Testing at diagnosis and progression

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EGFR sensitising and resistance mutations

Testing at diagnosis and progression

EGFR sensitising and resistance mutations

Epidermal growth factor receptor (EGFR) sensitising mutations are present in the tumours of approximately 30–47% of Asian and 10–22% of Western patients with non-small cell lung cancer (NSCLC).1–9

It is recommended that all patients with advanced NSCLC and adenocarcinoma histology be tested for EGFR mutations.9–13 However, EGFR mutation testing is not recommended for patients with a confident diagnosis of squamous cell carcinoma lacking any adenocarcinoma component, except in never/former light smokers (<15 pack years).9–11

A patient's tumour EGFR mutation status can be determined by performing a diagnostic EGFR mutation test to look for the presence or absence of mutations in tumour DNA encoding the EGFR gene. The EGFR mutation test should be robust, reliable, high-quality, and conducted in the shortest possible time, with a well-validated and aligned standard diagnostic practice.

For patients diagnosed with advanced NSCLC harbouring an activating or sensitising EGFR mutation, the standard of care is first line treatment with an EGFR tyrosine kinase inhibitor (EGFR-TKI), such as afatinib, erlotinib or gefitinib.9,11 The most common activating mutations observed prior to treatment with an EGFR-TKI are exon 19 deletions and an L858R point mutation in exon 21.14–17

Despite high initial response rates to first-line EGFR-TKIs, the majority of patients with advanced NSCLC harbouring an EGFR mutation will progress on treatment due to acquired resistance, with a median progression-free survival of 9.7–13.1 months.18,19

Mutation testing at disease progression can be used to help identify the mechanism(s) of acquired resistance. The most common mechanism of acquired resistance is the EGFR T790M mutation.20-23

EGFR Mutation

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Testing at diagnosis and progression

Testing at diagnosis

Approximately 90% of EGFR mutations are either exon 19 deletions or L858R point mutations in exon 21,15,28 for which there are extensive randomised clinical trial data to support sensitivity of tumours harbouring these mutations to EGFR-TKI treatment.4,5,15-17,29-31

At primary diagnosis of advanced NSCLC, EGFR mutation test results help physicians to decide if a patient is likely to benefit from treatment with an EGFR-TKI. EGFR mutation test results should therefore be reported clearly and include the mutation type to allow the physician to make a treatment decision based on the evidence available.

When testing for EGFR mutations, it is recommended that a tumour sample be used to confirm the presence of EGFR mutations prior to treatment. However, circulating tumour DNA (ctDNA) obtained from blood (plasma) may be used if a tumour sample is not available.32

The diagram below outlines the process of testing at diagnosis using tissue and plasma* samples.32

Testing at diagnosis

*Please note, EGFR mutation testing using plasma samples is not approved in Japan

Testing at progression

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At disease progression, known resistance mechanisms include additional EGFR resistance mutations (e.g. T790M), alternative pathway activations (e.g. HER2 or MET amplification) or phenotypic transformations (to small-cell lung cancer [SCLC] or epithelial-mesenchymal transition).33,34

The most common mechanism of acquired resistance to first-generation EGFR-TKIs is the EGFR T790M mutation.20-23 Studies have shown that the incidence of the EGFR T790M mutation in tumours that have developed resistance to first-generation EGFR-TKIs ranges from 51 to 68%.20–23,25

Therefore, it is highly recommended that, at the time of disease progression, a biopsy is performed to confirm the presence of the EGFR T790M mutation and any driver mutations (e.g. exon 19 deletions and L858R mutations) prior to further treatment.1,35,36

Testing for the T790M mutation is now possible using similar methods to those for EGFR mutation testing at the time of primary diagnosis. EGFR T790M mutation status can be verified using either a tissue-based or plasma-based test.36

The diagram below outlines the process of testing at progression using plasma* and tumour samples.36

EGFR Plasma

*Please note, EGFR mutation testing using plasma samples is not approved in Japan

Following disease progression, it can be more challenging to obtain a tissue biopsy than at primary diagnosis. ctDNA obtained from a plasma sample offers a less invasive and potentially quicker alternative for EGFR mutation testing, however, ctDNA testing is less sensitive for EGFR T790M than exon 19 deletion and L858R.37 When using ctDNA testing, it should be noted that false negatives have been reported (30–40%+).38,39 Therefore, if a plasma-based ctDNA test is used and the result is negative, it is recommended that this be followed-up with a tissue-based test.36

A tissue biopsy is highly recommended if the patient is well enough to tolerate the procedure, as this is the primary source of the mutations. When ordering a ctDNA test, it is suggested that a tissue biopsy also be requested, which can subsequently be used if the ctDNA test is negative.

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The treatment landscape for patients with advanced NSCLC and an EGFR mutation is constantly evolving, with the availability of the first 3rd generation EGFR-TKI, osimertinib, which is an oral, selective irreversible TKI that targets both EGFR-sensitising mutations and specifically the EGFR T790M mutation while sparing wild-type EGFR.36