In January 2018, NICE announced that it has developed a medtech innovation briefing [MIB137] on plasma epidermal growth factor receptor (EGFR) mutation tests for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC). The 7 technologies described in the briefing are plasma EGFR mutation tests. They are used to inform the decision to offer EGFR tyrosine kinase inhibitors (EGFR‑TKIs) for treating locally advanced or metastatic NSCLC in adults.
EGFR mutations occur in EGFR exons 18–21 and mutations in exons 18, 19 and 21 and indicate suitability for treatment with EGFR‑TKIs. Mutations in exon 20 (with the exception of a few mutations) show the tumours are EGFR‑TKI resistant and not suitable for treatment with EGFR‑TKIs.
Traditionally, EGFR mutation testing is done on a tumour sample obtained by tissue biopsy. More recently, plasma EGFR mutation tests that use free circulating tumour DNA (ctDNA) have been developed as an alternative. ctDNA is made up of fragments of tumour DNA that have entered the bloodstream. Only a blood sample is needed for plasma testing, so it is frequently called 'liquid biopsy'.
Plasma testing begins by using centrifugation to separate plasma from the other components of a blood sample. A DNA extraction kit is then applied to isolate ctDNA. Polymerase chain reaction (PCR) amplifies ctDNA in the sample. Depending on which test is done, EGFR mutations are detected by either analogue or digital methods. Analogue detection (known as real-time PCR) uses fluorescent markers that attach to specific mutation sites, making them detectable; fluorescence in the sample is detected as a whole. In digital PCR (dPCR) the sample is separated into many partitions, each tested individually, providing a lower threshold of detection. Fully quantitative plasma EGFR mutation tests can measure the levels of ctDNA in a sample; semi-quantitative tests display the results as above or below thresholds.
Seven kits assessed in the NICE report are:
- EGFR 29 mutations detection kit, SuperARMS EGFR mutation detection kit, and SuperARMS EGFR T790M mutation detection kit manufactured by AmoyDx. EGFR 29 mutations detection kit is analogue, semi-quantitative and detects 29 mutations. SuperARMS EGFR mutation detection kit is semi-quantitative and detects 41 mutations. SuperARMS EGFR T790M mutation detection kit is analogue, semi-quantitative and only used to detect the T790M mutation.
- Droplet digital PCR Dx system manufactured by Bio-rad. It is digital, fully quantitative and detects 13 mutations.
- PANAMutyper R EGFR manufactured by Panagene. It is analogue, semi-quantitative and detects 47 mutations.
- Therascreen EGFR plasma RGQ PCR kit manufactured by Qiagen. It is analogue, semi-quantitative and detects 21 mutations.
- Cobas EGFR mutation test v2 manufactured by Roche. It is analogue, semi-quantitative and detects 42 mutations.
The innovative aspects are that the tests measure ctDNA in a blood sample rather than the standard histopathological assessment of a tumour biopsy.
The intended place in therapy would be as an alternative to tissue EGFR testing or before tumour testing to inform decisions about prescribing EGFR‑TKIs. Plasma testing may be particularly useful for people whose disease has developed resistance to an EGFR‑TKI and who could be offered second-line EGFR‑TKIs, if appropriate, without having further tissue testing.
The main points from the evidence summarised in this briefing are from 7 non-UK-based prospective studies with 2,106 adults. They show that the diagnostic accuracy of plasma EGFR mutation testing has a similar specificity, but lower sensitivity, compared with tissue EGFR mutation testing in adults with locally advanced or metastatic NSCLC.
Key uncertainties around the evidence or technology are that tests for identifying EGFR‑TK mutations are rapidly evolving and there is no established gold-standard test against which to evaluate them.
The cost of plasma EGFR mutation tests range from 138.05 GBP to 230.22 GBP per unit (excluding VAT). The resource impact is similar to that of standard care but plasma EGFR mutation testing could be cost saving if it led to fewer tissue biopsies.