Alicia Morgans:  Hi, my name is Alicia Morgans, and I'm a GU medical oncologist and associate professor of medicine at Northwestern University. I am so excited to have here with me today, friends and colleagues, who are here to talk about AMG 160 and to do a little round table on the study itself and the implications for the future regarding this therapy in metastatic castration-resistant prostate cancer. Let's go through and introduce ourselves. First, Dr. Neal shore.

Neal Shore:  Hi, I'm Neal Shore. I'm the medical director at The Carolina Urologic Research Center in South Carolina in the U.S., and I'm a urologist.

Alicia Morgans:  Wonderful. Thank you. Next, Dr. Oliver Sartor.

Oliver Sartor:  Hi, Alicia. Glad to be here. I'm Dr. Oliver Sartor, medical director for The Tulane Cancer Center in New Orleans, and always happy to join my colleagues.

Alicia Morgans:  Wonderful. Thank you. And finally, Dr. Ben Tran.

Ben Tran:  Thanks for having me, Alicia, really happy to be here. I'm a medical oncologist. I lead the GU Medical Oncology Group here at Peter MacCallum Cancer Center in Melbourne, Australia.

Alicia Morgans:  Wonderful. Well, thank you all for joining us today, tomorrow, whatever day it is in your time zone so that we can share this information. First, Ben, can you tell us a little bit about what a BiTE is and how you designed the study to really understand the effects of this BiTE molecule in metastatic castration-resistant prostate cancer?

Ben Tran:  A BiTE is a bi-specific T-cell engager. I like to think of it as a molecule with two arms, with each arm targeting a different thing. So in AMG 160, the BiTE has one arm which targets CD3, which brings in T-cells, and the other arm targets prostate cancer by targeting PSMA. So, in tumors where you might think of it as having a cold immune microenvironment, I like to think of BiTEs as being able to bring the immune cells into the tumor.

Alicia Morgans:  Wonderful. And how did you design this study, which of course is a first in-Human study, to really understand the effects of this particular BiTE AMG 160 and prostate cancer cells?

Ben Tran:  So AMG 160 is an Amgen sponsored phase 1 First time in-Human Study. It's a dose-escalation study. There is a dose expansion cohort, and there is also a combination cohort with pembrolizumab. At ESMO 2020, I was lucky to present the preliminary results of the dose-escalation portion.

Alicia Morgans:  Wonderful. Can you review for us a little bit about some of the results that we saw, in terms of the efficacy of AMG 160 in the mCRPC patient population?

Ben Tran:  So as a preliminary result, where we described the results from patients at different dose levels, at this point in time, we have yet to reach the recommended phase II dose. But despite having several patients treated at lower dose levels and the, more recent, higher dose levels, we saw quite impressive efficacy. So around 68% of patients had a PSA reduction of any kind, and 34% of patients had a PSA 50 or greater. We had 6 patients out of the 43 who we reported on, that had been on treatment for six months or longer, and in those who were available for resist response, we had 3 patients with partial responses, 2 of those who were confirmed.

Alicia Morgans:  So that's really, really impressive data. And we are fortunate to have here with us today, both a medical oncologist and a urologist, who I'm sure to have questions. Dr. Sartor, what questions do you have for Dr. Tran?

Oliver Sartor:  One of the interesting things is with the PSMA-targeted therapy, we typically choose the patients after doing a PSMA scan, and you didn't do that.  But I want you to comment a little bit about the PSMA expression, at least as determined by scan, or what you know, what you don't know.

Ben Tran:  Yeah. So as you know, being here at Peter Mac, we have quite a lot of experience with lutetium-labeled PSMA, and Oliver, you rightly pointed out that for lutetium PSMA, we like to pre-select patients based upon SUVmean or SUVmax of the lesions using a PSMA PET scan. And the rationale for that in lutetium PSMA, is I like to think of it as you need enough crossfire to have enough tumor damage.

But for AMG 160, these bi-specific T-cell engagers, a one activated T-cell in the presence of PSMA can result in lysis and killing of multiple cancer cells. So the rationale for not pre-selecting patients was the fact that you would need a very low level of PSMA expression to induce enough tumor kill. Having said that, as a phase I study, we did conduct some PD studies. We had PSMA PETs and FDG PETs done at baseline, and again at 12 weeks. And once the study reads out, we will be able to look back at that data and see if PSMA expression is important in selecting patients, but at this point in time, we believe that it is not needed.

Oliver Sartor:  That is really interesting, Ben. For unselected patients, I think that's very impressive data.

Alicia Morgans:  I completely agree. And Neal, what questions do you have from a urologist perspective on the study?

Neal Shore:  Well, first of all, Ben, congratulations. A Really important first-in-man achievement in mCRPC patients. Well, one of the things I noticed is, when reading the poster is, this was a very heavily pretreated patient population. About 80% of the patients had three or more lines of therapy, inclusive of lutetium-based treatment, PARP inhibitors, and the usual CRPC agents. And you got this type of PSA declinations and also some radiographic responses. And then there was also some commentary about profound responses. Can you comment on that, please?

Ben Tran:  Yeah. So as a phase 1 study, we were targeting patients who had had prior standard therapies, and as such, almost 60%, well, over 60% of patients and had four or more lines of treatment for mCRPC. So very heavily pretreated patient. The median PSA of this patient population at baseline was 79, so on the higher end. And we are pleased to see activity in this group of patients. And we've seen, as you've mentioned, very profound responses. In fact, some of our patients have been pretreated with lutetium-labeled PSMA, and two of those reported here had quite deep PSA responses as well.

Alicia Morgans:  So, really exciting that we can have patients who are so heavily pretreated, and also encouraging that this truly is a unique mechanism of action if we see patients who are treated with PSMA targeted agents who are still able to respond. So all of this is really exciting and positive, but I think as we actually consider using these treatments in the future, and certainly moving through phase II and further phases of trials, we always need to consider the adverse events and how we really help to get patients through the treatment so that they can receive and reap those benefits. So, from an adverse event profile perspective, Dr. Tran, what are your thoughts, what are your comments on adverse events with the use of AMG 160?

Ben Tran:  Yeah, so the most common adverse event we saw was that of cytokine release syndrome, which is an expected toxicity with bi-specific T-cell engagers. Many of us who have some experience with CRS previously, link it to the CRS experience with CAR T-cell therapy, which can be really severe and many patients end up in intensive care and need a lot of vasopressins, a lot of care, to get through that. And the CRS we experienced with AMG 160 is very different. I believe it is much more manageable, and it's limited to the first and second cycle of treatment. Once patients go beyond the second cycle, the AMG 160 becomes very, very tolerable with very, very minimal CRS ongoing.

Now we had 60% of patients who had grade 2 CRS and 25% of patients who had grade 3 CRS, and it's really worth noting how CRS is graded. We use the Lee criteria, which was published in 2014. And for grade 2 CRS, this included grade 3 transaminitis, and for grade 3 CRS, this included grade 4 transaminitis. And this transaminitis made up the bulk of the CRS we experienced.  And in this setting, transaminitis is reversible spontaneously. So it is self-limiting and reverses within two or three days. There were some patients who needed low-flow oxygen, and there were some patients who experienced hypotension. And as this is a dose-escalation portion of the study, as we gained more experience with AMG 160, we were able to develop some mitigation strategies, which reduce the severity and incidence of CRS.

Alicia Morgans:  Can you tell us a little bit about those mitigation strategies, Dr. Tran? Because when I reviewed them or at least reviewed your presentation at ESMO, they didn't seem especially complex, but, of course, that may just be my perception from reading. What are your thoughts? How did you mitigate CRS and how complex were these strategies.

Ben Tran:  Well, there were a couple of simple things that we did and that was introduced dexamethasone pre-medication. So we had eight milligrams IV and eight milligrams oral prior to the first dose and all through the first cycle. Some clinicians opted to kind of continue that into the second and third cycle and then gradually taper it off. We also used intravenous fluid prophylactically to prevent hypotension, and that was also very successful. But the key mitigation strategies are that of a lower running dose. So by giving a lower dose initially, and then stepping up to the target dose, we were able to reduce that incidence of CRS. And in a cohort with a target dose that was the same when we compared those who had the mitigation strategies versus those who didn't. We saw no grade 3 CRS in the patients with the mitigation strategies and a lower number of SAEs as well.

Alicia Morgans:  I think to me, that's very exciting because certainly, most centers should be able to use things like fluid or fluid boluses and steroids, and even running things more slowly to start, and then kind of ramping up to an appropriate dose level. We do that even with things like rituximab in oncology and other settings, but I'm very curious to hear, Neal, what your perspective is from a urologist's point of view in terms of the implications of this treatment and how easily we will be able to potentially disseminate this therapy across more centers in the US. How possible do you think that will be?

Neal Shore:  Yeah. Well, first I'm so excited about this. This clearly, by specific targeted approach is combining both T cells and targets on the tumor cell as an engagement, has been elucidated, it makes it unique and it really adds to our quest for continued survival prolongation for CRPC patients. So this is really quite impressive. But that said, when we bring in new toxicity profiles and especially I think more so for urologists than medical oncologists, except for some who are getting more and more seasoned in terms of advanced parenteral therapies, this notion around understanding, cytokine release syndromes and all associated AE events. Having said that, clearly in medical oncology, in the community, and in Uro-oncology, there is a move towards outpatient treatment, right?

And so hospitalization, overnight stays, is something that clearly has to be attempted to be avoided for a health economic outsource benefit. I think for uro-oncologists who have adopted all of the other life-prolonging therapies with their associated unique adverse events, I think this will be embraced. It will be by a small segment, initially. I think if you have a very well seasoned infusion center or perhaps an ambulatory surgery center where you've been doing research, and you have the ability to do the type of monitoring at least early on, assuming that mitigation strategies that Ben points out, which I think will make the overall applicability for, this BiTE, this AMG 160 product more accessible, I think it is exciting. And I think that it won't be for everybody, but I think that with education, it will enhance the optimization of our patients with mCRPC.

Alicia Morgans:  I agree, and it may continue to strengthen our relationships between urology practices, medical oncology practices, and others who contribute to the multidisciplinary care of these patients. And I'm curious to hear your thoughts, Dr. Sartor because I think you have thought a lot about how we actually use treatments in practice and how there may be differences sometimes even between medical oncology practices in an academic center versus in community practices. What are your thoughts?

Oliver Sartor:  Two quick questions for Ben. Number one is, do you think this will be feasible in the outpatient setting for the majority of patients?

Ben Tran:  Yeah, I do. So this is a phase one study at the moment, right? So the primary objective of the phase one study is that of safety, evaluating the safety, and achieving a recommended phase II dose. So as we continue to use AMG 160 more, as we continue to fine-tune the way it's given and the way we manage the toxicity, the aim is to move this into an outpatient setting. And so in doing so, we hope that it will be much more widely accepted.

Oliver Sartor:  Very important. The second question is about the predictability and the timing, the kinetics of the toxicity. Is this something that you can kind of dial in and you know that four hours in that you're at high risk or is it somewhat unpredictable and maybe the next day you could even have a problem? So help me understand the predictability if you will.

Ben Tran:  Yeah, it's very predictable. It's so predictable that my fellow and I will set our watch to a certain time knowing that we might need to come down to assess the patients who may be experiencing some CRS. So it is something that is predictable, but I think in that aspect, it will help its use in the community.

Oliver Sartor:  Absolutely. Predictability is your friend.

Alicia Morgans:  Absolutely. And so Dr. Sartor with the answers to those questions, what do you think in terms of the ability for medical oncologists to give this therapy, whether it's in an academic setting, or maybe in the community?

Oliver Sartor:  Well, if it's an outpatient setting with predictable toxicity, I think you have a go, and it won't necessarily have to be a particularly specialized center. It could be one that is accustomed to infusions with a variety of agents. I mean, goodness gracious, we give chemotherapy, we give immunotherapy, and all of these are complicated in their own way. So it's a matter of a learning curve. And I think we can learn if it is predictable in outpatient pretty readily. So I like the activity. I mean, this is a phase I trial, you've done an awful lot of activity in heavily pretreated patients. So I am really anxious to be able to get my own experience with it. And we are one of the sites that will be coming on board relatively soon.

Alicia Morgans:  Well, I definitely have to say, I am jealous of that, Dr. Sartor. I wish I were one of those sites and I look forward to hearing about your experience in the future. And as we start to wrap up, I'd love to just hand it back to Dr. Shore and then Dr. Sartor to ask, Dr. Tran one final question, and then we'll give Dr. Tran the final word. So Dr. Shore, any questions that you have for Dr. Tran?

Neal Shore:  No. I'd really just like to reiterate my enthusiasm for the program and congratulations. You mentioned there is a second cohort with pembrolizumab and you still haven't reached yet the MTD. Can you comment, Ben perhaps on when we might see further data presented, roughly some timeline or a congress that you are looking at.

Ben Tran:  We haven't thought that far yet. So once we reach the recommended phase two-dose, we'll move into dose expansion and we will analyze that data and present that shortly after, but we hope that'll be soon.

Alicia Morgans:  Very nice measured response. Thank you so much, Dr. Tran and Dr. Sartor, what questions do you have?

Oliver Sartor:  Okay. Really quick, because I know we don't have a lot of time, but in terms of predictive biomarkers, do you have any handle right now? Any of the predictive biomarkers for response resistance?

Ben Tran:  Not yet, not yet. So we've collected enough specimens and blood and we have access to [inaudible] specimens, we have the PET data. And so we will be looking at that and trying to identify groups of patients who are more likely to benefit.

Oliver Sartor:  Thank you.

Alicia Morgans:  Thank you. And no softballs from our panelists today, Dr. Tran that's for sure. Thank you for your responses. And just to wrap up, what is your final word on this exciting data from AMG 160?

Ben Tran:  I'm really excited by AMG 160. I've been really interested in bio-specific T-cell engagers in prostate cancer for quite some time now. Immunotherapy has been largely ineffective in prostate cancer and with AMG 160, we have immunotherapy that looks like it can achieve a high proportion of responses and sustained responses to help our patients with mCRPC.

Alicia Morgans:  Well, thank you for your continued efforts. I think we are all eager to get our hands on what seems to be a very promising future therapy for our patients. I look forward to seeing how the data pans out and I look forward to your success and the success of this therapy. Thank you so much all of you for sharing your time tonight.

Ben Tran: Thanks, Alicia.