Urothelial cancer is quite a diverse disease. And we encounter, actually in clinic, not infrequently, quite a few different variant histologies. Most of the time, these are variant histologies that arise in the background of urothelial carcinoma. And so these are entities like, for instance, squamous or sarcomatoid or plasmacytoid. And, you know, generally, again, they’re present as a minority component with majority component urothelial...
Urothelial cancer is quite a diverse disease. And we encounter, actually in clinic, not infrequently, quite a few different variant histologies. Most of the time, these are variant histologies that arise in the background of urothelial carcinoma. And so these are entities like, for instance, squamous or sarcomatoid or plasmacytoid. And, you know, generally, again, they’re present as a minority component with majority component urothelial. Sometimes, though, we do see a more extensive varying component as well. Separate from that, we also see basically non-urothelial cancers that arise in the bladder as well. And that could be entities like pure squamous cell carcinoma, sometimes pure neuroendocrine carcinoma, adenocarcinoma, those are actually quite different. And we probably, you know, from a therapy standpoint, approach them quite differently than the first category I went over. The first category, so again, varying histologies that arise in the background of urothelial cancer, these are, you know, they certainly make us pay attention. I think, you know, this is something where, you know, when you see a patient like that in clinic, you zero in on this and you really think about, well, do I, should I somehow approach this patient differently, you know, than I would a patient with, you know, pure urothelial histology. There are now, you know, some trials to look at this question. Actually, Andrea Apolo at the NCI is running important studies there. There are other investigator-initiated trials as well. But I think we have some at least initial retrospective data from the UNITE study, the UNITE registry, where we looked at this question of whether, you know, the sort of newer potent systemic therapy that we use a lot now for patients with urothelial bladder cancer, namely EV and pembrolizumab, whether that works, you know, as well for these patients with variant histologies. And at least in the metastatic setting, again, what we’re seeing is that EV and pembrolizumab does have activity for these patients. So this is a, again, a retrospective analysis in a nice study that we did initially with looking at just enfortumab vedotin monotherapy. And actually, we published this data earlier this year in European Urology. Now we have a study looking at the same, well, outcomes in the same patients, but with the enfortumab vedotin-pembrolizumab combination. And that is data we presented as a poster at ESMO just this past year. But what we’re seeing is that actually enfortumab vedotin and pembrolizumab do have activity in patients with variant histology, though this activity does decrease as the extent of variant histology increases. So it’s highest for patients who have mostly urothelial histology with, you know, a component of variant. If they have majority variant with a component of urothelial, then the response rates are lower, but they’re still there. For pure variant histology, we see some responses with EV pembro, but they’re much fewer for sure. Now, it is encouraging that we do see some responses, and that’s why I, you know, often for these patients, this is certainly a regimen that I would consider. A histology where perhaps we should be more cautious with this approach are neuroendocrine or small cell bladder cancer patients. And because presence of that histology really, unfortunately, portends pretty poor outcomes. And I’m not as convinced that enfortumab vedotin-based regimens kind of work all that well there.
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