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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today a good friend and colleague, Dr. Tanya Dorff, who is a GU Medical Oncologist and Associate Professor of Medicine, as well as being the GU Section Chief at the City of Hope. Thank you so much for being here with me today, Dr. Dorff.

Tanya Dorff: It's great to be here.

Alicia Morgans: Wonderful. So I wanted to talk with you about some really exciting work that you and your team have been doing and presenting around BiTE therapies. And I'd love to start with AMG 160, and just hear what is a BiTE, if we could start there, and then tell me a little bit about that trial.

Tanya Dorff: Yeah. So, Bi-specific T-cell engaging antibodies are referred to as BiTEs. So they are a more advanced form of immunotherapy compared to something like a checkpoint inhibitor. They require a little bit more time in the hospital because of cytokine release syndrome, which can be pretty common. So they are kind of stronger immunotherapy, but with tremendous potential. There is really only one on the market, blinatumomab, for hematologic malignancies. So it's exciting to be at the forefront of trying to translate this to a solid tumor, and prostate cancer obviously has an unmet need for successful immunotherapy strategies. So AMG 160 is a BiTE targeting PSMA, and we are all very familiar with PSMA from the lutetium radiopharmaceutical targeting strategy. So AMG 160 is given every two weeks to try to help T-cells find the prostate cancer using the PSMA, and we've already presented some early results and the trial is ongoing in the recommended Phase 2 dosing expansion.

Alicia Morgans: I think it's so exciting because as you've said, it's a targeted immunologic response and there seemed, in the AMG 160 trial to be some pretty interesting PSA responses and some durability of response that also I think was really intriguing. And this is a patient population, as you mentioned, that definitely needs more therapies and more therapies that are perhaps harnessing different mechanisms of action. So I think this is really exciting. Can you tell us a little bit about those preliminary efficacy type signals, which of course are not the purpose of a Phase 1 trial, where we are really looking for safety, but we saw some, and I think that's really exciting.

Tanya Dorff: Yeah. So Ben Tran was the lead author on the ESMO presentation last year, which really looked at the dose exploration from very, very low doses all the way up to a dose that's higher than where we are expanding in Phase 2. So taking that whole population, about a third of patients had responses, whether you look at PSA confirmed responses of 50% or more. There were also radiologic responses seen, although you don't have to have measurable disease to enter into the trial. So obviously, looking at RPFs down the road will be important for all those patients who have only bone involvement, which is so common. There were also some interesting results in terms of circulating tumor cell conversions. So by any measure, it seemed like about a third of patients benefited and that, again, was using very low doses, very high doses. So we're hoping to see an even bigger percentage benefiting from the recommended Phase 2 expansion.

In terms of durability, so there are definitely a good number of patients who cross the six-month mark, which we take to be sort of a benchmark for how much durability patients are looking to get and clinicians too. I think we're hoping to do better than just a short-term PSA goes down, and it comes right back up, which you often see in these very heavily pretreated patient populations. And there was a handful who made it out past one year still exhibiting cancer control.

Alicia Morgans: I think that is an incredibly exciting part of this study.  And the other piece, of course, of Phase 1 that we want to think about and try to optimize when we get to Phase 2, and then ultimately, as we are able to move therapies that are successful into clinical practice are really how we manage the side effects that can come with treatment. And with these exciting efficacy type signals, that's going to be important I think as we consider cytokine release syndrome. So can you tell us a little bit about that and how you and the study team really worked to come up with a strategy to make this something that is manageable?

Tanya Dorff: Yeah. Amgen has done a phenomenal job all along of really looking for ways to mitigate and prevent the most severe grades of cytokine release. So there were some episodes of Grade 3, but many of them were actually due to elevated liver enzymes, which by the criteria can bump you up to Grade 3. So not many cases were actually patients with hypotension or hypoxia where they had to go to ICU. There were some, but very few relatively speaking. So a lot of Grade 1, Grade 2, about 90 plus percent of patients do have some level of cytokine release. So it's really important for clinicians who will use this to be familiar with it. It tends to happen within a few hours after the infusion is started or completed. The first infusion is 72 hours, all the subsequent ones are an hour. So some hours after, we see fevers and chills, very commonly.  There has been some nausea or diarrhea as well. Some of that maybe be from the demerol that we are giving for the chills. But-

Alicia Morgans: Yeah.

Tanya Dorff: It's very manageable. It's very predictable and very manageable. You use demerol, tylenol, all your basic management for fever and chills. There have been some preventative measures implemented such as dexamethasone for the first few doses, some saline boluses to help avoid the hypotension, things like that are going to help make it easier to roll out to a broader oncology community.

Alicia Morgans: And it looked, at least when I reviewed the data as if these mitigation measures, as you said, really did reduce the number of patients who experienced more of a Grade 3 event. And I think it reduced it almost to most patients having Grade 1 and 2, which is great when you think about durable treatment response. And when you also think about this cytokine release syndrome perhaps being a marker that the drug is working on some level, which is important too. So we don't want it to completely disappear, but we do want of course to have those supportive measures to get patients through. So you mentioned a Phase 2, and I know there are other BiTEs that are of interest. I'd love to hear about the ongoing studies as we wrap up.

Tanya Dorff: I just want to add that the cytokine release does seem to diminish over time so that by the time patients are in their second month of treatment, they are not having fever and chills. They can be taken off the dexamethasone pre-medication, and so it becomes much easier and better tolerated as you go on.

As far as the other trials, so we are participating in the AMG 509 which is a bi-specific targeting STEAP1, a different prostate cancer antigen, which is important since not every patient has a lot of PSMA expression, I mean most do. This is also slightly different because there are two heads for the STEAP1 antigen and one head for CD3, which looks for the T-cell. So how that construct will impact toxicity and efficacy will be really interesting to see

Alicia Morgans: Wonderful. Well, I am very excited about these new therapies. And like I said, any option to have a unique mechanism of action that really helps to target cancer in a novel way I think is going to be important for these patients as we try to really help them live longer and feel better throughout the illness that they face. So thank you so much for your time and for your expertise today.

Tanya Dorff: My pleasure. Thanks.