EGFR Exon 20 Insertion as a Therapeutic Target in Non-small Cell Lung Cancer - Episode 2

Variant of NSCLC vs EGFR Mutations

A discussion on how this variant of NSCLC differs from the (exon 19 and exon 21) EGFR mutations and the demographics of EGFR patients.

Alexander I. Spira, MD, PhD, FACP: I know we talked a little bit about this before, but how do you find that these variants differ from the other mutations and how do you test them? I will talk about how I test in a few minutes.

Joel Neal, MD, PhD: I always say that any testing that yields a positive result, I believe. Whether that’s a tissue test or a rapid PCR [polymerase chain reaction]–based test. We’re still doing PCR sequencing for EGFR exon 19, 21, and the exon 20 sizing assay because we can get those results from tissue in under a week. Sometimes we’ll do blood testing, and the blood-based testing, the ctDNA [circulating tumor DNA] testing, is fairly rapid turnaround. It takes up to a week and a half at this point, and a positive result from that is just as good, although the sensitivity can certainly be less than a tissue test. Then we reflect all patients to 130 gene next-generation sequencing [NGS] panel. Of course, we confirm the exact insertion sequence at that point. From the sizing assay, we don’t know what it is. We just know the exon 20 mutation is there. We also do ALK and ROS1 rearrangement and FISH [fluorescence in situ hybridization] probes in addition, which is fairly rapid. That is where we are for testing right now. I hope that, in the future, we get our NGS turnaround from 3 weeks down to maybe a week and a half, and then we can get rid of the fast rapid testing that we’re using on tissue.

Alexander I. Spira, MD, PhD, FACP: We are pretty much similar. We don’t have in-house assays, so we use NGS assays on everybody where possible. We can get that down, optimized to maybe about 2 weeks to 2½ weeks which is OK, but not great. Nevertheless, we jump right to the full panel to get all these results as well as everything back pretty timely. I also do blood-based assays all the time, because you never know what you’re going to get. You never know if you’re going to get enough. Yes, I agree, we have a very similar situation where sometimes you don’t have enough tumor to test, or it doesn’t come back fast enough. The blood-based assay isn’t perfect, but it’s sometimes perfect as the enemy of good. As you said to begin with, testing something is better than nothing. You like to do things, ideally, but we all acknowledge that testing still leaves a lot to be desired no matter who you’re looking at or what you’re doing.

Joel Neal, MD, PhD: In a high-enough-probability patient—we can talk a little about the demographics of patients who have EGFR exon 20 insertions—the lack of finding another oncogenic driver but not finding EGFR makes me want to test more. I won’t rest until I find an NGS test that has been negative and isn’t just blood. For a low burden of disease, often the NGS blood tests are negative.

Alexander I. Spira, MD, PhD, FACP: I agree.

Joel Neal, MD, PhD: Alex, do you want to share what you have noticed about the demographics of patients with EGFR exon 20 insertion in non–small cell lung cancer?

Alexander I. Spira, MD, PhD, FACP: This largely mimics other EGFR mutations: young nonsmokers tend to be the majority of the patients, although I’ve seen a bunch with a little history of smoking more often than you would think. It can be anybody. A lot of people will still focus on the nonsmokers that should be tested for mutations including EGFR mutations. I still think it has a propensity for the nonsmoking population or the very light smokers. How about you?

Joel Neal, MD, PhD: Yes, I think of the demographics as identical to those in whom we expect an EGFR-sensitizing mutation. It’s worth talking a little about the nomenclature and what the actual mutation is. How did these exon 20 insertions differ from the exon 19s, exon 21s, and other mutations that we find on a DNA level? Does that have any implications for the testing and the sensitivity that we find?

Alexander I. Spira, MD, PhD, FACP: Yes, I agree with that sentiment completely. It’s important. What you said is superimportant in terms of what we’re looking at right here.

Joel Neal, MD, PhD: Just conceptualizing it—when I think of EGFR, the relevant exons are exon 18, 19, 20, and 21. Exon 18 can have a couple of unusual mutations. The 709s or the 719s are key mutations—I think of them as sensitizing mutations, potentially, to these drugs. In exon 20, of course, the most famous is probably the T790M mutation. I want to caution listeners out there and say that if you find a report and it says exon 20 mutation, and you look more closely and that’s a T790M mutation, then this isn’t the EGFR exon 20 insertion mutation. That’s just a point mutation often associated with acquired resistance to EGFR inhibitors. We sometimes see an S768I mutation, and that’s also an exon 20 point mutation, which can be associated with sensitivity to TKIs [tyrosine kinase inhibitors]. Those are not the insertions that we’re talking about. Of course, exon 21 and exon 19 deletions that I skipped over—those are any deletions starting around 746 or 747 that then have a number of residues that have been knocked out.

These exon 20 insertions are amino acids that have been added, and the interesting thing about them is that a number of positions that can be added, and the properties are slightly different depending on where they are. Of course, the exon 20 mutation that’s most common is the L858R. When I think about and I talk to our residents and fellows about these and say, “Exon 19 is about 60% of EGFR mutations, the L858R exon 21 is about 30%, and then everything else is 10%,” of that 10% are these exon 20 insertions, which are about 4%, as you said before. Those 4 EGFR exons and all these are a little different, so when we’re talking about the exon 20 insertions, we have to think about the insertions. Alex, have you had any experience with that special EGFR exon 20 insertion? The EGFR-A763_Y764insFQEA one?

Alexander I. Spira, MD, PhD, FACP: I haven’t seen that 1. You will have to tell me about that 1.

Joel Neal, MD, PhD: The EGFR-A763_Y764insFQEA is the closest you can get to EGFR exon 19 deletions, and the biochemical structure of the protein is sensitive to the EGFR inhibitors. I had patients with the EGFR exon 20 EGFR-A763_Y764insFQEA—that’s 1 of the earlier residues, I think it’s 763—respond to erlotinib. You get an acquired T790M mutation and then actually respond to a third-generation TKI way back when, before we had these new drugs. That’s 1 to keep an eye out for, because it can be sensitive to other TKIs as opposed to these that are more resistant.

This transcript has been edited for clarity.