Immunotherapy Outcomes in Pure vs Mixed Urothelial Carcinoma Histology
Dr. Pal: So, I’ve got to tell you, one of the most pressing issues that I have in clinic, when I see patients with advanced bladder cancer, localized bladder cancer for that matter, is when they actually have variant histologies. They’re numerous. Can you tell us about some of the most frequent variant histologies that you tend to see in your practice?
Dr. Sonpavde: Right. The variant histologies is a disease for which we don’t have a good handle of treatment. Most of the clinical trials that evaluated new drugs, new regimens, and even platinum-based chemotherapy, have been patients that had predominant urothelial carcinoma. So that’s basically approximately more than 50% of the tumor had urothelial transitional cell carcinoma, but there are other variant components that can be presenting these patients. That includes squamous, adenocarcinoma, there’s sarcomatoid, there’s a micropapillary subtype, and there’s other subtype, like plasmacytoid subtype that’s also being discovered more and more, where pathologists who are beginning to understand this. So in patients that have a minority urothelial component and a majority variant component, these patients have really not been studied that much in trial, so these patients were not in these urothelial carcinoma trials. So we really had to look harder for drugs for these patients, and look at whether the outcomes might be improved with some different regimens.
Dr. Pal: At this particular meeting, at ASCO GU 2019, are you seeing any abstracts related to biologic findings in any of the populations, anything that really stood out to you?
Dr. Sonpavde: Well, one of the things we did was, we were keen on looking at whether PD-1/PD-L1 inhibitors have differential outcomes based on the variant histology, and we looked at this based on whether the patient had pure urothelial carcinoma or mixed urothelial carcinoma, a mixed urothelial plus a variant component. And there did not seem to be a difference in terms of response rate in patients who had pure urothelial versus mixed urothelial carcinoma. So at least in terms of this retrospective study, which was around 100 patients, it seems like it may not make a huge difference when you’re considering a PD-1/PD-L1 inhibitor. In terms of genomics, we don’t understand it that well yet, there are, you know, some indications that maybe the micropapillary subtype is enriched for the HER2 alterations. And the adenocarcinoma component might be somewhat less mutation burden-rich, less mutations, maybe suggesting that potentially that’s not going to be as responsive to PD-1/PD-L1 inhibitors. The plasmacytoid component might be somewhat enriched for mutation, somewhat mutation burden-high. So we’re learning some of these findings now, and we’ll wait and see if those have therapeutic implications.
Dr. Pal: That’s really interesting. So, you know, I’ve got to ask you about sort of the neoadjuvant setting, right, because we oftentimes think about application of chemotherapy there. You remember the SWOG data suggesting that mixed histologies might even do a little bit better than pure transitional. What about neoadjuvant therapy with PD-1/PD-L1 inhibitors? Is that something that’s kind of on your radar, something we should be considering in clinic now?
Dr. Sonpavde: Not ready for primetime yet, but there is, of course, promising data from a couple of small, non-randomized trials that looked at pembrolizumab alone, or atezolizumab alone, given for a brief two or three cycles before radical cystectomy, which yielded a pathologic complete response of 30 to 40%. So that looks promising, but these were small studies. There might be patient selection issues. There’s also a third study that looked at gemcitabine, cisplatin, plus pembrolizumab, in a non-randomized phase II trial that was a combination study, in which a pathologic complete response rate was around 44%, which looks interesting, but still needs validation in terms of a randomized study.
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