Alicia Morgans: Hi. I'm so excited to be at SOGUG 2022, where I am speaking with Professor Maria De Santis. Thank you so much for being here with me today.

Maria De Santis: Yeah, a pleasure. It's lovely to meet you.

Alicia Morgans: So it's lovely to meet with you, too. And I'm really excited to talk with you about urothelial carcinoma in the metastatic setting and some of the exciting advances that we've seen. Can you tell me a little bit about what excites you most?

Maria De Santis: Yes, I'm happy to refer to some of the data, and finally, we have something to report on bladder cancer. There have been many years with no good news, but now I think the most important part is avelumab maintenance therapy, which has become a new standard of care in the treatment of metastatic urothelial cancer.

So the standard would be platinum-based combination chemotherapy followed by avelumab maintenance in those patients who at least achieve a remission or stable disease on chemotherapy. And for the first time in 30 years, we saw an overall survival advantage with that concept. So this is really exciting, and yes, part of the guidelines now, and this is how we should treat our patients.

Alicia Morgans: Absolutely. And really just to emphasize that this is in an all-comers population, so it's not only patients who are PD-L1 high. It's really for all patients, as long as they have, as you said, a stable disease or better response in the setting of chemotherapy.

Maria De Santis: Yes, exactly. Well, following on that, we have a new drug on the block. There was the approval of enfortumab vedotin antibody drug conjugate, nectin-4 linker and monomethyl auristatin E as the payload. Very active, very toxic chemotherapy. And this enfortumab vedotin was tested in a randomized phase III trial showing an overall survival benefit in the third line setting in platinum and immunotherapy treated patients. So we have an approval by the FDA, by the EMA, and also in Europe we have started treating patients also outside of the clinical trials with the drug. And the response rates in the third line settings are really high. Something we have never seen with old fashioned taxanes, for example. We see 40% objective response rates and as already said an overall survival advantage with a 30% reduction in the risk of death.

Alicia Morgans: Well, and that is so exciting and I'm glad that it's really been able to spread around the world to help patients because it generally has been pretty well tolerated, at least in my clinical practice. One thing that's obvious though, that we certainly want to do with enfortumab vedotin is to move it into earlier lines and to use it perhaps where we have limitations even cis in ineligible patients in the metastatic setting. So can you tell us, have there been any reports on the use of EV or EV combos earlier on in metastatic disease?

Maria De Santis: Well, yes indeed. And actually this has led to the most exciting data in the cisplatin unfit patient population. EV plus pembrolizumab showed nearly 70% objective response rate and 93% disease control rate. This is very exciting data. And yes, of course this already led to a randomized phase three trial in the first line setting in cisplatin eligible and cisplatin ineligible patients. So in kind of all comer population and looking for an over-survival benefit, and we are very excited about that trial. It might lead, for the first time, to a platinum free treatment of those patients. So let's see, and fingers crossed for an over-survival benefit.

Alicia Morgans: Yeah, very exciting. Now, antibody drug conjugates, I think, have been of interest, not just with enfortumab vedotin, but sacituzumab govitecan also is an antibody drug conjugate that seems to benefit patients with metastatic urothelial carcinoma, again, in that later line setting. Can you tell us a little bit about that?

Maria De Santis: Yeah, sure. Also, SG is an exciting drug. The difference to enfortumab vedotin is that the antibody is a Trop-2 and the payload is the SN-38, which is very similar to irinotecan. So the effect and the side effect profile are completely different from EV, and this drug is also working after EV or before EV. So the only common thing is the antibody drug conjugate as a principle. So the SG led to a 27% objective response rate in the third line setting, which is also more than we have seen with the taxanes, for example. And also with the SG, there is a randomized phase III trial ongoing in a pure third line population pretreated with platinum and with immunotherapy. And we are of course very eager to see the results, also for that trial. This is the tropics-04 trial.

Alicia Morgans: Wonderful. Well, as we begin to wind down, I just want to ask one more thing. We've talked a lot about immunotherapy over the years, and certainly now we're very excited about antibody drug conjugates. There is some data that perhaps we can combine antibody drug conjugates and immunotherapy, immune checkpoint inhibitors and have some potential synergistic response. Can you tell us a little bit about that?

Maria De Santis: Well, there is actually that there are some hints that there might be a synergistic effect, which yes, hopefully will lead to also not only higher response rates, as we saw in the cisplatin unfit patient population in the first line, but also in the new adjuvant setting and giving the chance of high complete response rate. So the synergism seems to be there, actually. Still, we have to confirm it in a randomized phase III fashion. So what we have seen with conventional chemotherapy and immunotherapy has been kind of disappointing. But with the antibody drug conjugates, maybe this can be reversed and actually leads to improvement in all the endpoints.

Alicia Morgans: Wonderful. So if you had to summarize these advances, which are truly exciting and game changers for many of our patients, what would that be?

Maria De Santis: Game changer. New drugs with immunotherapy, I think this is the way to go and to be open for the advances that come from translational research, not to stop clinical trials in urothelial cancer.

Alicia Morgans: Absolutely. I could not agree more. Thank you so much for your time and your expertise.

Maria De Santis: Yeah, pleasure. Lovely to be here.