Dr. Mouw on preclinical work with ADCs plus radiation in bladder cancer

In this video, Kent W. Mouw, MD, PhD, describes the background and key findings from the work, “Activity of enfortumab vedotin and sacituzumab govitecan with radiation in preclinical models of bladder cancer,” for which he served as the senior author. Mouw is an assistant professor of radiation oncology at Dana-Farber Cancer Institute and Brigham and Women's Hospital in Boston, Massachusetts.

Video Transcript:

Could you describe the background for this work?

Both enfortumab vedotin and sacituzumab govitecan are exciting new therapies that are now approved in the advanced bladder cancer setting. The goal of this work was to understand the activity of those 2 agents with radiation in preclinical models of earlier disease, with an eye towards hopefully, if we saw activity, having this work motivate the potential for future clinical trials combining with radiation in the muscle-invasive bladder cancer setting.

What were the key findings?

We used a variety of different preclinical bladder cancer models that we have in my lab, both cell lines and then in vivo models in mice bearing bladder tumors. Our goal was to understand what the combined activity of each of these ADCs with radiation was. We asked a variety of questions. One of the first questions we asked was, what role does radiation have on expression of the membrane bound proteins that are targeted by these antibody drug conjugates? So, Nectin-4 for EV and Trop2 for SG. We thought this was an important question because if your goal would be to combine these ADCs with radiation, then you would want to understand what impact radiation might have on the expression of the targets on the bladder cancer cells. We saw some variability in the response of these expression levels to radiation. I would say that, in general, those effects were modest compared to baseline differences that existed in the expression level of these targets across the bladder cancer models at baseline.

Overall, we felt that that was promising insofar as if we had seen very significant downregulation of either target following radiation, I think that would give you pause about the potential utility of combining these ADCs with radiation. But instead, we saw relatively modest changes, a little bit of increased expression in some of the models, decreased expression in others, but by and large, those differences were small compared to baseline differences that may exist across the models. Taken together, I think that gave us some encouragement to continue looking, and we combined then each of these ADCs with radiation, first in cell lines, and then in the in vivo models. What we saw was additive cytotoxicity and additive tumor control. The mice bearing bladder tumors were treated with a combination of either EV plus radiation or SG plus radiation, [and] the tumor growth control was better in the combined groups than using either ADC or radiation alone. That was done, and they were delivered in reasonably clinically relevant ways, we thought. As best we could tell, there was no significant toxicity, with the important caveat that these are preclinical models.

This transcription has been edited for clarity.