Combination Antibody-Drug Conjugate Strategy and the Future of Bladder Treatment

A roundtable discussion, moderated by Peter O’Donnell, MD, discussed the advanced urothelial treatment landscape, as well as recent trial data from ESMO 2023. Dr. O’Donnell was joined by Terence Friedlander, MD; Matthew Galsky, MD; and Jonathan Rosenberg, MD.

In the next segment of the roundtable series, the panel discussed the double antibody-drug conjugate trial that assessed sacituzumab govitecan plus enfortumab vedotin.

Watch the next segment in this series.

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Dr. O’Donnell: One of the last data sets that we should talk about from ESMO is a signal of where the puck might be going, and that is, how do we start building on the backbone of EV [enfortumab vedotin]/pembrolizumab? Could we start combining some of these newer drugs like the antibody-drug conjugates (ADCs)? There was a phase 1 study that looked at the combination of sacituzumab govitecan, another drug that has an approval in this disease, but maybe struggling to find a place, so sacituzumab plus EV. I don’t know if you guys saw that data set. It had a really high objective response rate in a refractory population. Jonathan, I’ll start with you. Do you think this idea of combining ADCs will have a role?

Dr. Rosenberg: I think it will, in fact. We’ve known in oncology forever that single-drug therapy doesn’t have the maximal benefit, that you need to combine treatments with different targets, different toxicities to get the maximum benefit. I think the big question from this is going to be what plays well with the third agent would be immune checkpoint inhibitor. Whether the 2-drug combination plus the checkpoint inhibitor is going to be better than EV… This 2-drug combination plus pembrolizumab is going to be better than pembrolizumab, to me is unclear. I think it’s clearly worth exploring. There are a lot of other ADCs that are out there now with other cytotoxics, other Trop-2 ADCs that are investigational. I think there’s some real interesting opportunities for combinatorial therapies. This is maybe one of the first times that urothelial cancer is actually leading the way. This was the first double ADC combination trial, I think, that’s ever been reported. I think we should see more of these in bladder cancer going forward.

Dr. O’Donnell: Matt, do you want to comment on that?

Dr. Galsky: Yeah, I think it’s interesting data. I mean, the principles of independent drug action, 1 of the principles, is that giving drugs together rather than sequentially could be beneficial if you don’t have to compromise the dose of 1 of the drugs. Here, you do a little bit, and so whether or not it’s the right strategy, I think we just need to sort that out based on larger studies.

Dr. Friedlander: I would just add, it was a close to 70% response rate. But what we don’t have is a lot of correlative data from that. One of these agents targets Nectin-4, one targets Trop-2. Are they both expressed on the same cell? Are they expressed on different populations of cells in the microenvironment, which makes it even more attractive? One of the thoughts I had actually after seeing the data was giving them together also has an increased risk for toxicity, which is expected for both of these agents. Could you do an approach where you gave 1 agent and then the next cycle, gave the other agent? Sort of an intermittent approach. You can think of all these perturbations of what to do and you obviously might compromise efficacy, so I don’t think that’s the first study I would run to. But if you’re really trying to get it sort of mechanisms of resistance, maybe these are different ways to sort of address that. I completely agree that adding a checkpoint inhibitor here and moving this up in the treatment regimen, at least for pretty fit patients, might be fruitful. We’ll have to see.