UNITE Study: Impact of Squamous, Other Histologies on Outcomes With EV

A panel discussion, hosted by Vadim Koshkin, MD, brought together different participating clinicians of the UNITE study, a multisite retrospective study of patients with advanced urothelial carcinoma treated with targeted agents, including enfortumab vedotin (EV) and sacituzumab govitecan. Different analyses of UNITE patient subgroups were presented as oral abstracts and posters at the American Society of Clinical Oncology Genitourinary Cancers Symposium 2024. Dr. Koshkin was joined by Amanda Nizam, MD; Matthew Campbell, MD, MS; and Omar Alhalabi, MD.

In the second segment of the panel discussion, the impact of squamous and other histologies on outcomes with EV are dissected.

View more segments from the panel discussion.

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Dr. Koshkin: Maybe Dr. Campbell, that is a good segue to your discussion. As you mentioned, many patients we see in clinic would not have qualified for EV-301. For instance, patients with variant histologies. We would not know the outcomes with enfortumab in those cases, right?

Dr. Campbell: Yes, and for example, bladder tumors can sometimes have mixed histologies, similar to non-seminomatous germ cell tumors, which is different from what we typically see in kidney cancer where it is more likely to be pure. We might observe squamous features, adenocarcinoma, micropapillary, plasmacytoid, or small cell variations. Most trials are designed with the requirement that the urothelial component be predominant, often excluding cases with small cell involvement, for instance.

The challenge arises when we receive abstracts later that discuss variant histologies, typically representing a small percentage of cases. The question then is whether these variants are driving the tumor or not. While there have been studies focusing on variant histologies, they tend to be small and single-arm. Our goal was to assess how EV performs in these cases. We analyzed 150 patients with some degree of variant histology, categorizing them based on whether the variant histology was predominant or pure. Pure cases were limited, with only 14 patients, while predominant cases were more common.

We found some promising results, particularly in challenging variants like plasmacytoid. Plasmacytoid bladder cancer is aggressive and tends to metastasize rapidly, often leading to complications such as bowel obstructions or pleural effusions. In our study, we observed a positive response to enfortumab vedotin in patients with mixed plasmacytoid histology. This finding is significant given the limited treatment options for such aggressive variants.

However, we did not observe any activity in patients with small cell variants. This suggests that an EV strategy may not be suitable for these cases initially, and we should explore other treatment options. Similarly, for squamous variants, while we observed some responses, the overall response rate decreased as the proportion of squamous histology increased.

These findings underscore the importance of personalized treatment approaches for variant histologies. While targeting Nectin-4 shows promise, combination therapies may be necessary for certain variants. Nonetheless, there is still much to learn about the best strategies and targets for these variants.

Dr. Koshkin: That is an excellent summary. Did any of this data surprise you, Dr. Campbell, or anyone else?

Dr. Alhalabi: To me, this data is very exciting and important, as Dr. Campbell highlighted. The findings on squamous histology were particularly intriguing. While not entirely surprising based on our clinical observations, the resistance to enfortumab vedotin in squamous variants raises questions about whether it is due to loss of the target or resistance to the payload. This underscores the need for further investigation, particularly in cases of pure squamous histology.

Dr. Koshkin: Indeed, it is an interesting point. Is the resistance primarily to EV itself or to its payload? Dr. Campbell, are there any other variants you would like to highlight?

Dr. Campbell: Adenocarcinoma also showed responses in our study. We are beginning to differentiate between urachal and adenocarcinoma, recognizing potential biological differences between them. While we have encountered relatively few pure adenocarcinoma cases, they have historically been challenging to treat. Variant histology in bladder cancer remains a significant area of unmet need, but it is promising that we have several agents in development that may offer new treatment options.

Dr. Koshkin: Indeed, there is potential for enfortumab vedotin, or perhaps combinations involving it with pembrolizumab, to benefit some of these patients early on.