Optimizing Selection of ADC Therapy in Metastatic Urothelial Carcinoma


Focused discussion on the optimal selection and use of antibody-drug conjugate therapies in patients with metastatic urothelial carcinoma.


Petros Grivas, MD, PhD: It’s one great idea to do a trial and look at sequence. I think there are trials looking at combinations. I think, Guru, you are doing a study with enfortumab vedotin plus sacituzumab govitecan; tell us about it.

Guru P. Sonpavde, MD: That’s right. We are doing a trial combining both antibody-drug conjugates. We call it the DAD trial for short, double antibody-drug conjugate trial. The reasoning of course was that these drugs target different membrane antigens and have different payload toxins, so there might be a synergism without any overlapping toxicities. We also have a phase 1 study that is combining enfortumab vedotin and erdafitinib. Again, enfortumab vedotin like you all mentioned does have activity in patients with FGFR3 alterations. It does not seem to be compromised, at least in retrospective studies, not huge studies, so that might be interesting. We’ll have to wait and see; it’s going on in a phase 1 trial.

Petros Grivas, MD, PhD: Very interesting, it will be interesting to see the results, and toxicity and efficacy as well. A question, Cora, if you have a patient with really bad neuropathy after platinum, grade 2 neuropathy, and is FGFR3 negative, would you use sacituzumab [govitecan] before enfortumab [vedotin] in that patient, or would you still go with enfortumab?

Cora Sternberg, MD, FACP: I think if the patient has really bad neuropathy, I wouldn’t be too anxious to give them enfortumab vedotin because I’ve seen too many problems. I’ve seen car accidents. I’ve seen people falling. I’ve seen things that I really don’t like to see. We try to treat them with medicines but that wouldn’t be my first choice. I would probably go with sacituzumab govitecan in that case if possible.

Petros Grivas, MD, PhD: Got you. Tian, would you do the same?

Tian Zhang, MD, MHS: Yes, I think neuropathy is really hard to get around. I would probably dose reduce the medication. My threshold for dose-reducing enfortumab vedotin is quite low, so if a patient could see it, I would give some lower dose potentially to start. Certainly, sacituzumab govitecan would be a great alternative for that patient.

Petros Grivas, MD, PhD: I think it’s interesting when we think about the patient and the particular adverse effect profile, it’s good education. It’s very important whatever agent we decide to use. Srikala, a question for you; you have a patient with a hemoglobin A1C [glycated hemoglobin] of 9.5%, uncontrolled diabetes. You try to educate the patient, the diet of course, whatever treatment for diabetes. Would you use enfortumab [vedotin] in that case, or would you change?

Srikala Sridhar, MD, MSc, FRCPC: I think it’s a good question. I like the response rates with enfortumab, and I like getting my endocrinologist involved, and so that’s probably what I would do. I wouldn’t use uncontrolled diabetes as a reason not to give enfortumab vedotin, but I think it highlights that we need to be careful. Often, I’ve seen diabetes in patients who have no history of diabetes whatsoever. All of a sudden you check their blood, and their sugars are going up, so I think it’s an important thing to keep in mind. Other toxicities, we’ve talked about neuropathy as well, and even with erdafitinib, I think we have to be aware of some of the new toxicities: eye toxicities, nail and skin toxicities. The latter may be worse for patients than we give it credit for because they see it every day. They’re using their hands. It’s something that I think we really have to be aware of.

Petros Grivas, MD, PhD: Absolutely, and skin rash can happen with either. It’s more hand-foot syndrome for erdafitinib, and the skin rash with enfortumab [vedotin] is very variable.

Cora Sternberg, MD, FACP: It’s very variable. I was on a committee and saw many different kinds of skin rashes. I had one patient of mine who was white-skinned and he turned completely black. His skin turned black, no matter how much sunblock he used or whatever during the enfortumab. He finally progressed, and we stopped, and it went back to his normal skin color. So the skin rashes can be rather strange. That’s not the typical skin rash that we see.

Petros Grivas, MD, PhD: That’s very interesting, and in my mind is there any correlation between toxicity and efficacy in any of those drugs? Like immunotherapy, it’s an interesting correlation. It is hard to tell of course, but that’s why we’re doing studies to learn more about them.

Srikala Sridhar, MD, MSc, FRCPC: Looking for biomarkers of both response and toxicity, and maybe they’ll be overlapping sometimes.

Petros Grivas, MD, PhD: Absolutely, I cannot emphasize enough all your points and how important it is to educate the patients and follow up with them, and make sure they don’t underreport adverse events, and make sure the nurses and advanced practice providers and attending physicians all educate the patients about potential toxicities across the therapies we do.

Transcript edited for clarity.

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