Sequencing Later-Line Therapies for Metastatic Urothelial Carcinoma


A brief review of second-line and subsequent treatment strategies in metastatic urothelial carcinoma and novel therapies being explored in this space.


Shilpa Gupta, MD: Mamta, could you walk us through what happens after platinum and immunotherapy [IO]? What are the available agents, and how do you best sequence them?

Mamta Parikh, MD, MS: Yes, I think that’s an area that is very dynamic right now. We’re in a very good position with bladder cancer because we have more options than we did before. There are a number of drugs that have been studied in patients who are both platinum refractory and refractory to immunotherapy. Enfortumab vedotin [EV], which we’re all familiar with, was studied in patients who had gotten platinum and IO therapy. It was used in a randomized study vs chemotherapy and was shown to be superior to chemotherapy. It had an overall survival advantage as well as an objective response that was higher than chemotherapy. Enfortumab vedotin is a very good option for patients.

Sacituzumab govitecan was also studied in TROPHY U-01 in patients who had progressed on platinum as well as IO therapy. It also had a very good response rate. That study had patients who were slightly more refractory, so the objective response rate was a bit over 30%, but I hesitate to compare that to the EV data because they are very different patient populations. But that is an approach for patients. Then we also have erdafitinib, which was studied in the BLC2001 study. This was a single-arm study in patients who had select FGFR2 or FGFR3 alterations, or FGFR fusion mutations. This also showed a response rate of around 40%. We have 3 drugs that are very good for patients who have been through platinum and IO therapy. I think the question is how to sequence them, and a lot of that comes down to the individual patients and adverse effects we might be concerned about from the various therapies.

Obviously, when patients have been treated with platinum-based chemotherapy, they may have residual peripheral neuropathy. Enfortumab vedotin can cause peripheral neuropathy, so we do take that into consideration when deciding whether someone should be treated with enfortumab vedotin vs sacituzumab, for example. If patients have FGFR alterations, I think erdafitinib is a very good approach, but it’s a question of whether you want to start them with enfortumab or with sacituzumab and then switch to erdafitinib. We have a paucity of data right now in that situation in terms of sequencing. I think there are trials that are going to give us more information about that over time.

There have been some data showing that after enfortumab, sacituzumab does still have a response, so I think it’s quite reasonable to try another antibody-drug conjugate once you’ve had one. They do have different mechanisms, and different antibodies that are targeted. Enfortumab targets NECTIN4, and sacituzumab targets TROP2, so they’re different antibodies with different payloads, so there is reason to believe you could still have a response.

Transcript edited for clarity.

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