Mobocertinib for NSCLC With EGFR Exon 20 Insertion Mutations

Alexander Spira, MD, PhD, FACP: We know a lot about all the different EGFR mutations; the classic exon 19 and exon 21, we have good treatments with osimertinib. We are now developing new treatments for resistance as well against something called HER3, datopotamab as well as amivantamab, looking in the resistance setting. Exon 20 EGFR insertions are unique. That’s only in about 4% of patients with non–small cell lung cancer, and until recently, there was no FDA-approved drug. Now we have amivantamab, which was just approved for this, in the second-line setting. In the first-line setting, I always tell people, consider a clinical trial, but outside of a clinical study, I use platinum-based therapy based upon some of the other outstanding data. I don’t typically use checkpoint inhibitors, and I usually treat with chemotherapy alone to begin with.

Mobocertinib is a small molecule TKI [tyrosine kinase inhibitor] specifically against exon 20. We’ve known about this for a while. Updates were published by [Suresh] Ramalingam, [MD, FASCO,] at ASCO [the American Society of Clinical Oncology annual meeting] earlier this year, as a follow-up to the phase 1/2 study led by [Gregory] Riely, [MD, PhD,] at Memorial [Sloan Kettering Cancer Center]. The bottom line is this drug works. Depending on how you look at the data, they used both an independent review as well as an investigator-assessed review, the response rates were in the high 20% to low 30% range, which is very good, considering the heavily pretreated population. A lot of this is still immature. Progression-free survival is somewhere in the 7- to 10-month range, with a median duration of response, there were some patients on over a year, telling us that this is a very active drug. I have a couple of thoughts. First, we’re a little blinded by the fact that a lot of our other TKI therapies, such as RET inhibitors, EGFR inhibitors of the routine kind, exon 14 skipping, have phenomenal response rates, and this is probably not in the same league. But No. 1 is to consider how heavily pretreated many of these patients were, and then considering there’s nothing else out there, it is, along with the amivantamab data, practice changing. We expect and hope that mobo [mobocertinib] will be approved later this year, and that’ll give us 2 options in this real but rare mutation subset.

Mobocertinib is the right drug for almost anybody with an EGFR exon 20 insertion mutation. We don’t know, and this is going to be a bit of a plethora of riches, with both mobocertinib and amivantamab approved, can you use one after the other? There will be some data later this year looking at sequencing, a lot of it is currently based on a molecular level. But at this point, mobocertinib can be used in anybody, once it’s approved of course, with an exon 20 insertion mutation. We expect the first approval to be in the second line setting after platinum-based chemotherapy.

TRANSCRIPT EDITED FOR CLARITY