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Novel EGFR Exon 20 Directed Therapies for NSCLC

Panelists: Joshua Bauml, MD, University of Pennsylvania; D. Ross Camidge, MD, University of Colorado School of Medicine; Robert Doebele, MD, PhD, University of Colorado School of Medicine; Benjamin Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Zofia Piotrowska, MD, Harvard Medical School
Published: Friday, Aug 16, 2019



Transcript:

Benjamin Levy, MD: So obviously good data coming out with adding antiangiogenesis or chemotherapy; we’ll see where the winner is with the addition of these agents to TKI [tyrosine kinase inhibitor]. But we had some novel drugs that have been presented as well. Some novel EGFR-directed therapies. One of them was TAK-788, specifically looking at EGFR exon 20 mutations. Ross, do you want to talk briefly about that data?

D. Ross Camidge, MD: EGFR exon 20s are the rarer EGFR mutations. Maybe they’re somewhere between 5% and 10% of EGFR mutations. And they are traditionally not sensitive to most of the drugs that we have. There’s one exception, FQEA, but that’s actually pretty rare.

TAK-788 was at least a rationally designed drug. It was trying to work in exon 20s, and the challenge is to inhibit exon 20 insertions without hitting the wild-type form of the EGFR too much. Poziotinib hits the wild-type far more than it hits exon 20. TAK-788 is just about reversed. And what we saw today, larger data sets, probably about a 40% response rate, and at their recommended dose, which is 160 mg, the dose reduction rate was only about 25%. It’s still not free from toxicity, but it’s a lot better than we’ve seen before, and I think it definitely is looking like one to watch.

Benjamin Levy, MD: It may be a welcome change from the toxicity that we have seen from poziotinib as you’ve highlighted. This drug seems to be as active if not more with much better toxicities. We’ll have to see how it all plays out. Josh, you were a senior author on another abstract, 9009, looking at JNJ-372, a bispecific antibody. Do you want to walk us through that data? And that also had some patients who were exon 20 as well.

Joshua Bauml, MD: This was a bispecific antibody that targets both EGFR and MET. MET is known to be a mechanism of resistance to EGFR-directed therapy, and this is an infusional therapy. The results were pretty good. The overall response rate was about 30%, and that was seen in exon 20, which is actually pretty consistent. The response rate was 30% in exon 20, it was 30% overall, and we also saw responses post-osimertinib. And that was regardless of the mechanism of resistance.

The toxicity of the drug is interesting. There’s not a lot of rash or diarrhea. The first day of infusion, very frequently patients have an infusion reaction. It has not been dangerous for any persons. It can be dramatic, but that goes away on all subsequent infusions. The way it was administered on the trial is there’s a day 1 where we would give a very small amount of the drug, and you give pretreatment, and if they have an infusion reaction you stop, you come back the next day and you finish the dose. Then after that, it’s once a week for 4 weeks and then it’s every other week.

Toxicity beyond that was actually pretty good. And the response rates have been pretty impressive. The factor that was brought up at the oral presentation is trying to identify who the patients are who really benefit, is really unanswered. It doesn’t seem to be limited to patients with MET amplification. It’s unclear exactly who benefits most.

Benjamin Levy, MD: Where is this drug going? Is it going in a post-osimertinib space? Is it going into treatment-naïve space? Is it going just for exon 20? Do we know?

Joshua Bauml, MD: I think that there are a lot of paths forward for this drug. There’s a cohort that is opened in Korea right now that is combining JNJ-372 with lazertinib, which is a third-generation tyrosine kinase inhibitor. Because in the preclinical data for JNJ-372, when they combined JNJ-372 with osimertinib, they saw remarkable responses, much more so than would be seen for either osimertinib or JNJ-372. There could be some real synergy there. It’s being developed along with lazertinib, which is another Janssen compound. That’s where things are for that right now. But I think exploration in the exon 20 space is a real area of interest because as we’ve discussed, many of the other drugs in this space are quite toxic, and this one is much less so.

D. Ross Camidge, MD: Can I ask you a couple of questions on that one because I didn’t get a change to ask Eric Haura, MD in that presentation.

Benjamin Levy, MD: Absolutely.

D. Ross Camidge, MD: There were two things that I thought weren’t shown in the presentation. One, this is supposed to work against MET. I don’t care about MET amplification. Is there MET protein? Is that a relevant factor? You didn’t stain for MET IHC [immunohistochemistry].

Joshua Bauml, MD: One of the issues, and you actually wrote an excellent editorial on this. It was really good.

Zofia Piotrowska, MD: Was Bob a coauthor?

Joshua Bauml, MD: No, it was really good. But the issue is that measurement of MET is highly problematic, figuring out what MET level we care about. Is it IHC? Is it overexpression? Is it amplification? And on this study, the way they were looking for MET, in reference what you were saying before, was on ctDNA [circulating tumor DNA] amplification in terms of classification.

D. Ross Camidge, MD: Oh yes.

Joshua Bauml, MD: And in the first part of the study, there were not required pretreatment biopsies. So now that we’re getting into the second stage, all patients have pretreatment biopsies, and we will be staining for MET. But on the first part, not everyone had a sample to do that.

D. Ross Camidge, MD: Here’s my second question.

Joshua Bauml, MD: I’m ready.

D. Ross Camidge, MD: We got a response, what was the duration of response? I saw a spider plot on the exon 20, I didn’t see it for the main cohort.

Joshua Bauml, MD: The patients who I’ve seen, who have responded, have had responses that are similar to what we’ve seen with TKIs. It’s somewhere on the order of 9 months or so, but I don’t believe that it’s been formally measured or a median has been reported. But the patients who I have seen on this drug who have responded, it’s been just like any other EGFR therapy. I found that the rash on this drug is better than most TKIs. Maybe it’s similar on the level to what we see with osimertinib.

Benjamin Levy, MD: Who would have thought 3 years ago having all these novel therapies specifically for exon 20? The JNJ-372 drug, high-dose osimertinib, and then TAK-788, all options for our patients. And this is an unmet need. These patients need good drugs that hopefully can outperform chemotherapy or even after chemotherapy.

Transcript Edited for Clarity

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Transcript:

Benjamin Levy, MD: So obviously good data coming out with adding antiangiogenesis or chemotherapy; we’ll see where the winner is with the addition of these agents to TKI [tyrosine kinase inhibitor]. But we had some novel drugs that have been presented as well. Some novel EGFR-directed therapies. One of them was TAK-788, specifically looking at EGFR exon 20 mutations. Ross, do you want to talk briefly about that data?

D. Ross Camidge, MD: EGFR exon 20s are the rarer EGFR mutations. Maybe they’re somewhere between 5% and 10% of EGFR mutations. And they are traditionally not sensitive to most of the drugs that we have. There’s one exception, FQEA, but that’s actually pretty rare.

TAK-788 was at least a rationally designed drug. It was trying to work in exon 20s, and the challenge is to inhibit exon 20 insertions without hitting the wild-type form of the EGFR too much. Poziotinib hits the wild-type far more than it hits exon 20. TAK-788 is just about reversed. And what we saw today, larger data sets, probably about a 40% response rate, and at their recommended dose, which is 160 mg, the dose reduction rate was only about 25%. It’s still not free from toxicity, but it’s a lot better than we’ve seen before, and I think it definitely is looking like one to watch.

Benjamin Levy, MD: It may be a welcome change from the toxicity that we have seen from poziotinib as you’ve highlighted. This drug seems to be as active if not more with much better toxicities. We’ll have to see how it all plays out. Josh, you were a senior author on another abstract, 9009, looking at JNJ-372, a bispecific antibody. Do you want to walk us through that data? And that also had some patients who were exon 20 as well.

Joshua Bauml, MD: This was a bispecific antibody that targets both EGFR and MET. MET is known to be a mechanism of resistance to EGFR-directed therapy, and this is an infusional therapy. The results were pretty good. The overall response rate was about 30%, and that was seen in exon 20, which is actually pretty consistent. The response rate was 30% in exon 20, it was 30% overall, and we also saw responses post-osimertinib. And that was regardless of the mechanism of resistance.

The toxicity of the drug is interesting. There’s not a lot of rash or diarrhea. The first day of infusion, very frequently patients have an infusion reaction. It has not been dangerous for any persons. It can be dramatic, but that goes away on all subsequent infusions. The way it was administered on the trial is there’s a day 1 where we would give a very small amount of the drug, and you give pretreatment, and if they have an infusion reaction you stop, you come back the next day and you finish the dose. Then after that, it’s once a week for 4 weeks and then it’s every other week.

Toxicity beyond that was actually pretty good. And the response rates have been pretty impressive. The factor that was brought up at the oral presentation is trying to identify who the patients are who really benefit, is really unanswered. It doesn’t seem to be limited to patients with MET amplification. It’s unclear exactly who benefits most.

Benjamin Levy, MD: Where is this drug going? Is it going in a post-osimertinib space? Is it going into treatment-naïve space? Is it going just for exon 20? Do we know?

Joshua Bauml, MD: I think that there are a lot of paths forward for this drug. There’s a cohort that is opened in Korea right now that is combining JNJ-372 with lazertinib, which is a third-generation tyrosine kinase inhibitor. Because in the preclinical data for JNJ-372, when they combined JNJ-372 with osimertinib, they saw remarkable responses, much more so than would be seen for either osimertinib or JNJ-372. There could be some real synergy there. It’s being developed along with lazertinib, which is another Janssen compound. That’s where things are for that right now. But I think exploration in the exon 20 space is a real area of interest because as we’ve discussed, many of the other drugs in this space are quite toxic, and this one is much less so.

D. Ross Camidge, MD: Can I ask you a couple of questions on that one because I didn’t get a change to ask Eric Haura, MD in that presentation.

Benjamin Levy, MD: Absolutely.

D. Ross Camidge, MD: There were two things that I thought weren’t shown in the presentation. One, this is supposed to work against MET. I don’t care about MET amplification. Is there MET protein? Is that a relevant factor? You didn’t stain for MET IHC [immunohistochemistry].

Joshua Bauml, MD: One of the issues, and you actually wrote an excellent editorial on this. It was really good.

Zofia Piotrowska, MD: Was Bob a coauthor?

Joshua Bauml, MD: No, it was really good. But the issue is that measurement of MET is highly problematic, figuring out what MET level we care about. Is it IHC? Is it overexpression? Is it amplification? And on this study, the way they were looking for MET, in reference what you were saying before, was on ctDNA [circulating tumor DNA] amplification in terms of classification.

D. Ross Camidge, MD: Oh yes.

Joshua Bauml, MD: And in the first part of the study, there were not required pretreatment biopsies. So now that we’re getting into the second stage, all patients have pretreatment biopsies, and we will be staining for MET. But on the first part, not everyone had a sample to do that.

D. Ross Camidge, MD: Here’s my second question.

Joshua Bauml, MD: I’m ready.

D. Ross Camidge, MD: We got a response, what was the duration of response? I saw a spider plot on the exon 20, I didn’t see it for the main cohort.

Joshua Bauml, MD: The patients who I’ve seen, who have responded, have had responses that are similar to what we’ve seen with TKIs. It’s somewhere on the order of 9 months or so, but I don’t believe that it’s been formally measured or a median has been reported. But the patients who I have seen on this drug who have responded, it’s been just like any other EGFR therapy. I found that the rash on this drug is better than most TKIs. Maybe it’s similar on the level to what we see with osimertinib.

Benjamin Levy, MD: Who would have thought 3 years ago having all these novel therapies specifically for exon 20? The JNJ-372 drug, high-dose osimertinib, and then TAK-788, all options for our patients. And this is an unmet need. These patients need good drugs that hopefully can outperform chemotherapy or even after chemotherapy.

Transcript Edited for Clarity
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