EGFR Exon 20 Insertion–Positive NSCLC: CHRYSALIS and EXCLAIM Trial Outcomes


The trial results of CHRYSALIS and EXCLAIM, which investigated amivantamab and mobocertinib, respectively, as second-line therapy for EGFR exon 20 insertion–positive NSCLC.


Joel Neal, MD, PhD: Amivantamab was FDA approved based on the CHRYSALIS study. This was a study of 81 patients with EGFR exon 20 insertion mutation lung cancer who had been previously treated. They were treated with this drug, and as I mentioned, it was given at [a] weekly dosing. The initial starting dose is split into 2 days in a row. The first day is a third of the total dose; the second day is two-thirds of the remaining dose. Then the next week on day 8, [the] same dose is given as 1 day, and then weekly dosing for the first month, then the same dose is given basically every 2 weeks.

In this CHRYSALIS study, 81 patients were treated. The overall response rate was 40%. The progression-free survival, the time until [the] tumor grew or progressed, was 8.3 months. And then out of that 40% of patients who responded, the duration of response was 11.1 months.

There were adverse effects, and most of these adverse effects I would consider expected within the class of EGFR inhibitors and MET inhibitors. For example, rash often on the face, the chest, and the back; paronychia [was] very common. In addition, there were MET-related adverse effects, such as peripheral edema. Another EGFR-related adverse effect of diarrhea seemed to be less common overall, with constipation being somewhat more frequent with amivantamab. So, mostly EGFR- and MET-related adverse effects.

This approval, as I said, was in May of 2021, and it seemed to be relatively tolerable despite all these adverse effects. Only 13% of patients had dose reductions. Only 10% of patients had drug discontinuations overall. One unique adverse effect of amivantamab that we often talk about though, is infusion-related reactions. This is most common on the first day of the first dose. Patients are heavily premedicated with steroids, and H2 and H1 [histamine receptor] blockers, etc. The infusion is given very slowly and [is] slowly increased over time. It’s not clear what leads to this infusion-related reaction, but the second day, in my experience, and then all the subsequent weeks, are much less likely to have infusion reactions than that first day.

The infusions can take a fair amount of time, many hours, up to 8 hours in my experience, the first day. It’s good to schedule patients really early. But on the second day and days beyond, it doesn’t seem to be as much of an issue. And as long as the drug [is] on board, in [a] steady state, and hasn’t been held for a long time, the risk of infusion-related reactions later is quite low. I think about this like rituximab, for example, where many patients get a reaction at the initial dosing, but usually not much of an issue after that.

The second drug that was FDA approved is mobocertinib. This oral EGFR tyrosine kinase inhibitor [TKI] was approved based on the EXCLAIM study. This was a phase 1/2 study with an expansion cohort at the maximally tolerated dose for patients who had been previously treated with platinum-based chemotherapy. This had a total of 114 patients. The response rate was 28%, slightly lower than the 40% for amivantamab. Progression-free survival [was] 7.3 months, a little lower, but roughly equivalent to the 8.3 months for amivantamab. But the duration of response of 17.5 months for those 28% of patients who had a good response, was longer than the 11 months for amivantamab.

The adverse effects here [are] more like EGFR TKIs, with diarrhea being common and present in 91% of patients, but grade 3 or higher only in about 20% of patients. Most patients also got [a] rash, paronychia, dry skin, [and a] bit of amylase/lipase increase. Then one of the unique adverse effects here is QT prolongation of the EKG [electrocardiogram], so it is recommended to get baseline EKGs and do at least some EKG monitoring along the way.

Transcript edited for clarity.

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