Potential Translational Relevance of Preclinical Findings With Seribantumab

EP: 1.Use of the Anti-HER3 Antibody Seribantumab in Preclinical Models

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EP: 2.Potential Translational Relevance of Preclinical Findings With Seribantumab

Transcript:

Alexander Spira, MD, PhD, FACP: Hi, everyone. Thanks for joining us. We’re going to be doing a journal club on a paper, the “Anti-HER3 Monoclonal Antibody Seribantumab Effectively Inhibits Growth of Patient-Derived and Isogenic Cell Line and Xenograft Models With Oncogenic NRG1 Fusions.” I’m Alex Spira with Virginia Cancer Specialists, and I’m joined by my colleague Dr Ross Camidge from the University of Colorado. Hi, Ross. Always good to see you.

D. Ross Camidge, MD, PhD: Good to see you, Alex.

Alexander Spira, MD, PhD, FACP: We talked about this paper, and now we’re going to talk about some of the key takeaways. I learned a lot. I learned more about afatinib. Afatinib is a drug that’s been around for a long time and has really been studied in typical EGFR mutations. But we forget it’s a pan–HER [human epidermal growth factor receptor] drug, so there’s activity in these NRG1 fusions as a downstream effect. As I looked at some of its effects and where things are, and my take-home message is it does work. It might be a tough drug to give when I think about the toxicity in the achievable doses. I’m seeing some responses with the monoclonal seribantumab, and there’s some evidence of activity in both the western blots looking at responses and, most important, some responses in the PDX models. What are your thoughts?

D. Ross Camidge, MD, PhD: When these NRG1 fusions started to come out, they did a retrospective survey at an ASCO [American Society of Clinical Oncology Annual Meeting] a few years ago. Afatinib had about a 20% response rate. It was proof of principle, but it didn’t blow us out of the water. Was it that you couldn’t get up to these high enough doses, or was it that there’s some underlying heterogeneity in NRG1 fusion? Now that they’re coming at these from a different point of view with the anti-HER3 antibodies, this is a lot more interesting. Seribantumab looks like it’s got the chops to do it. It downregulates the signaling and causes shrinkage but the issue is, is it going to work in a patient? In what proportion of the patients?

Alexander Spira, MD, PhD, FACP: That’s why we obviously have the ongoing studies, but we have some good preclinical data. They remind me that we have to think about things differently. I think about things as being TKIs [tyrosine kinase inhibitors], and that’s how we normally think about targetable therapies, but we’re using something downstream to target NRG1 fusions. It’s just a different concept. Do you want to talk briefly about NRG1 fusions in lung cancer?

D. Ross Camidge, MD, PhD: They’re rare. I don’t know that they’re going to be a part of everybody’s next-generation sequencing panel. Your starting material for the next-generation sequencing can either be a DNA extraction or an RNA extraction. But the pickup rate will probably much higher if it includes an RNA extraction because if 2 random things are fused together, you don’t have to have primers that span everywhere between, like in an DNA extraction. You can have 1 that starts in NRG1, and it will run into whatever is nearby. The pickup rate will probably be higher for those who have an RNA-based element there, but we’re still talking about only 1% of lung cancers at best.

Alexander Spira, MD, PhD, FACP: It’s funny that you mentioned that Ross. I’m sure you don’t remember this, but we were at an ad board many years ago, and you stood up on the table and said, “We must be doing RNA.” You were 1 of the few institutions that was really focusing on RNA testing. I’m sure you don’t remember that, but I do.

D. Ross Camidge, MD, PhD: I don’t think I stood on the table, but yes.

Alexander Spira, MD, PhD, FACP: It made enough of an impact that day. For me, it’s a reminder of the importance of next-generation sequencing. RNA is going to be better than DNA, and it’s a reminder that if you don’t test, you can’t find these. It’s also incredibly rare. Looking at these drugs, it’s a tough study to do. You’re looking at a very small percentage of patients, but if you don’t test, you can’t identify it. One of the next steps is that we have enough preclinical data, and there are ongoing studies and those studies just need to get done. There have been some negative studies with a newer generation of drugs, partially done out of your institution as well. But for me, 1 of the next steps is to identify these patients and get these patients on study. Preclinically, it makes sense. Biologically, it makes sense. Now we just need to identify this and start testing it in humans and looking at some of these newer data. You alluded to some of the retrospective data published at ASCO with afatinib. We would all probably agree, based on what we’re seeing in the anecdotal data, that it’s not the way to go. But looking at some of the new molecules, seribantumab is an important next step.

D. Ross Camidge, MD, PhD: As with seribantumab, there were several anti-HER3 antibodies that had case-report-level data of somebody with a NRG1 fusion experiencing tumor shrinkage. You don’t have a denominator, which is hard when it’s a rare cancer, so we had some clinical proof of principle. Seribantumab has a study that started. They’re not the only ones. At this year’s ASCO, there was another drug called xentuzumab, which was maybe a HER3/EGFR or HER3/HER2 bispecific antibody that showed around a 40% to 60% response rate. They captured the narrative a little, whereas seribantumab hasn’t shown any data. But it is starting to look actionable, and it will appear on that NCCN [National Comprehensive Cancer Network] list of options that you should be looking for at some point. But you’re right, how do you do a study with something that’s so rare? We’ve got NTRK inhibitors licensed, so that’s the model the company’s following. There are NRG1 fusions in diseases other than lung cancer, and you can throw this tumor-agnostic approach and hope that you have a good enough response such that the FDA goes, “Let’s give you a single-arm study license.”

Alexander Spira, MD, PhD, FACP: My only hope is that since the NTRK story came out 4 years ago, we’re testing more. If you’re not testing it, then you can’t find it. It will be great based on this preliminary response rate to get some of this out there soon, so those studies can be done. I’ll let you talk about the translational relevance of this data. We talked a lot about this already, but the efficacy of seribantumab appears to be a little better, at least based on the doses you can give as well as the track record of afatinib. We certainly should pursue clinical studies at this point, and we are.

D. Ross Camidge, MD, PhD: When you see these data, it’s almost like it’s necessary, but not sufficient. You must have those data just to go forward into the clinic. They’ve known for a long time, even when they were going back to doing cytotoxic therapies, that if it didn’t work in a cell line, it wouldn’t work in a patient. But just because it worked in a cell line, that didn’t mean it would work in the patient. It downregulates the molecule and the signaling that it’s supposed to. From there, it suppresses growth and increases apoptosis. It causes delay in growth in tumor models, and it causes actual tumor shrinkage, so it checks all the boxes. The other thing we saw in the preclinical models was that if you were on it for a period of time, there were some suggestions that you could develop a quiet resistance. That’s an area that 1 needs to explore. What’s going on there, and what will be happening in the patient? The other elephant in the room is that we shouldn’t forget this is an antibody, so 1 would expect CNS [central nervous system] to be a liability. What will the study design be? Will it include no brain metastases, or will it include treated brain metastases? Those are the things I’d expect to see in a clinical trial.

Alexander Spira, MD, PhD, FACP: It’s amazing now that it’s become such an important part of drug development: not just systemic adverse effects but brain metastases as well. It’s amazing—this has happened before—that we’re reinventing an older drug. This drug already completed phase 1 and a lot of developments, and it didn’t work well enough. Now we’re rehashing it. What thoughts do you have? We talked a little about this before. What questions do you have from the paper, to go forward based on what we saw on this paper?

D. Ross Camidge, MD, PhD: In all these experimental models in the cell line, it’s sitting there with the drug on it and everything else. But in a patient, this is an intravenous infusion. How often are you going to have to give it? What’s the trough level that you’ve got to keep going, and how long is it going to take for acquired resistance? As we said, is the CNS going to be a bugaboo in terms of acquired resistance as a site of disease?

Alexander Spira, MD, PhD, FACP: You hit all the high points. The dosing of a monoclonal antibody in a mouse leads a lot to come from there, but we already have a lot of the clinical data from before. What did we learn from this paper that can impact our practice? Foremost, we have activity of a drug that targets a rare fusion. We’re getting a little off topic, but we don’t do enough testing, especially in lung cancer, so it’s important to do that. How do we think about the biology of the drugs, and how do we think about dosing of the drugs? A lot of data from afatinib have been some of these 1-off studies. You’ve given somebody afatinib for this as well, but it’s important to think about the dosing and really looking at the preclinical data and some of the issues you’re running into. We at least learned some preliminary information that you may have a drug that works off label for this. But if we really look at some of those models, you say, “Maybe it’s not really a good effect.” Maybe it’s better to put somebody on a clinical trial for that. Those are my take-home messages. Your thoughts?

D. Ross Camidge, MD, PhD: Just like with the clinic, I’m always asking, what’s plan B? I’m thinking, where is this going to go to next? We didn’t do a clinical trial. We mentioned that anti-HER3 antibody-drug conjugates [ADCs] are out there. There are some data that when you combine an ADC with an irreversible TKI, like afatinib, you get a double whammy because you achieve increased internalization and delivery of the toxin. Are we going to see some combination of antibodies and TKIs in NRG1 fusions? I think so. I think we’re at the beginning of the journey rather than the end, and it’s exciting.

Alexander Spira, MD, PhD, FACP: Do you know what I love about that conversation, Ross? I’m wondering if we’re going to get this drug and when to get the study done. You’re already thinking about the next 3 studies down the road, how we’re going to get it combined, and the next generation of our targeted approaches.

D. Ross Camidge, MD, PhD: That’s what you have to do.

Alexander Spira, MD, PhD, FACP: That’s fair. We had a great discussion today. Thanks, as always, for talking with me. I hope everybody got something out of this.

D. Ross Camidge, MD, PhD: It was great. Thanks, Alex.

Alexander Spira, MD, PhD, FACP: Thanks, Ross.

Transcript edited for clarity.