ASCO 2026 | Real-world outcomes by HER2 expression in la/mUC in the SGNDV-003 study

In just recent years, we’ve learned more and more that a lot of advanced urothelial tumors actually express HER2, and we now actually have targeted therapies, you know, specifically against HER2, including antibody drug conjugates that we think work pretty well. In particular, in recent years, we’ve had data come out with, well, first of all, trastuzumab-deruxtecan, which is an antibody drug conjugate that’s now approved in advanced urethral cancer, but specifically for tumors with a high bar of expression, so that are HER2-3+, bioimmunohistochemistry. But now we have data with another antibody drug conjugate, it’s said, datopotamab-deruxtecan, suggesting that it also has pretty good activity, both as monotherapy and in combination with a checkpoint inhibitor, in patients whose tumors express HER2. We typically divide HER2 expression into patients who are essentially HER2 positive, and that’s defined as having immunohistochemistry of 3 plus or 2 plus and FISH positive. And those who are, have a lower bar of expression, don’t meet quite that high a bar, but still have HER2 expression. Those are 1 plus or 2 plus and FISH negative. And then, of course, there are those that are HER2 zero. Now, we know that a drug like datopotamab-deruxtecan works reasonably well in 2+, 3+, patients, even has some activity in 1+, has not really been extensively investigated in HER2-0 patients. But what we don’t know is whether how this HER2 expression affects outcomes to other treatments and also whether it is prognostic. And so this large retrospective study was really undertaken to address that knowledge gap. And so what this was is this was, first of all, an international study, including multiple sites in both U.S. and Europe. It included almost 400 patients where we collected their tumor samples and assessed them for HER2 expression in a central laboratory. So this is centrally defined HER2 expression, not defined at individual sites, which is a critical point here. That we have some confidence, and again, this is a fairly objective assessment of HER2 status. And then importantly, we collected the patient’s clinical data and specifically how they did with standard of care therapies after platinum-based chemotherapy. And that should align, you know, pretty well with, again, the data we have in clinical trials of HER2-targeted drugs like datopotamab-deruxtecan. So what did we find in this study? Well, first of all, we wanted to see what percentage of patients even expressed HER2. We have some of that data from some prior data sets already. We think it’s somewhere between 60% and 80% that have some degree of HER2 expression. And that’s really what we found here as well. So in this study, 70% of patients had HER2 expression to some extent. 20%, well, 19% to be exact, had high HER2 expression. So IHC3+, HER2+, and FISH positive. Next, we actually looked at how many patients or to what extent does HER2 expression affect outcomes in all patients. So in other words, whether it is a prognostic marker. And what we see is that there is some hint that patients with no HER2 expression, so HER2 zero, have worse outcomes. This was not a, I should stress, this was not a direct comparison in this trial, but, you know, a hypothesis generating finding suggesting that those with, again, no HER2 expression, HER2 zero, do worse. Their overall survival curve looked not as good as patients with HER2 expression, regardless of the treatment received. And then we looked at patients receiving specific therapies and how HER2 expression impacted those outcomes. In particular, of course, we were interested in outcomes with enfortumab-vedotin. I will highlight again that this was a patient population who previously had platinum-based chemotherapy and then received subsequent therapies. But the index date, the date from which we calculated outcomes and responses to subsequent therapy, was specifically the date after progression on platinum-based chemotherapy. And so what we saw is that actually the extent of HER2 expression, whether patients were HER2 high, HER2 low, or HER2 zero, really did not impact outcomes to immune checkpoint inhibitors, to enfortumab-vedotin, to other chemotherapies. So really, responses to those therapies were consistent across the board, regardless of basically the degree of HER2 expression. And so this does, you know, potentially give us some hints of who we should prioritize for, let’s say, HER2-targeted therapy as opposed to, you know, standard of care therapies. And this is something, I think, to look into further. And as additional data comes out from clinical trials, again, targeting HER2, you know, we’ll have a better sense of, you know, how that data compares to this real-world data, in a sense, of outcomes to standard of care therapies based on HER2 expressions.

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