I'm joined by Gopa Iyer, a GU medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.
So Gopa, welcome. Great job yesterday. Great talk. Always good to see new drugs in bladder cancer. Like, every time I see one, I get a little bit excited that we're really making progress in this disease.
So tell us a little bit about the study you presented, and then I have some questions for you about it.
Gopa Iyer: Yeah. Thank you so much, Betsy. It's a pleasure to be here.
So this is the NEXUS-01 study. It was a phase one trial of a drug LY4052031, doesn't have a generic name yet. And this is an anti-Nectin-4 targeted antibody drug conjugate, and it has a unique topoisomerase 1 payload, camptothecin 98.
In preclinical studies, it seemed like that was a more potent topoisomerase inhibitor than some of the other ones that are out there right now. And so this was a standard dose escalation phase one study initially, and then a randomized dose optimization specifically in patients with metastatic urothelial cancer.
One of the interesting points about the study is that prior EV or EV+P was allowed, and we know that almost all of our patients now with metastatic disease are going to be exposed to that drug. And this is a really sort of unproven space. I think there's a lot of possibility for new treatments in the post-treatment space.
Elizabeth Plimack: Absolutely, yeah.
Gopa Iyer: Yeah. So on the trial in terms of efficacy, what they found was that there was a 42% objective response rate in the efficacy evaluable population. And then if we drill down into the patients who had received prior EV, it was 33% objective response rate.
In a specific dose level, the 3.6 milligram per kilogram dose level, which most patients had gone onto, it was actually 47% in that post-EV+P space. So pretty promising results and suggesting also that this sort of Nectin-4 targeting approach after having already gotten a Nectin-4 targeting therapy is feasible and actually does result in efficacy in that patient population.
Elizabeth Plimack: Right. Absolutely. Interestingly though, prior topo, tell us about that group.
Gopa Iyer: Exactly. So there were 18 patients who had received a prior topo payload containing ADC, and so that included T-DXd, trastuzumab deruxtecan, and sacituzumab as well.
And there were no responses in that patient population, and it really underscores that we may really have just one shot on goal because of cross-resistance to topo 1 inhibitor payloads. After you get one, it may be very unlikely that you're going to have a response to another one after that.
Elizabeth Plimack: So it sounds like we can recycle targets, but probably not the payload that would be unique.
Gopa Iyer: Exactly.
Elizabeth Plimack: Interesting.
Gopa Iyer: Exactly.
Elizabeth Plimack: There was a really interesting aspect of this study, which was the liver metabolism-
Gopa Iyer: Yes.
Elizabeth Plimack: ... of the drug and how you noticed toxicity and then figured out why, and then started screening patients. Tell us a little bit about that.
Gopa Iyer: Exactly. And so early on in the study, they found that there were some patients who were having significant toxicity and not something that they had predicted. And so this was mostly prolonged neutropenia.
And usually, unfortunately, these patients were refractory to growth factor support. It would usually require hospitalizations for two to three weeks while we're waiting for their counts to recover, so a real issue.
To their credit, the company basically suspended enrollment immediately when they started to see this happen. And they went back and their preclinical data already showed that this specific topoisomerase inhibitor is metabolized primarily by CYP2D6.
And so they went and genotyped CYP2D6 to see what is the metabolic function of CYP2D6 specifically in these patients. And in all of them that they were able to test, it was low. You can generate what's called an activity score that kind of is reflective of the metabolic function of CYP2D6, and the activity scores were either zero, meaning there was no detectable activity or 0.25, which was very low metabolic function of CYP2D6.
Anybody who had a CYP2D6 score of 0.5 or higher, which was considered normal metabolic function, they really didn't have these significant issues unless you got to very high dose levels basically.
Elizabeth Plimack: Fascinating. Do you think this can explain some of the toxicity we saw with the other topo payloads and, going forward, are you going to genotype all your patients?
Gopa Iyer: Yeah, that's a fantastic question. I think that certainly for like SN-38, for those types of compounds, we do know that UGT1A1, which is another liver-related enzyme that also metabolizes that specific payload, that there are patients that have low levels of that.
So I don't know that CYP2D6 necessarily, but I do think that we may need to be looking more closely at these specific liver enzymes. Yeah, for sure.
Elizabeth Plimack: Right. To understand and mitigate toxicity.
Gopa Iyer: Exactly.
Elizabeth Plimack: Absolutely.
Gopa Iyer: Exactly.
Elizabeth Plimack: Okay. So I think you said in your talk that you might have one shot on goal with the type of topo, and you said it again today.
Gopa Iyer: Yeah.
Elizabeth Plimack: So what topo would you use? Which one out there is the most interesting to you?
And if you don't know, you can say that, too, but I think we're all going to be looking to answer that question for ourselves.
Gopa Iyer: Exactly. I think you're totally right about that.
So in a sense, we have the most data with SGE. I mean, even though it's not an FDA-approved option, it is still listed as an NCCN-listed option for patients. So I think that's always something to consider in our patients.
I would say in the post-EV+P space though, if I'm not going to give platinum chemotherapy, I would say go for a trial and try one of these drugs that are in study right now.
Elizabeth Plimack: Right.
Gopa Iyer: I think the one time that I wouldn't necessarily do a trial is in a patient who has maybe three plus or two expression. And in that patient, I may prioritize trastuzumab deruxtecan since we have that option for a target.
Elizabeth Plimack: Right, right. You know the target, yeah.
Gopa Iyer: Yeah, exactly. Biomarker-driven.
Elizabeth Plimack: Right. Right, right. Great answer. Clinical trial, always the right answer.
Gopa Iyer: Always go for that.
Elizabeth Plimack: Well, Gopa, thank you for pushing the envelope in bladder cancer, for testing new drugs. Great presentation. Thanks for chatting about it.
Gopa Iyer: Thank you so much for having me. It's been great.