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Leslie Ballas: Hi there, I'm Leslie Ballas. I'm a radiation oncologist at Cedar Sinai in Los Angeles, and it is my great pleasure to introduce Dr. Kent Mouw. He's an assistant professor at Harvard Medical School and is practicing at Dana-Farber Cancer Institute and Brigham and Women's Hospital. He recently had a publication in European Urology regarding the activity of enfortumab vedotin and sacituzumab govitecan with radiation in a preclinical model. It is my pleasure to get to ask him questions about this publication and just chat with him generally about the importance of this work. So welcome, Dr. Mouw, thank you for doing this.

Kent Mouw: Yeah, my pleasure. Thanks for having me.

Leslie Ballas: If you don't mind, could you explain to our listeners why it is important to evaluate the combination of enfortumab vedotin and radiation in this preclinical setting?

Kent Mouw: I think that given the excitement and the expanding clinical role for these antibody-drug conjugates in advanced bladder cancer, it makes sense to think about how we can study them and potentially integrate them earlier in the disease. I think that these types of preclinical studies, although clearly no substitute for clinical trial work in this space, can provide some interesting insights and help guide how we design and execute the clinical trials.

Leslie Ballas: What did you find when you looked at this in the preclinical space and with your mouse models?

Kent Mouw: My lab has a variety of different preclinical bladder cancer models, and we wanted to test specifically what the activity of both enfortumab vedotin, as well as, separately, sacituzumab govitecan were in combination with radiation. And so, to do that, we tested the impact of these combinations on cell death, on cell signaling readouts, both in vitro and then also in these mouse models of bladder cancer that we use. I would say that, overall, these results were quite encouraging to us. It looked like in both cases, both with EV and SG, there was nice additive toxicity as read out by things like treatment-induced cell death in cell lines as well as in tumor growth control in the mouse models. And so I think that this provides a sort of evidence that would give you confidence that moving forward this would be a rational combination in the clinical space.

Leslie Ballas: When you described it just now, you said radiation and these ADCs as combination treatment, how did you time the delivery of the drug versus the radiation?

Kent Mouw: Yeah, great question. We tried to do our best to model this as clinically relevantly as we could, with the important caveat that these are obviously preclinical systems. For the in vivo work, so for the mouse bladder cancer models that we use, we used fractionated image-guided radiation that we hope approximates how we're treating our patients. Obviously, the courses are a lot shorter, but in this case, we delivered these concurrently, and so the mice received treatment with the ADCs several times a week plus daily radiation treatments in an attempt to sort of get as close as we can to modeling how we think that these things should behave in patients.

Leslie Ballas: Do you think that the timing matters? So if you were to give an ADC before radiation, do you think that you can extrapolate from your results increased cytotoxicity based on either increased NECTIN4 or TROP2? How do you envision it in terms of clinical timing if it wasn't concurrent?

Kent Mouw: Yeah, that's an important question and one of the topics that I was actually most interested in studying with the preclinical systems is to try to address the question: what is the impact of radiation on the expression of these ADC targets? Because, for example, if radiation significantly downregulated the expression of these targets, you would want to know that because it would impact the way that you, perhaps, try to combine them clinically.

We had a variety of both cell line and in vivo models. In general, I would say that the impact of radiation on the expression of both TROP2 and NECTIN4 was modest. There were some models where there was a little bit of increased expression on the timescale of hours to days after radiation. In other models, there was a slight decrease. But in general, I would say that the differences induced by radiation were relatively minor compared to the baseline differences that we knew existed among these different models in terms of NECTIN4 and TROP2 expression at baseline in the pre-radiation space. And so I think that encouraged us that there weren't at least signals that radiation was downregulating the targets that we're hoping to really engage with these ADCs.

Leslie Ballas: When you described the radiation and the elaborate planning that I'm sure goes into your mouse IMRT, is there an equivalent human dose? Are you giving what we would think of as 2 Gy per day, which is a common radiation dose, what was used on SWOG 1806 or what's commonly used for the RTOG prior bladder cancer trials? And does that dose even matter, do you think?

Kent Mouw: I think the dose matters. The dose we used here, and unfortunately, we're not doing IMRT, but we are using clinically relevant doses. I think we use 3 Gy per fraction, which, when you think about hypofraction, the 55 in 20 regimen that we frequently use, that's 2.75. I feel like we're in the right ballpark. In the cell lines, we did a little bit of dose-finding experiments where we asked if the impact of radiation on NECTIN4 and TROP2 expression is dose-dependent. So we went all the way from a relatively low dose to a higher dose that you could imagine being more clinically relevant in an SBRT-like approach. In general, that dose didn't really seem to matter, with the caveat that these, again, are cell line models. But in general, we try to come as close as we can to modeling the fractionation schedule and the dose, at least the approximate dose, that is used to treat patients.

Leslie Ballas: Commonly, or at least in the advanced bladder cancer studies, EV has been combined with pembrolizumab in terms of achieving a good clinical outcome or a robust clinical outcome. Do you think that the addition of Pembro would make a difference in the preclinical space in terms of either your cytotoxicity or perhaps just toxicity?

Kent Mouw: Yeah, that's a great question. It's something we're certainly interested in continuing to study. Everything that was in the paper that was just published involved human cell line or human bladder cancer models grown in mice, so we don't get to study impacts of the immune system. The advantage of doing it that way is that the human tumors have human NECTIN4 and human TROP2, which are targeted by the ADCs. But we're actively working on trying to develop the platforms and the tools that will allow us to study combining ADCs with immune checkpoint blockade in these types of preclinical models because I think I'm interested and excited about the possibility of combining ADCs with IO with radiation in this space and in these models.

Leslie Ballas: Well, I thought that the paper and the work were really exciting and instructive for what we are looking for in the clinic, and I agree, the possibility of combining the ADCs either with or without immunotherapy and radiation is certainly something that all of us radiation oncologists who treat bladder cancer are looking to figure out. Is there anything else that you wanted to tell us or highlight from the work you're doing?

Kent Mouw: No, I'm glad that the timing of this work out well. This is an area that I think is ripe for clinical investigation, and so I hope our work can help, at some level, inform how these trials are designed and how they move forward. But ultimately, these types of works, as important as they are, are really no substitute for the clinical trials that need to be done to really move this paradigm combining radiation with, in this case, ADCs or with IO, and really, ultimately, trying to prove the activity and the efficacy of these combinations in our patients.

Leslie Ballas: Oh, actually, I do have one other question that I realized I forgot to ask, which is, you do make a comment about how, in combination treatment, the weight of the mice didn't change. For someone like me who doesn't do a lot of mouse experiments, is that a good measure of toxicity?

Kent Mouw: It's our best measure in this context. And so, mouse weight and mouse overall health, as sort of visibly assessed, that's the limitation of the preclinical systems. That's really how we're monitoring toxicity. The mice refuse to fill out quality of life forms, and so we're left with mouse weight as the proxy.

Leslie Ballas: And there was no difference, correct?

Kent Mouw: Correct. Yeah. And so that was important. These are relatively shorter timeframes than we treat our patients over, but when you try to combine things, often you see at least additive and sometimes more than additive toxicity, and so it was encouraging in this case that the mice seemed to tolerate this pretty well. I think that was one of the advantages also of using the relatively more conformal radiation techniques that we were able to use in this preclinical system rather than exposing large portions of the mouse to radiation, which I think would increase the risk and would be less relevant for how we actually treat our patients today.

Leslie Ballas: Great. Well, thank you so much for taking the time to talk with us about this and explain this work. It is very exciting. Again, Dr. Mouw, we really appreciate it.

Kent Mouw: Thank you. My pleasure.