Major Advances in NSCLC: EGFR Exon 20 Insertion Mutations - Episode 3

EGFR Exon 20 Insertion Mutations as a Therapeutic Target in NSCLC


In the setting of non–small cell lung cancer, experts consider the importance of EGFR exon 20 insertion mutations as a therapeutic target.


Catherine Ann Shu, MD: Exon 20 is an interesting part of the EGFR story. The EGFR story has historically been about L858R and the exon 19 deletion. Those are historically the targetable EGFR mutations. Those are the ones in which we’re using osimertinib. If you think about EGFR as a whole, it’s 10% to 15% of nonsquamous non–small cell lung cancers, but maybe 4% to 5% of them have an EGFR exon 20 insertion. It’s a small but definite population. And those have a low response rate with the currently approved tyrosine kinase inhibitors like osimertinib. EGFR exon 20 is characterized by either in-frame insertions or duplications near the C-helix of the EGFR kinase domain. It’s a very heterogeneous mutation. It’s not the same with every patient, which is the way L858R looks. With the EGFR exon 20 insertion, the active site is altered. It’s like the steric hindrance that prevents TKI [tyrosine kinase inhibitors] binding, and therefore TKIs have very low response rates with EGFR exon 20 insertions.

Erminia Massarelli, MD, MS, PhD: In my practice, our institution [City of Hope] has PS65 molecular tests available. If a patient comes undiagnosed, we’ll do the molecular test. It’s an NGS platform, so it includes mutation analysis and fusions, and we also have some research background data. My advice is to do a broad molecular test like NGS in the metastatic incurable setting. You can also have liquid biopsies. If there’s a very small amount of tissue, I usually do liquid biopsy and NGS because at least you’ll have data in about 2 weeks. If liquid biopsies come out negative and there’s the option to do a tissue biopsy without delaying the care of the patient, I encourage that.

On the other side, if you have a positive liquid biopsy, you can proceed with treatment recommendations. The exon 20 insertion mutations are detected by NGS testing as well as liquid biopsies. However, with positive liquid biopsies, tumor burden contributes to cancer cells shedding into the blood steam. For patients with small tumor burden or only malignant pleural effusions, the liquid biopsy might be negative. Therefore, for malignant pleural effusions, we’re very successful obtaining tumor blocks to test for NGS.

The identification of the EGFR exon 20 insertion mutation significantly impacted the patient care because they aren’t very sensitive to the FDA-approved EGFR tyrosine kinase inhibitors, including osimertinib. Therefore, now that we have FDA approval, it’s definitely improved the care for these patients.

Transcript edited for clarity.