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Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today by Dr. Matt Galsky, who is a medical oncologist at the Icahn School of Medicine in Mount Sinai.Matt, thanks very much for joining us today.

Matt Galsky: Thank you.

Zach Klaassen: So we're discussing your ESMO presentation, looking at RC48G001 Cohort C. So please take us through the intro of this trial and the results that you presented at ESMO.

Matt Galsky: So these are the preliminary results from the RC48G001 Study Cohort C.We know that vedotin-based antibody-drug conjugates have changed the treatment landscape for metastatic urothelial cancer. Of course, enfortumab vedotin is an antibody directed against nectin-4 with MMAE, a vedotin-based payload conjugated to it. So that's changed the landscape.We also know that this is a biomarker-directed approach, and if we're able to direct antibodies to targets that are relevant to individual patients, then potentially, we can improve outcomes.

One of those potential targets that we've known about for a long time in urothelial cancer and other cancers is HER2, and the data regarding HER2 expression in urothelial cancer in the literature is really across the board.Depending on the study that you look at, there can be lower versus higher prevalence of HER2 expression. That's due to several things, including the antibodies that are used, the scoring that's done in terms of what type of scoring is used to determine the level of HER2 expression.But if you look at contemporary literature, it's anywhere about 60 to 80% of urothelial cancers express at least some amount of HER2 expression. So this is a target that's present in most patients.

So there is a HER2-based antibody-drug conjugate called originally RC48, now called disitamab vedotin. This was developed initially in China, so we have a good amount of clinical data already with this drug, both as a single agent and in combination with PD-1 blockade.But now this drug is being developed internationally, and so this is really the first glimpse at RC48, now called disitamab vedotin plus a PD-1 inhibitor in an international patient population.What I'm going to tell you about is Cohort C of the study. So this is a safety run-in of the combination treatment of RC48, or disitamab vedotin rather, plus the PD-1 inhibitor pembrolizumab.

Here’s the trial schema: Patients eligible for this cohort have metastatic urothelial cancer, they are treatment-naive, and they have HER2-expressing tumors.This is where the details are important. So in this study, HER2 expression is defined as follows: Patients can have HER2, quote-unquote, positive disease, which means that by immunohistochemistry there's 3+ expression or there's 2+ expression plus positive FISH—so 2+ expression plus amplification of HER2.Or they could have HER2 low disease, and HER2 low disease is 2+ by IHC with FISH negative or 1+ expression. Both cisplatin-eligible and cisplatin-ineligible patients were eligible for this cohort.The safety run-in is 20 patients to really get some experience with this combination regimen.

Then you can see on the slide that's blurred out, there's a phase II portion that's currently enrolling, which is randomized to assess the contribution of components, so disitamab vedotin plus pembrolizumab versus disitamab vedotin alone.I should mention that the treatment schedule of this regimen is a bit different than some others that we've used. Here, pembrolizumab is given once every six weeks, and the antibody-drug conjugate is given every two weeks.

Here are the characteristics of the 20 patients enrolled in Cohort C: You can see that the majority, 70%, were in that HER2 low category, and about 75% of patients have visceral metastatic disease.So this is a frontline treatment-naive metastatic population but with a relatively large disease burden. Median follow-up of the cohort is nine months.

Here’s the activity in these 20 patients: This is a small patient cohort, but the response rate is 75%, and importantly, that response rate lines up almost exactly with what's been seen in the study in China with disitamab vedotin plus the PD-1 inhibitor toripalimab. So almost identical response rate. Nice to see that holding up.You can see here in the waterfall plot the degree of regression of the tumor in individual patients. It's color-coded based on HER2-positive versus HER2 low disease—green is HER2 low, blue is HER2-positive.The important point about this, of course, is that activity is seen in both categories, HER2-positive and HER2 low.

Now, based on the way that HER2 expression is defined, whether or not there could be some correlation between the degree of HER2 expression by immunohistochemistry and the depth of response will obviously need larger patient numbers to determine that.But the take-home is that there's activity in this combination regimen, regardless of HER2 expression, when there is at least 1+ HER2 expression. Then you can see from the spider plots that some of these responses are quite durable. The median duration of response in this cohort has not yet been met.

Here’s the safety: The safety profile of this regimen is a bit different from what we see with enfortumab vedotin plus pembrolizumab, and that is a potential distinguishing factor between the two.With an MMAE payload, we still see neuropathy. Whether the neuropathy is really the same in terms of the degree and when it develops will need larger patient numbers to determine that.You can see a rash, but we don't really see high-grade rashes with this regimen to date, and there can be some GI side effects as well. We haven't really seen some other side effects that we sometimes see with EV, like hyperglycemia.

So in summary, disitamab vedotin plus pembrolizumab demonstrated encouraging activity in this small cohort of patients with metastatic urothelial cancer who are treatment-naive and have at least 1+ HER2 expression based on immunohistochemistry. Importantly, these results line up quite well with the experience with disitamab vedotin plus PD-1 inhibition from studies done in China. The complete response rate in this small cohort was 35%.So this is an active regimen, and the safety profile is consistent with what's been seen in the studies in China as well. There is now an international phase III study enrolling, comparing disitamab vedotin plus pembrolizumab versus platinum-based chemotherapy.So thank you for your attention.

Zach Klaassen: So Matt, thanks so much for taking us through that data.It's interesting you mentioned in your background that 60 to 80% of tumors in the urothelial setting have HER2 expression. So I think it sort of lends to the fact we're seeing FGFR, we're seeing HER2. This really speaks to the importance of understanding the symptomatic mutations in these tumors. So maybe just speak to the importance of every single one of these tumors getting tested, correct?

Matt Galsky: Yes. Right now, in metastatic urothelial cancer, there are really two biomarkers that are actionable. One is the presence of FGFR3 alterations, as you mentioned, and that's really based on DNA sequencing, and HER2 expression because there is this basket indication, as I mentioned, for a HER2 antibody-drug conjugate in patients with 3+ expression by immunohistochemistry.So all patients with metastatic urothelial cancer should have testing for those two biomarkers.Of course, those two biomarkers are tested differently. One is with next-generation sequencing, the other is based on immunohistochemistry. I would not rely on next-generation sequencing to inform HER2 status. That said, we do know that there's a pretty strong correlation between copy number alterations of HER2 found on NGS and high HER2 expression, and even HER2 mutations, which we see in urothelial cancer, and high expression.But all patients should have IHC testing regardless of the NGS result.

Zach Klaassen: Yeah, excellent. So you mentioned in Cohort C we’re going to have—or the phase II part—we're going to have a randomized portion, I think it was 75 patients, the DV plus pembro versus DV alone. How is that enrolling? When do you think we'll see some results from that portion of the trial?

Matt Galsky: So that’s been enrolling for some time. I suspect that we’ll see results from that within a year or two.

Zach Klaassen: Excellent, excellent. Great discussion. Maybe a couple of take-home messages for our listeners today?

Matt Galsky: So HER2 is an important target in urothelial cancer. This is a real target right now that needs to be tested for. We saw a lot of disappointments, so to speak, with strategies targeting the HER2 activity, the kinase activity of HER2 in urothelial cancer with small molecules.But using HER2 as a target for selective delivery of cytotoxic agents is a completely different strategy, and now we have proof of concept that this is important. So look for further results with disitamab vedotin alone, disitamab vedotin plus PD-1 inhibition, and other HER2-based strategies that are coming forward.

Zach Klaassen: Excellent. Matt, thanks so much for your time and expertise and for contributing this for our listeners. Appreciate it.

Matt Galsky: Thank you.