Alicia Morgans:  Hi, my name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Tanya Dorff, who is an associate professor of medicine, as well as being the director of the GU group at The City of Hope. Thank you so much for joining me today, Tanya.

Tanya Dorff:  Hi, nice to be here.

Alicia Morgans:  Wonderful. Well, Dr. Dorff, you really held quite a big position in the AMG 160 trial as being, I believe the top recruiter in the US and really someone who has been pioneering in terms of immunotherapies here in the US for some time. We are really excited to talk with you about AMG 160, and to think about that trial, as we try to understand the data and also think about how we can move this type of treatment forward in clinical practice. Can you tell us a little bit about the study?

Tanya Dorff:  Sure. AMG 160 is a bi-specific antibody, so it tries to attract a T-cell and a prostate cancer cell so that the immune system will then attack the cancer. So it has a domain for PSMA, and that is the antigen it's looking for, which we know is already a pretty well-validated therapeutic target for prostate cancer. And unlike a prior iteration that required continuous infusion, this particular BiTE antibody has been formulated so that it can be dosed once every two weeks.

Alicia Morgans:  Wonderful. And I think that is something that we definitely should talk about when we get to the technical administrative aspects. But in this study, one of the things that I thought was so exciting is that this was the First-in-human use of this BiTE, bi-specific T-cell engager approach, like you said, with that PSMA target. So can you tell us a little bit about the patients who enrolled in this trial and were they heavily pretreated? What did the patient population look like?

Tanya Dorff:  Yeah. This was a population of metastatic castrate-resistant, prostate cancer patients who had already gone through an androgen receptor-targeted agents, such as abiraterone or enzalutamide, as well as at least one taxane chemotherapy, but they could have had two lines of taxane, two lines of androgen receptor therapy. And so overall the majority of patients were on the fourth line and beyond.

Alicia Morgans:  Wow. So generally, as I think about that population, of course, these are often older men, and these are patients whose bone marrows had already been hit with some pretty challenging therapies and who had, had a disease that was progressing probably at a fairly rapid pace going forward. So you then treated patients with AMG 160?

Tanya Dorff:  Yes. This was a dose exploration study, so the earlier cohorts were as low as 0.003 milligrams, and the highest cohort was 0.9 milligrams. What was encouraging is, responses were really seen across a broad range of dose cohorts and that there are still ongoing responses. So a couple of patients out around a year already, suggesting that maybe there will be some patients who get longer-lasting benefits from the agent. So we saw PSA responses, CTC conversions, because circulating tumor cells are being evaluated, some objective responses. So for this being a First-in-human study, there are some very encouraging results already.

Alicia Morgans:  And that's the other thing that I thought was so interesting. I mean, there were certainly PSA responses, as you said. And what percentage of patients remained on treatment essentially at the time of data evaluation? It was a fairly sizable percentage of the patients, right?

Tanya Dorff:  Yeah. It's hard to say exactly because the different cohorts came online at different times and patients who didn't make it through the DLT period are not included, but I think we're probably going to have to get better data on that when we have the expansion at the recommended phase II dose.

Alicia Morgans:  Great. Well still I think for a heavily pretreated population of older patients to have a portion, at least over a quarter, so it seemed, maybe even up to 40% or so still on treatment, I think seems really promising. Now, one of the things that we have talked about or thought about as a field, as we've seen this data, is that there were some adverse events and it's always important for us as clinicians who think about using therapy to really understand those adverse events as we go into it, so we can prepare ourselves for how to care for those complications. And also, of course, prepare our patients. Can you talk a little bit about the adverse event profile?

Tanya Dorff:  Sure. So the expected profile is cytokine release syndrome. That's sort of what we hope to see, meaning the T-cells start attacking and there is this big inflammatory reaction with cytokines that can result in hypotension, fever, chills, sometimes some nausea or diarrhea, and one unique aspect of this particular immunotherapy is there are these transient elevations in AST and ALT. So when you look at the grading of cytokine release, you typically think of a grade three as someone going to ICU and needing blood pressure support, or maybe oxygen.

And those characteristics can make a cytokine release a grade three, but here also, the transaminase elevation was the criterion that pushed some people into grade three. So I say that because otherwise, it might look daunting, but the fact that the cytokine release was very, very predictable, I think makes it a little bit easier to manage. This is something that happens right after they finish the infusion, sometimes right when they are getting the flush and is usually winding down by 24 to 48 hours and also seems to get less with subsequent doses.

So all of those factors make it a little bit less daunting to manage. Furthermore, Amgen has worked a lot on innovation strategies and some of those were presented as part of the presentation at ESMO. So there was dexamethasone pre-medication, which eventually you can discontinue for some patients. For higher dose cohorts, giving some fluid bolus to try to prevent that hypotension and some other dose strategies that are still being worked out. But they did show that when they implemented these types of mitigation strategies, that there was actually no grade 3 CRS and an optimized cohort.

Alicia Morgans:  I think that was one of the most exciting pieces, because like you said, we look for these types of responses or complications because that may be ultimately associated with the response, that, of course, remains to be seen, but it is definitely something that we expect when we are using these kinds of treatments and to use mitigation strategies like hydration and steroids, to reduce the rate of grade 3, which are the complications that are the most stressful. Of course, if we have to go to the ICU, then that's wonderful. Now you have been actually quite experienced with Car-T approaches, certainly with AMG 160. What do you think about the, I guess the ability of us to sort of disseminate this approach to either academic practices or community practices that are less familiar? Are these things that you think can be done outside of an academic institution that is really focused on immunotherapies?

Tanya Dorff:  I think eventually this will be something that we can move out into the community. And of course, that is something we want. We want all oncology patients to be able to access this without necessarily having to travel to an NCI designated cancer center or some other facility that does a lot of cellular immunotherapy. And that's where, again, a focus on dosing strategies and mitigation strategies is going to help. Ultimately there will be education required as well, and I'm not sure what exactly that will look like, but as physicians become more accustomed to immunotherapies, I think these side effects and strategies will fall within a comfort zone for most oncologists.

Alicia Morgans:  Wonderful. And really that brings us back to the other piece, the administrative requirements, not just the side effects.  But you mentioned, this is a BiTE therapy that did not require a continuous infusion over long periods of time. Can you tell us a little bit about the evolution of that and why that is so important if we actually want to deliver this to outpatients?

Tanya Dorff:  So blinatumomab, which is the approved BiTE antibody on the market for ALL, does require continuous infusion. And that is cumbersome to be in a facility for 30 days or an extended period of some sort is a barrier perhaps to uptake. And when prostate cancer is such a common disease, we would want something a little more accessible. So there is some inpatient observation in this early phase one dose escalation. How much overnight observation or what types of on-site capabilities will be needed as this rolls out to broader types of oncology practices, I think we will have to pay a lot of attention to.  And it may be that there is at least for the first couple of doses, some sort of period of observation that might be longer than just a chemotherapy sort of infusion situation.

Alicia Morgans:  Great. So as I think about this, it looks like about two-thirds of patients had some sort of PSA decline, about a third of patients actually had that PSA decline being greater than the PSA 50. So a really robust PSA decline. There were a number of patients, a good portion around 40% or so who remained on therapy at the time of data cut. So these all seem really promising, particularly in a therapy that is a new mechanism of action for us in prostate cancer. How would you sum up these data?

Tanya Dorff:  I think that the efficacy data, as you summarized, are really promising, especially for phase I. The durability of response, I think, really has yet to be established because we tested so many different dose ranges. And so once we expand, we will be better able to say what percentage benefit and on average for how long, but the signal is definitely there. This is an active therapy, and as the development continues, as we talked about earlier, the goal will be to get this into a dosing strategy where everyone within a reasonable perspective has access to it and can administer. So prostate cancer patients can benefit from it. It is probably the most active immunotherapy we've seen so far.

Alicia Morgans:  Wonderful. Well, thank you so much for sharing your expertise and your experience with AMG 160. I really look forward to hearing more as this therapy develops and moves into later phases. And of course, the data that are presented, where it is combined with other therapies, and we just get to learn more. So thank you so much for your time.

Tanya Dorff:  My pleasure.