NSCLC: Amivantamab for Patients With EGFR Exon 20 Insertion Mutations


Considerations for the FDA approval and practical use of amivantamab in patients with EGFR exon 20 insertion mutations in non-small cell lung cancer.


Catherine Ann Shu, MD: Amivantamab [Rybrevant] is an EGFR-MET [epidermal growth factor receptor-mesenchymal-epithelial transition] bispecific antibody with immune cell directing activities. It’s different from your traditional TKI [tyrosine kinase inhibitor] and has a completely different mechanism of action. It binds at the extracellular domain, or the top, as opposed to diffusing through the membrane. Amivantamab can therefore inhibit ligand binding. It can also promote receptor antibody complex on endocytosis and degradation. It can induce trogocytosis by macrophages and ADCC [antibody-dependent cell-mediated cytotoxicity] by natural killer cells. It has a whole triple or quadruple prong approach.

If you think about the EGFR exon 20 insertions, it alters the active site that then causes steric hindrance to prevent the TKI from binding. But that’s all inside the cell so, if you think about it, the mechanism of action of amivantamab is great because it’s extracellular so all of that stuff that’s happening inside the cell is irrelevant to it.

CHRYSALIS was the first in human phase 1 dose-escalation and dose-expansion trial. I was very fortunate to be one of the first investigators on this amazing trial. It had several different cohorts. Some cohorts are still ongoing, but cohort D in particular was for patients with EGFR exon 20 insertions.

The primary endpoint was objective response rate and limiting the incidences of toxicity because remember this was a phase 1 trial, first in humans. The pivotal efficacy population included 81 patients with EGFR exon 20 insertions who had progressed on platinum-based chemotherapy. The safety profile included rash, paronychia, stomatitis, and most importantly, this infusion-related reaction that occurred in about two-thirds of the patients but almost exclusively on cycle day 1.

As we treated more patients on amivantamab we learned more and more about this infusion-related reaction. It is seen mainly on day 1. We’re able to pre-medicate with steroids and Benadryl and Tylenol and such to lower the incidents. And then if you stop the infusion and then just slow it down most patients are able to continue and complete that first day. The first infusion is split up between day 1 and day 2 and that way the patient gets a little taste of it on day 1 and then they get the rest of it on day 2. With all of those precautions, the infusion-related reactions have been very manageable. This paper was published in the Journal of Clinical Oncology and the important takeaway numbers are the ORR [overall response rate] was 40%, which is quite good in a post-platinum population. The median PFS [progression-free survival] was 8.3 months and the median duration of response was 11.1 months.

The FDA [Food and Drug Administration] approved amivantamab on May 21, 2021, for patients who had progressed on or after platinum-based chemotherapy. Your patients would have had to receive a platinum-based doublet first and after that, they could go on to amivantamab. The NCCN [National Comprehensive Cancer Network] also updated the exon 20 insertions as a new targetable mutation and amivantamab is a treatment option there.

The approval of amivantamab for patients with EGFR exon 20 insertions is huge. These patients didn’t have any targetable options previously and now you’re giving them new hope with new drugs. It’s a really exciting time for them.

Transcript edited for clarity.

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