Alicia Morgans: Hi, I'm so excited to be at ESMO 2022 with Dr. Jonathan Rosenberg. Thank you so much for talking with me.

Jonathan Rosenberg: My pleasure. It's good to be here today with you.

Alicia Morgans: It is great to see you today. I'm so excited to talk about Cohort K and the results that were presented at ESMO. Can you share a little bit of those data?

Jonathan Rosenberg: Sure. Cohort K is one of several cohorts in a multi-cohort phase 1B/2 study of enfortumab combined with multiple different agents. The data presented at ESMO is with pembrolizumab. It was a randomized cohort of enfortumab and pembrolizumab or enfortumab as monotherapy. The purpose was to really try to tease out the contribution of enfortumab monotherapy and pembrolizumab to the combination of enfortumab and pembrolizumab together.

The primary endpoint was objective response rate. About 75 patients were accrued to each cohort. They were stratified in the randomization by liver mets and performance status. The patients received enfortumab on a day one and eight schedule every 21 days, pembrolizumab every 21 days in the combination arm, and enfortumab monotherapy on a day one and eight schedule every 21 days. Notably, that's different than the FDA-approved dosing of enfortumab, which is day one, day eight, and day 15. It seems like the dosage is equivalent, essentially, so the Q3 week regimen was what was used in this trial.

The primary data shows that enfortumab and pembrolizumab have a 64.5% response rate in this cohort with about 10% of patients having complete responses. The prior data from cohort A and dose escalation showed an objective response rate of 73%. This looks relatively similar. The 95% confidence intervals essentially overlap. Enfortumab monotherapy showed a response rate of 45%, which is very consistent with enfortumab across the clinical trial program from 101, 201, 301, and now EV103.

This really does suggest that the combination probably adds substantially with a much higher response rate. Preliminary data from duration of response, PFS and OS, are not mature. DOR has not been reached. PFS also has not been reached. Overall survival is clocking in at 22 months plus, but even that is actually immature data, and the tail of the curve there are just one or two patients contributing events. I suspect that number will change over time. I think it'll probably lengthen, but it could go either way. We're looking forward to seeing further data in the future from this cohort.

The safety profile also seemed reasonably manageable. There was more skin toxicity with EV pembro than with enfortumab or with pembrolizumab. That's not a surprise given that it's an on-target toxicity for both drugs. Pneumonitis was also observed in a small proportion of patients, but generally, the immune-related adverse event profile was similar to pembrolizumab and the EV toxicity profile of fatigue, neuropathy, hyperglycemia... All of that was consistent with prior data.

Alicia Morgans: That was quite a whirlwind of success and really exciting. I wonder if you can comment on the 10% complete response rate that was seen in this combination arm. How often would you expect to see that happen in this cohort, CIS ineligible? This is an advanced disease cohort.

Jonathan Rosenberg: There are almost no complete responses with gemcitabine and carboplatin. At best, it's a 2 or 3% complete response rate. In the large phase three trial that was done years ago, I believe that number was zero.

The durability of response is also appearing to be dramatically different than with cytotoxic chemotherapy. In cohort A, which was just published in JCO very recently, the median duration of response was about two years. The median overall survival was over two years in patients treated with the same regimen. I'm optimistic that this is going to be a transformative therapy.

There are three phase 3 trials that are going on right now that are looking to confirm these results and justify full approval. The main one is EV302, which is randomizing patients to EV pembro or gemcitabine and platinum. Depending on their platinum status, they can get platinum or carboplatin. That will really show the clinical benefit of the combination. If it does, I expect that'll lead to full approval, then probably international approval.

There are two other studies looking at muscle-invasive bladder cancer, KEYNOTE-B15 and 905, and those are looking at either cisplatin-eligible or ineligible patients as preoperative therapy for urothelial cancers.

Alicia Morgans: I think the big question might be, as this moves into this cisplatin-ineligible space, how do you make a decision between EV pembro and gem carbo followed by avelumab maintenance and the trials you've described? Don't exactly answer that question unless investigators decide to give some maintenance.

Jonathan Rosenberg: Right. EV302 has actually incorporated maintenance into it now.

Alicia Morgans: Wonderful.

Jonathan Rosenberg: Although, the penetration of that across the study and across sites around the world remains to be seen.

There was one clear group of patients who probably are not going to tolerate EV pembro very well, and that's patients with significant peripheral neuropathy. Those patients should probably continue to get gemcitabine and carboplatin followed by avelumab maintenance, if they respond. I think people with very poor performance status might be better suited for single-agent checkpoint. Complex multiple comorbidities also might not be well suited for even carboplatin-based therapy, much less EV pembro.

I think we're going to have to pay attention to the patient-specific factors in terms of tolerability for them until we see the totality of the data across cisplatin eligibility in urothelial cancer. There may be some other subsets. Hyperglycemia patients, poorly controlled or brittle diabetics may not be the people you want to put on EV pembro, or even EV monotherapy for that matter.

Alicia Morgans: I think all of that is fair. I almost cringe because of asking the question, because I don't think it's a question we can answer, but it is a question we will answer on an individual basis for each of our patients and is one that I'm glad to have the opportunity to make. This is a patient population that has not had opportunities that have been really life-prolonging in a way that was tolerable for patients, and both of these approaches are things that have been transformative for the field.

Jonathan Rosenberg: I think the data from Cohort A suggests that we're doubling PFS and OS in this patient population, and that's really unheard of in bladder cancer, for one. It is potentially opening up a new age of combination immunotherapy and ADC therapy. I think there's a lot of excitement for other combinations in the future.

Of course, we need to try to figure out the relatively small proportion of patients who are resistant to EV pembro. Why is that happening? What can we do to get those patients to respond to that regimen, or is there an alternative approach we should be taking?

Alicia Morgans: Absolutely. There's always more work to be done, but congratulations on the work that has been completed by you and your team, and certainly congratulations to the patients who have participated in this really exciting work. I appreciate your time and your expertise.

Jonathan Rosenberg: My pleasure. It's always a pleasure to talk.