Dr Christopher Arendt Explains Mutually Exclusive Nature of EGFR Exon 20 Mutations in Metastatic NSCLC

Christopher Arendt, PhD, head of the Oncology Therapeutic Area Unit at Takeda, discusses pathogenesis and characteristics of EGFR exon 20 mutations in metastatic non–small cell lung cancer (NSCLC).

The EGFR exon 20 mutation in non–small cell lung cancer (NSCLC) is a progressive and genetic disease that can occur regardless of smoking history, with response to conventional chemotherapy tending to be very poor in these populations, said Christopher Arendt, PhD, head of the Oncology Therapeutic Area Unit at Takeda.


Can you discuss the “mutually exclusive” nature of EGFR exon 20 mutations, which makes it important to find a treatment that can target them in metastatic NSCLC?

Absolutely, so let me start by stating that EGFR is a transmembrane growth factor kinase that's associated with alterations in different exon regions that are associated with NSCLCs. And so patients that have mutations in what's known as the exon 20 region have actually insertional mutation—so, extra genetic sequence that's located there that converts EGFR into an oncodriver to promote lung cancer.

What we mean by mutually exclusive is that it's defining patients who have a distinct subtype of disease in EGFR lung cancer and therefore require a specific targeted therapy in order to address that. In other words, it can't be addressed by the same medicines that would target, for example, an exon 20 defect or lesion in EGFR.

Can you discuss the populations most likely to have EGFR exon 20 mutations? Why are nonsmokers of particular interest?

Yeah, so it turns out that patients with exon 20 disease—so these exon 20–specific EGFR oncodriver mutations, who develop NSCLC as a result—these patients tend to be in the middle of their lives, in fact. Often they're either infrequent smokers or never smokers. It's a significant population of that EGFR space, that EGFR oncodriver space in lung cancer.

So, about 10% of patients who have an EGFR-driven lung cancer are ones who experience that through an exon 20–specific lesion. So, in terms of that connection to smoking, we know that smoking can drive genetic alterations in lung tissues that can lead to cancers, but when it comes to exon 20 disease, it's rather a genetic lottery.

You can think of it as sort of as this genetic lottery, one would pick up this lesion in lung tissue, again, sort of in midlife, and that can happen independent of your smoking history and result in a disease that's actually very devastating.

When you look across the different EGFR subtypes of disease, so, again, these lesions can occur in different exons, 19, 20, 21—those patients with the exon 20 insertional oncodriver mutations tend to have a worse prognosis within that EGFR cluster. And in fact, their responses to conventional chemotherapy tend to be very poor.

So, these patients are desperately in need of options, and that's why we're so excited and privileged really to be advancing what we hope can be the first orally available targeted medicine that can specifically address the needs of this patient population.

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