Thomas Powles: Hi.
Tian Zhang: He is chair of Barts Cancer Center in London in the UK. Tom, thanks so much for joining us here at GU ASCO.
Thomas Powles: Thank you for inviting me.
Tian Zhang: Tell us a bit about your work that you presented here. One of them was the Phase II study of disitamab vedotin in HER2-expressing previously-treated advanced urothelial cancers. Tell us a little bit about the trial.
Thomas Powles: Urothelial cancer expresses HER2. HER2 is a biomarker. About 80% of urothelial cancers express HER2, either in 1+, 2+, or 3+. Only about 20% are absolutely negative. We use this drug called disitamab vedotin. It's a HER2 ADC with an MMAE payload. We know from China it has activity. This is a global trial. Essentially, we treated about 150 patients, some with lower expression, some with slightly higher expression, with disitamab vedotin. It has the same payload as enfortumab vedotin, so we know that payload's really active in this disease, and because so many patients express HER2, we thought the drug would be active, and indeed, we did show a lot of activity. We showed about 45% response rates. That didn't seem to be particularly enrichment in the higher expression. So 1+, 2+, 3+, we showed quite good response rates. And we showed a toxicity profile distinct from enfortumab vedotin. We showed maybe less skin rash, but fatigue and peripheral neuropathy. And about 41% of patients had Grade 3 or 4 adverse events. So overall, active drug, biomarker-directed, predictable toxicity profile, in line with what you expected from the Chinese data. Where do we go next with it? Well, it's straightforward. We've done a big randomized Phase III study with pembrolizumab in biomarker-selected patients in the first-line setting, like the disitamab vedotin/toripalimab study that we saw Jungo present brilliantly in China at ESMO in one of the plenary sessions. I would expect a similar result. Is this clearly better than EV and EV/pembrolizumab? No. Do we know it's better? Will it be tested against it? I suspect not. Is it an alternative? Yes. Do you need a biomarker? I think we do. Have we nailed the biomarker? I'm not sure we have.
Tian Zhang: So let's go there a little bit more. So that biomarker, we are testing some of our patients, most of our patients hopefully are getting some HER2 testing in urothelial cancer, mostly relying on IHC or on genomic sequencing analyses. You introduced FISH in this particular trial. So tell us a little bit more, do we need the FISH or can we rely on IHC/genomic sequencing?
Thomas Powles: So because the enrichment, because we showed activity in 1+, 2+, and 3+, the FISH is only distinguishing between the high and the very high. And so, actually, from a practical perspective, it's not needed. Now, had we shown in the FISH-positive and the 3+ 90% response rate and 30% CR rate, you could argue, oh goodness, we'd need to enrich under those circumstances, and then it would have become useful. But the answer is no, we're not using it, it wasn't used in the randomized trial. In the randomized trial, it's only 1+, 2+, and 3+. And so, I think, honestly, the whole biomarker-high or positive versus low, the complication will all go. Do you express any HER2? If you do, this is a potential drug combination or single agent for you.
Tian Zhang: IHC is easy in our pathology labs and we can do that and apply it right now.
Thomas Powles: We can, yes.
Tian Zhang: Very good. And so, should we be doing HER2 testing today to find our patients?
Thomas Powles: No.
Tian Zhang: No? Okay.
Thomas Powles: Let's wait for the trial.
Tian Zhang: Okay.
Thomas Powles: It's not approved yet, and there may be cross-resistance between EV and DV because it has the same payload. So I'm not sure, unless we know about that cross-resistance, we should be jumping into this quite yet. And I think this issue around sequencing ADCs is complicated. I also think, by the way, you get one really good go at treating urothelial cancer. And so, while I love the idea of sequencing drugs and sequencing ADCs, I'd much rather we got more effective first-line therapies and we build on that. Don't get me wrong, I think this is an active drug, but I don't think it will replace enfortumab vedotin, and I suspect we won't be combining the two together because they have the same payload.
Tian Zhang: Same payload. So when you think we have resistant disease, do you think it's resistant to the vedotin payload or is it lack of a change in the ligand binding?
Thomas Powles: I think there's a little bit of evidence of both, as you'd expect, and I think that's probably true. But in my experience, most of the resistance is coming from the payload.
Tian Zhang: Very good. Takeaways for our UroToday audience?
Thomas Powles: ADCs work in urothelial cancer. Enfortumab vedotin and pembrolizumab's incredibly active, but there are other combinations, while the single agents and other combinations that are active, disitamab vedotin, a HER2 ADC with MMAE payload is one of those. We haven't defined its role yet. It does need a biomarker.