Targeted Therapy Options for EGFR Exon 20-Mutated mNSCLC

Dr Piotrowska highlights the currently approved targeted therapies for EGFR exon 20 mutation-positive mNSCLC.

Joel Neal, MD, PhD: Zofia, we've spent a while talking about testing, but I think that's the point, it is what matters for non-small cell lung cancer, testing, testing, testing. If we don't find the targets, we can't give the targeted therapies. But you and I have spent a lot of time, and a lot of research interest in finding targeted therapies for EGFR Exon20 insertion, what are the therapies that you think about? And then we'll go through some of the data on each of these.

Zosia Piotrowska, MD: Yes. So, I think it's exciting to say in 2022 that we have two approved therapy options for this patient, and I think what else is also nice is that we have two drugs with different mechanisms of action. One is mobocertinib which is an oral EGFR tyrosine kinase inhibitor, and the second is amivantamab which is an intravenous antibody, which is a bispecific antibody targeting EGFR and MET. So, both of these are approved in the post-platinum chemotherapy setting for patients for EGFR Exon20 insertions, and we'll go through the data for both of these, but, for a patient like this who's young and healthy, I certainly hope that they would have access to both of these during their treatment course. And we may touch on as well on the fact that there's also a lot of ongoing clinical trials, and a lot of research going on in this area so, that in addition to these two drugs that have accelerated approval, we hope to have additional agents down the road, and certainly, this is a patient that I would also think about referring for clinical trials if there's an institution nearby if that's an option.

Joel Neal, MD, PhD: You also ran an ECOG-ACRIN clinical trial looking at the efficacy of third-generation EGFR TKI Osimertinib, what did you find from that? Before we had these FDA-approved options, I know many of us were talking about the role of osimertinib in high dose, specifically.

Zosia Piotrowska, MD: Exactly. So, the study that we ran was looking at osimertinib at a dose of 160 milligrams daily, so twice the approved dose for standard EGFR mutations, which was based on some pre-clinical data that suggested that the higher dose may be more active against the Exon20 insertions. So, a relatively small study, only about 20 patients enrolled, and we found that the activity of osimertinib 160 was modest. The response rate in our study was 24%, the median progression-free survival was about nine months. And interestingly, around the same time, there was a second study that was done in Europe called the POSITION20, same idea, the OC 160 for patients with Exon20 insertions, and very similar outcomes, so I think what that tells us is osimertinib can have some activity, although I would say that it's modest. You have to really be cautious with use of off-label osimertinib in these patients, and one word of caution is you can't assume that it will have the same CNS activity that it would for the common mutations. Again, I know we covered that earlier, but I think that is sometimes a reflex that people have to say, "Hey, we can try osimertinib, maybe it'll work in the brain," and you have to remember that across the board, it's less likely to work here. These are small studies, and we hope to generate more data, but so far, I would say that it does seem to have modest efficacy.

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