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Alicia Morgans: Hi. My name is Alicia Morgans and I am a GU medical oncologist and an associate professor of medicine at Northwestern University in Chicago in the United States. I'm so excited to have here with me today, Dr. Ben Tran, who is a consultant GU medical oncologist in Melbourne Australia, where he is able to talk to us a little bit about the AMG 160 trial that he has recently presented at ESMO, the virtual meeting, 2020. Thank you so much for being here with me today, Dr. Tran

Ben Tran: Delighted to be here, Alicia. Thanks for having me.

Alicia Morgans: Wonderful. Before we really get started on this study, can you tell us a little bit about what a BiTE is? What is AMG 160?

Ben Tran: AMG 160, is a BiTE, as you mentioned. It's a bispecific T-cell engager. Essentially it's a little molecule that has two arms. One arm is used to target T-cells through CD3 activation and the other arm is used to target cancer cells. And in the case of AMG 160, it's targeting PSMA, which we know is now a very validated marker for both the imaging and treatment of prostate cancer. Essentially the way I see it is, a BiTE molecule brings the immune system activated immune cells towards the cancer. And that's particularly important in prostate cancer where we know that it's essentially an immune desert, there aren't many that activated immune cells there to fight against cancer, which perhaps is why immune checkpoint inhibitors have been quite unimpressive to date.

Alicia Morgans: I think that's a really important point and really to emphasize that this PSMA protein has actually been something that you and your team in Melbourne have really been able to capitalize on in multiple therapeutic approaches. Very exciting. And I know you have a lot of experience with this. As you recognize your experience in this and certainly your experience with immunotherapies, can you tell us a little bit about the study that was put together to really understand the activity of AMG 160 in men with metastatic castration-resistant prostate cancer?

Ben Tran: Delighted to. AMG 160 is a second-generation BiTE. There was a first-generation BiTE named AMG 212 but that molecule was very small and had a very short half life and it needed to be given as a continuous IV infusion. The results of that study have been presented at previous meetings with there was some activity seen in patients with metastatic castration-resistant prostate cancer, but giving a drug that is given as a continuous IV infusion is very difficult for patients. And so this half-life extended version was created and we decided to conduct a phase one study to see if this was as efficacious or more efficacious than the previous agent. Essentially the phase one study, which I presented at ESMO 2020, is a dose that has three components. One is a dose exploration phase. There's a dose-expansion phase of AMG 160 as monotherapy. And also there's a part two, which is a combination of AMG 160 with pembrolizumab. Although that part two has initiated enrollment, the results weren't presented at this meeting but will be presented at subsequent meetings.

Alicia Morgans: Very important and very interesting. Well, can you tell me, what did you find as you did this study?

Ben Tran: The types of patients we recruited were, as you'd expect from phase one study were quite heavily pretreated. The median number of treatment lines for patients coming into the study was four prior lines of treatment with 60% having four or more prior lines of therapy. And what we were able to see was there was some very early signs of efficacy. We had PSA reductions in 68% of patients with a PSA 50 response in 34% of patients. And this is particularly impressive as we're still in dose exploration and the results we presented were for multiple dose levels and as yet, we haven't determined the recommended phase two dose to go on with further studies. And so at this very early stage of the study, we're hoping, we didn't expect such great activity and hence the report at ESMO 2020

Alicia Morgans: That's really important and interesting because I think for most of us, when we review phase one trials, we really try to think about the safety profile and the recommended phase two dose. It sounds like you and the team, as you said, have actually not reached that maximum tolerated dose, that MTD, that would be really the recommended phase two dose. Can you speak to that a little bit? How are you proceeding? Are you continuing on with this phase one analysis? Or how are you proceeding?

Ben Tran: We're really close to achieving the recommended phase two dose. A lot of the current first exploration is to determine the best way to give AMG 160 and mitigate some of its side effects. One of the most important side effects associated with this class of agent is that of cytokine release syndrome. As the drug engages, these may express themselves and engage a CD3, there's a whole release of cytokines. That's predominantly a first dose-effect and as we've observed in our study, occurs within the first or second cycle and it can be a limiting step in escalating the dose in patients.

What we've been able to do is mitigate CRS through three different strategies. One has been dose priming where a lower dose is given initially prior to getting to the target dose. And then there's the use of steroid pre-medication prior to dosing the first cycle or two. And also the use of intravenous hydration as prophylaxis for hypotension. CRS can manifest itself in different ways. When some people hear CRS, they get quite scared given what's been experienced with CAR T-cells, where some patients become quite unwell with CRS. The CRS experienced with biomolecules is much less severe and as we mentioned, can be mitigated. Patients do get some fevers, they can get rigors or chills on occasion. We've noticed some drop in blood pressure and hence the use of intravenous fluid and also some nausea, vomiting, diarrhea can occur. What we also noted was a rising liver transaminase. However, these rises were transient and would resolve to grade one within one to three days.

Alicia Morgans: That's really important as you said, because I think that part of our understanding of how to use these treatments and part of our enthusiasm about these treatments is that we are able to actually give them to patients who are older, maybe more frail than those patients who ultimately engage in the clinical trials. Because when we generalize these therapies to the real world, we have to deal with all of the real world issues that patients have. Is this therapy a therapy that we were able to give it within this trial that you were able to give as an outpatient? Or were patients in the ICU, as we did sometimes with IL-2 administration or some of the CAR T therapies?

Ben Tran: As a phase one study and given the potential risk of CRS, the study was designed such that patients were hospitalized for observation in the first cycle and two, and the second cycle as well. However, as I experience with AMG 160 has grown and as the mitigation strategies we've used have had quite a positive effect in reducing a serious CRS, we're now exploring how to give this in an outpatient setting. I'm really hopeful that as we reach our recommended phase two-dose and the dose mitigation strategies are fine-tuned, that we'll be able to give this treatment in the outpatient, in the community setting.

Alicia Morgans: I think that's fantastic. And even if we have to administer something in the hospital, if we can get a good disease response, that can be very, very worth it for patients, for families who are really hopeful that that patients will not have to have further therapies, at least in the short term, as they're dealing with their advanced prostate cancer. Can you tell us a little bit about the responses that you saw in this trial?

Ben Tran:  Yeah, so as I mentioned, the PSA response rate, well there was a PSA reduction in 68% of patients with a PSA 50 in 34% of patients. Like you'd expect with immunotherapy, there were durable responses as well. 19 patients remained on the study at the time of analysis and six patients have had treatment for six months or more, which I think is quite impressive for this very heavily pretreated population. There were only 15 patients who were evaluable for resist, had resist measurable disease and out of those 15, there were three partial responses observed, two were confirmed, and one was unconfirmed at time of data cutoff.

Alicia Morgans: I think that's phenomenal. And to have patients still on trial, when we're talking about a phase one study is really phenomenal. As you're thinking about moving to the next phases and as you're thinking about advising other clinicians who may ultimately participate in phase two or ultimately potentially phase three studies with AMG 160, what would your guidance be? What would your recommendation be in how to best select patients and then best how to care for them?

Ben Tran: Well, unlike the lutetium PSMA and as you alluded to, I look at Peter Mac, the way Michael Hofman and the team have really led the way in using lutetium PSMA in prostate cancer patients. Unlike lutetium PSMA, where patient selection has been guided upon PSMA-PET in concordance with FDG-PET, at least at our center with SUV mean and max being used to identify patients most likely to respond. That hasn't been the case in this phase one study. Once we have done PSMA and FDG-PETS at baseline and at week 12, to explore potential predictive biomarkers, we haven't enrolled patients exclusively on that. And we've also seen patients who've responded or having previously progressed on lutetium PSMA suggesting that although the target is the same, the mechanism of action is different and patients can benefit from both.

Alicia Morgans: I think that's really exciting. And just a point I want to drive home that the mechanism of action of this approach to therapy is very different than anything that we're currently using. And certainly, even though the target may be the same, as you mentioned for things like lutetium or other PSMA targeted radiopharmaceuticals, this is really a distinct, very distinct actually, approach to trying to target that cell class and really cause some cell damage. I wouldn't necessarily expect that there would be a mechanism of resistance that would make patients resistant to things like lutetium as well as AMG 160. And it's good to see that in practice that that is actually the case. If you had to summarize this study, your phase one AMG 160, what would it be? And what is the message to folks who are thinking about this as it moves forward through the treatment paradigm?

Ben Tran: A couple of things, we all thought immunotherapy wasn't going to be effective in prostate cancer based upon the data we've seen over the last few years. But I think AMG 160 demonstrates that different approaches to stimulating the immune system to fight prostate cancer can be effective. We've also demonstrated that AMG 160 for all the concerns around cytokine release, it's a manageable treatment and it has a manageable safety profile, particularly with the mitigation strategies we put forward. I think the impressive activity seen in these very heavily pretreated patients is very promising. Again, this is a phase one study we haven't set our recommended phase two dose yet, but I'm hoping that as we move onto the next stages and move onto dose exploration where we gain more experience with AMG 160, that this early activity will be confirmed and hopefully they'll move on to further studies.

Alicia Morgans: That's wonderful. Well, I sincerely appreciate your time, especially as we've had to coordinate time between Melbourne, Australia and Chicago in the United States. We would love to have been together with you at ESMO this year, but appreciate that you were able to help us talk with you, even though we are many, many thousands of miles apart. Thank you so much for your time, Dr. Tran, and for your essential work in the care of these men with metastatic castration resistant prostate cancer.

Ben Tran: Thanks, Alicia. Always great to talk to you.