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Testing for EGFR Exon 20 Insertion Mutations, a New Targetable Biomarker in Advanced NSCLC

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Professor Keith M. Kerr, FRCPath

Professor of Pulmonary Pathology
Faculty of Medicine & Dentistry
Aberdeen University
Consultant Pathology
NHS Grampian
Aberdeen, United Kingdom

Professor Keith M. Kerr, MB ChB, FRCPath, FRCPE, has disclosed that he has received consulting fees and/or fees for non-CME/CE services from AbbVie, ArcherDX, AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Debiopharm, Diaceutics, Eli Lilly, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Regeneron, Roche, and Ventana.

View ClinicalThoughts from this Author

Released: August 5, 2021

Activating EGFR mutations, which are predominantly located in exons 18-21, are on average found in approximately 25% of patients with appropriately tested advanced non-small-cell lung cancer (NSCLC) globally. The most common of these mutations, EGFR L858R and exon 19 deletion (ex19del), are targetable with EGFR tyrosine kinase inhibitors (TKIs), with the third-generation EGFR TKI osimertinib now being standard of care in this setting. Several noncanonical mutations (eg, exon 18 G719X and exon 21 L861Q) are also susceptible to these agents. However, currently available EGFR TKIs at standard doses are not effective against the vast majority of EGFR exon 20 insertion (ex20ins) mutations, a diverse family of mutations that, until recently, have been known as “resistance mutations” due to this insensitivity to EGFR TKIs. This paradigm has recently started to shift with the development of new therapies specifically targeting these mutations (eg, the bispecific EGFR/MET antibody amivantamab was recently approved by the FDA for patients with EGFR ex20ins–positive advanced NSCLC and progression on or after platinum-based chemotherapy), thereby ushering in yet another new biomarker with promise to significantly affect how we manage patients with NSCLC. Below I share my thoughts on the importance of testing for EGFR ex20ins mutations in patients with advanced NSCLC, including guidance on how, in whom, and when to test.

Importance of Testing for EGFR ex20ins Mutations in Advanced NSCLC
EGFR ex20ins mutations are molecular drivers of NSCLC in the same way as the common EGFR mutations L858R and ex19del. We were initially under the impression that these mutations were uncommon, but this was likely because they were not being looked for. Instead, laboratories were testing for L858R and ex19del because physicians had approved drugs with which to target these mutations when found. However, through careful and broad sequencing of EGFR exon 20 in patients with advanced NSCLC, we have since found that EGFR ex20ins mutations account for up to 12% of all EGFR-activating mutations, making them the third most common type of EGFR mutation after ex19del and L858R at approximately 45% and approximately 40%, respectively. Furthermore, EGFR ex20ins–mutated cases comprise approximately 1%-2% of nonsquamous NSCLC overall, which is comparable to other targetable oncogenic drivers we test for in advanced NSCLC as standard of care, including ROS1, which is targetable with the multikinase inhibitors crizotinib and entrectinib, and more recently, RET, which is targetable with the selective RET inhibitors pralsetinib and selpercatinib. With the emergence of new agents targeting EGFR ex20ins mutations, testing for this biomarker could significantly affect how we manage these patients.

How to Test
EGFR mutations, including ex20ins mutations, are tested for by sequencing DNA. This can be accomplished with polymerase chain reaction (PCR)–based methods or DNA-based next-generation sequencing (NGS) assays, with DNA-based NGS now being the preferred technology to use considering its comprehensive nature and the growing numbers of targetable biomarkers that need to be tested for as standard of care in patients with advanced NSCLC. In the United States, oncologists have had access to NGS for many years, but the global reality is that NGS is not universally available. However, it is no longer practical to test for individual biomarkers separately, so my hope is that adding EGFR ex20ins mutations to the list of biomarkers to test for may push more widescale adoption of NGS.

There are a couple of important points to keep in mind when testing for EGFR ex20ins mutations by NGS. First, it should not be assumed that all NGS testing assays cover EGFR ex20ins mutations; the details of the assay should always be confirmed. Second, not all EGFR ex20ins mutations are created equally. This is a large family of complex mutations, of which a small number is sensitive to traditional EGFR TKIs. Thus, it is important that the details of the specific mutation identified by NGS are reported as well as are understood by those receiving the reports so that the appropriate therapy, whether a standard EGFR TKI or a new agent specifically targeting EGFR ex20ins mutations, is delivered to the patient.

Historically, EGFR-specific detection techniques based on highly targeted or “allele-specific” PCR-based assays were commonly used. Although these techniques are convenient—you put biopsy tissue in a black box, and without having to think too much about it, it spits out an answer—they do not comprehensively cover the entirety of exons 18-21, so mutations that we now know are important are missed. Furthermore, these stand-alone targeted techniques do not cover enough of exon 20 to give us the information we need on this very broad and diverse family of EGFR mutations. Even so, these single-gene EGFR assays are still being used in some situations. Because NGS has a longer turnaround time for reporting results than these ‘black box’ tests, some institutions, especially smaller labs that must outsource NGS, are opting to simultaneously do quick allele-specific tests, which is paradoxical, given that we often do not have enough tumor tissue available for some of these patients. Furthermore, there is an interesting rise again, almost from the ashes, for use of these single-gene EGFR assays in early-stage disease where the only biomarker that currently needs to be tested for is EGFR, with the presence of L858R and ex19del mutations indicating that the patient may be a candidate for adjuvant osimertinib, where it is approved, after tumor resection. However, there are currently no tests with the capability of only looking for EGFR ex20ins mutations, and I do not anticipate there ever being a situation where we are only looking for these mutations.

Whom and When to Test
It is standard of care to use comprehensive NGS testing for all patients at diagnosis of advanced NSCLC to guide first‑line therapy decisions, and that should now include testing for EGFR ex20ins mutations, as per drug availability. As I mentioned, we know that EGFR ex20ins mutations are oncogenic drivers like EGFR L858R and ex19del mutations. They also appear to be found in the same demographic of patients—those with adenocarcinomas without a history of smoking. However, of course, you can still find these mutations in patients who have smoked. With the same test population, the strategy for selecting patients for testing does not have to change. Testing for EGFR ex20ins mutations is simply another item on the testing menu for the same group of patients who are being tested.

Whereas upfront testing is ideal, there may be an interim period where patients who have progressed on chemotherapy or chemoimmunotherapy in the first-line setting will need to receive retrospective NGS testing of their original biopsy for EGFR ex20ins mutations to receive drugs available for second-line treatment. As I mentioned, amivantamab is currently the only approved agent targeting these mutations and this is only in the United States. Furthermore, additional agents targeting EGFR ex20ins mutations (eg, mobocertinib) are currently being evaluated in the second-line setting. However, I anticipate that with more widescale testing and better identification of EGFR ex20ins mutations, we will eventually see clinical trials of these agents in the first-line setting followed ultimately by their being a part of the suite of first-line drugs that are available for patients with advanced NSCLC.

Your Thoughts?
Are you using NGS testing to identify EGFR ex20ins mutations in your patients with advanced NSCLC? I encourage you to answer the polling question and join the conversation by posting a comment in the discussion section.

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