GU Cancers 2021 | EV-201, EV-301 and UNITE: enfortumab vedotin in advanced urothelial cancer

There were a number of studies presented on enfortumab vedotin which is, of course, an antibody drug conjugate targeting Nectin-4. This is already approved on an accelerated basis by the US FDA as therapy following platinum-based chemotherapy and PD1/L1 inhibitors. So, this was based on the Phase II trial, the EV-201, which looked at this drug in a non-randomized Phase II trial and identified a response rate of approximately 45%.

Now, at the GU ASCO Symposium 2021, we had a couple of major studies on this drug. One was the EV-301 study, which was a Phase III study in the post-platinum and PD1/L1 inhibitor setting that compared enfortumab vedotin versus historical chemotherapy, which was taxane or vinflunine. So, in this setting, enfortumab vedotin improved overall survival. The median survival was 12.9 months for enfortumab versus 9.0 months for historical chemotherapy.

So, the hazard ratio was 0.70. The median PFS, progression-free survival, also improved from 3.7 months to 5.6 months. The hazard ratio was, again, impressive at 0.61. The overall response rate was also similar to what has been seen historically, 40.6% for enfortumab vedotin and 17.9% for historical chemotherapy, which was significant. So, based on these data, enfortumab vedotin should be considered as an established third-line agent in the post-platinum and PD1/L1 inhibitor setting.

Also, another important data set presented at GU ASCO Symposium was the EV-201 Cohort 2. So, remember that initially enfortumab vedotin was approved in the post-platinum and PD1/L1 inhibitor setting as a third-line treatment based on a different cohort in the study. Now, this Cohort 2 is a cohort which gave enfortumab vedotin in the second-line setting post PD1/L1 inhibitor exposed patients, but these patients were cisplatin-ineligible. So, really, a second-line treatment in these patients who are cisplatin-ineligible.

In these patients, the response rate looked similar. It held up with the response rate, which was impressive at 52%, including, impressively, a complete response rate of 20%. And the median duration of response was also impressive at 10.9 months, and the median overall survival exceeded one year at 14.7 months. The toxicities were consistent with what has been seen: peripheral neuropathy, rash, hyperglycemia.

So, based on these data, enfortumab vedotin looks like an active drug. Again, I would remind you that this is not FDA-approved yet in this second-line post-PD1/L1 inhibitor space. However, in this space, there is gemcitabine-carboplatin, which has been used in the community. So, enfortumab vedotin might also, hopefully, be in this space for use in the clinic in the near future.

And thirdly, we were also interested in looking at whether enfortumab vedotin has activity in FGFR2 or 3 activating genomic alterations. So, the question has always been in patients with somatic FGFR3/FGFR2 activating mutations where erdafitinib, the oral FGFR-inhibiting TKI is approved, how do we sequence these agents? Is enfortumab active in these patients?

So, we looked at patients who received enfortumab vedotin and looked at the association between FGFR3 or 2 activating mutations or fusions with response, and there are a few different datasets in the space. In our dataset of 40 patients at Dana-Farber Cancer Institute, which was a multicenter collaboration, we did not find a statistically significant difference between the activity of enfortumab with FGFR3/2 genomically altered patients, and those who did not have the FGFR3/2 genomic alterations. Response rate was not statistically different.

There are other datasets which we can discuss, some of which was the UNITE Study, which was a multicenter consortium led by UCSF and University of Michigan in which we participated, which also had a cohort of patients with FGFR3 or 2 activating genomic alterations. And in this group, the response rate with enfortumab was approximately 45%. So, in combination, when you look at all these datasets, enfortumab vedotin does have activity in patients with FGFR3 or 2 activating alterations. I caution you that we don’t still have a prospective large dataset yet in this group. Therefore, at this time, in patients with FGFR3 or 2 activating genomic alterations, I would lean towards erdafitinib as the established standard of care in post-platinum patients. And enfortumab probably would be, I would sequence after erdafitinib and not before. Of course, there are patients where enfortumab might be a better choice than erdafitinib, but this is the overall strategy that I would apply based on the data so far.