognize it and destroy it and kill it. So let's [inaudible], and it seems to work in several models that are included in clinical models and human models that we are seeing [inaudible] right now.

So AMG 160, I guess, is the first BiTE, which is being developed for prostate cancer use.  It is targeting PSMA, which is potentially a major target of the disease. We know the [inaudible] from PSMA lutetium experience, for example. And I'm saying that because PSMA is overexpressed in most men with advanced disease who have failed already the standard treatment, hormonal agents, chemotherapy, or [inaudible], most of the patients actually express PSMA, and actually, most of their lesions do express PSMA. So it is fully potentially a very important target for us.

Alicia Morgans:  Wonderful. And it... I think we are becoming very familiar with PSMA. It's a really exciting target on these cancer cells. A Way for us to identify the prostate cancer cells. And so that's what you've targeted with this BiTE in the AMG 160 trial. Can you tell us about this? It was a First-in-human trial, right?

Karim Fizazi:  It is. So we started with what we felt was [inaudible] enough. And then we rose with some higher doses and other ways also to give the drugs, either alone or together with steroids, hydrations, all those things. So basically I guess, several good news, obviously the most important one is that it works and it works quite tremendously in terms of PSA drops, but also in terms of clinical benefit and some imaging response. Of course, in prostate cancer, it's harder to show because not all patients have measurable disease by resist criteria, as we all know, it's mostly a bone disease, but still, we do have some patients with lymph node disease or liver metastasis with a clear reduction in the size of the disease. On top of that, again, most men derived benefit from PSA. And please remember that those patients were Phase 1 patients.

So they had, in other words, they had already existed on not only abiraterone or enzalutamide or both, but also very often on a taxane or two. So not much remaining regarding the options for these men. So a very clear effect on efficacy, we don't know much at the moment regarding the duration of efficacy. That's too early to say, its only the very first analysis that we've made. And on top of that, what we saw was that we can... There are some side effects, we will come back to that, but there are ways to circumvent them. So basically the side effects we are seeing are the ones we are expecting, because when you are stimulating hard, the immune system, patients might actually develop what we call the cytokine release syndrome, which basically is quite like the flu if you will. So it is fever, sometimes hypertension, you don't feel very good, but as compared to the flu, it doesn't last very long.

And actually, typically, it lasts two days in most men. And actually, in some patients, you really have to take care of them. So these patients were hospitalized and we had to manage them in the ICU with some [inaudible] some anti-hypertension drugs, hydrations, all these things.  But with more time and more experience, we realized that using systematically prophylaxis with steroids and hydration can really mitigate significantly those side effects. And in the last levels that we tested, it was actually much better as compared to what we saw, say last February or so, when, either the dose and [inaudible] were perhaps the most toxic we had experienced in all the patients. Again, the good thing is that everything is reversible without consequences to the patients. And actually, in my experience, I saw patients quite tremendously affected by the side effects.

But when I came back to them with their PSA, telling them, you know, what, you were very brave because you were not doing so good just a week ago with this flu syndrome, but I have good news for you. Your PSA is going down, et cetera. The patients were telling me, you know what, I'm going to carry on. And you can tell that it's not horrible for patients. And on top of that, we are very happy that it really seems that the process to mitigate the side effects actually are working. So hopefully with further development, we've confirmed that, and we will be able to launch a larger trial on top of this ongoing Phase 1 and 2.

Alicia Morgans:  I think that's really so important because these mitigation strategies, as you mentioned with the steroids and using some fluids, running things maybe a little bit more slowly seems to actually just improve things to the point that there were no grade 3 toxicities after those mitigation strategies were employed. And granted, the numbers are small. This is a First-in-human, but it's really impressive. And the other thing that I think is so impressive is that I think we have to remember what the purpose of a First-in-human study is, or a Phase 1 study, really the purpose is to define the dose and the tolerability, understand that side effect profile so that if we can find a reasonable dose, and if the side effects are manageable, we can move into Phase two, where we actually start to look for early efficacy.

In this situation, you actually saw pretty convincing signs of efficacy, even in a Phase 1 trial, which is actually not necessarily as common as we wish it would be. So can you comment a little bit more on that efficacy?  Your patients seem to at least appreciate, for many patients the PSAs did seem to respond.

Karim Fizazi:  Correct. Actually, all my patients have experienced a PSA drop and across the board in the trial, I can't remember the exact numbers, but when you see the waterfall plot, it's only a minority of those men who were absolute refractory to the drug with a PSA rising.

All the adverse actually had a drop in PSA. And we have, of course, the magnitude varying from patient to patient. On top of that, I can tell you that there is also symptomatic efficacy, of course, in the context, of a Phase 1, it is hard to measure that. I can tell you that in some men I could dose reduce the opioids, and some patients who are just telling me, I feel better, that I can add more, all those things. As I said, we also saw a couple of patients with measurable disease and measurable responses from the bone scan. It's harder to see and to share. And it takes time. As you know, we actually... We don't know exactly what it means, but we also, in some patients had some PSMA PET responses because in some patients we were able to not only have a baseline PSMA PET screening but also to monitor patients with PSMA PET. And we saw that the disease was actually shrinking by PSMA PET.

Of course, we don't really know what it means and what is actually associated in terms of benefit to the patient from that. But I just want to mention that. So, whatever way, we are looking at the data.  We do see indeed efficacy and, and actually, an expansion of Phase 2 is the plan when we will have a solid and a robust [inaudible] for further development.

Alicia Morgans:  That's really exciting. Are there other studies after that expansion Phase 2 planned already, or are you still considering where to best evaluate this molecule?

Karim Fizazi:  I think that the company is very seriously thinking about larger development with a comparative arm. I'm not sure data are public, and I'm not sure actually if they have made their final decision regarding those. But of course, it makes all sense to randomize this agent versus standard of care, or perhaps on top of tentative care in the various situations of a disease. So we will see what the company decides, but I think it's great to see that besides PSMA mutation, for which we should have Phase 3 data pretty soon, now we will also have other means to target PSMA in this disease. So that is just great.

Alicia Morgans:  It is, it is wonderful, very exciting. And I really do look forward to more to come. And I wonder if you have some final words just to close things out for our listeners.

Karim Fizazi:  Well, I would say that we see two new things here. One is BiTEs, and it is a very new thing for prostate cancer, and it could be a very important one, not only, AMG 160, but you started with the concept of BiTEs, I think it's very appealing, for one. And so we will see with more targets perhaps in the prostate, but also perhaps in other fields of GU oncology. And on top of that, when you think about PSMA, it's kind of fun, because we know PSMA, or sad maybe, I don't know, but we know PSMA scientifically for a long time, maybe 20 years, but we haven't been able for maybe a decade or so to do anything about it. Either in terms of imaging or as a target for treatment. And now, all of a sudden PSMA is changing the field in various situations of disease, and PSMA as a target for treatment is also a very appealing thing. So it is good to see that sometimes an old target if you will, has a revival and becomes very important. I think this is also the reason for the future.

Alicia Morgans:  I couldn't agree more. And we saw this enthusiasm and resurgence of clear efficacy when we figured out how to target the androgen receptor again after we had our ADT standard and we started using these next-generation targeted treatments. And like you said, we're getting into this now with PSMA. Very exciting. And like I said, I sincerely look forward to more data, more to come, and I appreciate your work on this project as well as your time today. Thank you so much.

Karim Fizazi:  Thank you, Alicia, take care.


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