Read the Full Video Transcript

Vadim Koshkin: So my talk is on radioligand therapies in bladder cancer. So again, a bit of a change of pace here. I have eight minutes, so I'll just cover a couple of targets. Here are my disclosures. Starting with FAPs. So FAP, or Fibroblast Activation Proteins, are, of course, commonly expressed on cancer-associated fibroblasts present across the board in many epithelial cancers.

And so as a result, they are a potentially attractive imaging and therapeutic target. There is some data published on a few of the compounds used for imaging applications, and I'll go over some of that next. And then, you can also label some of the compounds like FAP-2286 or conjugate them with Lutetium-177 and then use that as a theranostic agent. And so I'll talk about that in a little bit as well.

But first starting with some imaging data. So this was actually an IAT we had, and still have actually, at UCSF with Tom Hope as a PI. So this is a gallium-FAP-2286 imaging study, first-in-human Phase I/II study of this compound. It included multiple solid tumors, including urothelial cancer as well, and included patient cohorts with both confirmed metastatic disease and nonmetastatic disease as well.

The bladder cancer subset here included 21 patients. Among all tumors, bladder cancer actually had the highest absolute FAP uptake across all tumors. There was a pretty good FAP uptake across a variety of metastatic lesions, regardless of location, in urothelial cancer. And importantly, there was pretty good detection of small nodules and small lymph nodes—those as small as under a centimeter, even under 0.5 centimeters, as you can see in the figure—which, of course, would have appeared completely unremarkable on conventional imaging.

So here's an example of a case. This is a patient with muscle-invasive bladder cancer who was indicated for neoadjuvant chemotherapy followed by radical cystectomy, which is the standard of care for this, but had a FAP scan first. This actually highlighted two pelvic nodes that were potentially positive.

And then one of the nodes, while although it decreased in size, still had residual uptake even after chemotherapy. And then at the time of cystectomy actually there, this node with fatty uptake actually was positive for cancer. So this highlights, again, potential for more accurate staging in the perioperative setting, which can impact our decision-making. And there are further studies being designed to really address this.

This scan can help identify false negatives on conventional imaging. Again, this is very important because it can actually change the treatment course for some patients, such was the case with this patient here. So this was another patient with muscle-invasive disease who was about to undergo basically radical cystectomy, but then had a FAP scan which highlighted a lymph node in his neck, actually, which was FAP positive. It was a fairly small lymph node, which really would have and actually did appear completely unremarkable on conventional imaging.

But because this node was detected, we ended up biopsying it, and then it actually did confirm distant spread of metastatic disease. As a result, the patient was spared radical cystectomy, which is a big and significant surgery, which would not have helped this patient, and instead started on systemic therapy.

So this compelling imaging data, of course, suggests the potential for therapeutic applications of FAP targeting. And this was the LuMIERE trial. So this is a Phase I/II study evaluating safety, dosimetry, preliminary activity of Lutetium-FAP-2286 in advanced solid tumors. This was initially a dose-escalation study with a Phase I component and now an ongoing Phase II component.

So the Phase I data were actually presented at ESMO, and this included 27 patients across six US sites. It was determined to be reasonably well tolerated. I mean, about 50% of patients had treatment-related adverse events, but most of these were low grade, so only 7% were Grade 3 or greater. And there were not a lot of cytopenias seen with this therapy, which, of course, is pretty important.

The recommended Phase II dose was reached. It was actually the highest dose attempted, and Phase II is currently ongoing. But the Phase I portion did not enroll a lot of urothelial cancer patients, so it actually will not include a urothelial cancer cohort.

I'm switching gears now to talk about Nectin-4, which is a very important marker and target in urothelial cancer. This is a surface protein, which is pretty ubiquitously expressed in advanced bladder cancer. It is important because there is an antibody-drug conjugate, enfortumab vedotin, that targets Nectin-4 and has an MMAE chemotherapy payload that has really transformed the treatment landscape in metastatic urothelial cancer.

So the combination of enfortumab and pembrolizumab in the front line metastatic setting has actually doubled the median overall survival in this disease with the data that came out just a couple of years ago. And so really transformed the landscape. It's potentially moving even earlier into the perioperative setting, as there are now ongoing neoadjuvant adjuvant studies or actually trials that have enrolled and probably will read out later this year. And so many patients are and will be getting enfortumab vedotin and even more so probably over the next couple of years.

And so it is important to understand the mechanism of acquired resistance to a drug like this, and this is only now starting to be explored. It is potentially not due to target downregulation. There's data, at least preliminary data, that Nectin-4 expression is actually preserved following EV treatment.

So this brings up the opportunity to consider other therapies with an alternative mechanism of action for patients who are refractory to EV but, of course, retain Nectin-4 expression. And this can include more experimental approaches—well, first of all, other antibody-drug conjugates—but maybe more experimental approaches as well, like BiTEs or CAR T cells, but, of course, relevant to this talk, radioligand therapies as well.

We can image Nectin-4 expression. There's actually a pretty interesting study from this group in China published in Clinical Cancer Research of Gallium-N188, which is the radiotracer with high affinity for Nectin-4. In this study, these PET scans detected Nectin-4-positive tumors. They can non-invasively quantify Nectin-4 expression to help select patients for Nectin-4-targeted therapy.

And of course, you can—there are a variety of things you can do with this—both appreciate the heterogeneity of Nectin-4 expression in different metastatic lesions, for instance, or even sequential imaging while on treatment to identify potential resistance.

In this study also, there is strong correlation between Gallium-N188 SUV values and Nectin-4 expression on histopathology, which was not seen in FDG-PET, as you see in this figure. There was an additional study also looking at this imaging agent. This was 62 patients with 16 different malignancies, so really across many different tumors, including urothelial cancer.

And these patients were imaged with both Gallium-N188 and FDG-PET. There were comparable detection rates across the two modalities, but Gallium-N188 showed a positive correlation, again, with membranous Nectin-4 expression, though not with cytoplasmic Nectin-4 expression.

So the next step, of course, is potentially Nectin-4-targeted radiopharmaceuticals. And there is an upcoming trial of this first-in-class Nectin-4-targeted radiopharmaceutical from Aktis Oncology. This will be a dose-escalation study initially with metastatic urothelial cancer, followed then by dose expansion across multiple tumor types, including mUC. And again, a potentially very promising approach.

So to summarize, FAP-targeted imaging has pretty promising data in urothelial cancer. There is a potential for a role for FAP-targeted radiopharmaceuticals as a result. Nectin-4-targeted imaging can also potentially select patients for targeted therapy, especially as there are already Nectin-4-targeted drugs available. And there are important clinical trials of Nectin-4-targeted radiopharmaceuticals that are coming up as well.

I didn't much cover other targets, but of course, there is a possibility of radioligand therapies for other important targets in urothelial cancer as well. One would be actually Trop-2, addressed in one of the prior talks. HER2 would be another good option. And then, there's a potential to use this in earlier treatment settings, from non-muscle-invasive and muscle-invasive disease as well, which are actually curative-intent treatment settings. That concludes my talk and I look forward to the discussion.