A 64-Year-Old Male With Lung Cancer - Episode 4

Novel Second-Line Therapy for EGFR Exon 20 Insertion-Positive NSCLC

A comprehensive discussion on novel second-line agents amivantamab and mobocertinib, approved for EGFR exon 20 insertion–positive non–small cell lung cancer.


Joel Neal, MD, PhD: Now, for this patient for whom we’re at a treatment decision point, the patient has progressed on platinum-based chemotherapy. The question is, what do we do next? And very exciting in the middle to late part of 2021, there were 2 new FDA-approved therapies for second-line treatment of EGFR exon 20 insertion-mutated lung cancer. One of these is amivantamab, approved in May 2021.

Amivantamab is a little different than the classical EGFR TKIs [tyrosine kinase inhibitors]. It’s actually an antibody that’s bispecific. Half of it targets EGFR, but the extracellular portion of EGFR, not unlike other drugs that have been approved for a longer time, such as cetuximab or necitumumab. The other part of amivantamab, the bispecific part of it, targets MET. MET is another tyrosine kinase that’s extracellular transmembrane bound, and signals through many of the same downstream pathways. Interestingly, MET is one of the known proteins that gets amplified in the setting of resistance to EGFR. It’s not exactly clear why the bispecific amivantamab is better than EGFR antibodies plus a mixture of MET antibodies, but it does seem to work potently in EGFR exon 20 non–small cell lung cancer.

In addition to amivantamab, there have been a number of tyrosine kinase inhibitors that are developed to be more specific and potent against this EGFR exon 20 insertion mutation. One that was FDA-approved in September of 2021 is mobocertinib. Mobocertinib is an oral EGFR tyrosine kinase inhibitor structurally very similar to osimertinib with some modifications. And this has activity against not only EGFR exon 20 insertion lung cancer, but some other EGFR mutations, as well as some activity against HER2-positive insertion mutation lung cancer, which is similar structurally to these EGFR exon 20 insertions. Mobocertinib was approved as a daily dosing. Amivantamab, in contrast, is IV [intravenous] dosing.

The decision was made to start this patient on amivantamab. They’re both FDA approved, one is IV, one is oral. I think the main differences, in addition to some of the differences that we’ll talk about in structure as well as efficacy, [are] administration and convenience. Patients may have different preferences of IV weekly therapy for a month followed by every 2-week therapy, versus oral daily dosing for mobocertinib.

Transcript edited for clarity.