Prevalence of Epidermal Growth Factor Receptor Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer in Europe: A Pragmatic Literature Review and Meta-analysis

Abstract

Background: Information on the epidemiology of uncommon EGFR mutations including exon 20 insertions amongst non-small-cell lung cancer (NSCLC) is lacking.

Objective: The objective of this pragmatic literature review (PLR) and meta-analysis was to generate robust prevalence and incidence estimates based on ranges of exon 20 insertion mutations reported in the literature.

Materials and methods: Searches of MEDLINE, Embase, congresses and reference lists for articles published from 2013 in key European countries of interest (Belgium, France, Germany, Italy, The Netherlands, Spain, Sweden, Switzerland, United Kingdom) were performed. Articles were reviewed against pre-specified criteria and their quality was appraised using a published checklist. Prevalence estimates were synthesised by random-effects meta-analyses.

Results: Eighty unique studies of moderate-to-high quality were included in the PLR. The meta-analysed prevalence for EGFR mutations was 12.5% (95% confidence interval [CI]: 11.0, 14.1) in any stage NSCLC and 14.8% (12.8, 17.1) in advanced/metastatic NSCLC. The prevalence of exon 20 insertions was 0.7% (0.4, 1.1) in any stage NSCLC and 6.1% (4.0, 9.4) in any stage EGFR-positive NSCLC. Mutation status was primarily measured using direct sequencing or a combination of methods. One study reporting exon 20 insertions in advanced/metastatic disease was identified, which reported a prevalence of 0.5% in overall NSCLC and 4.0% in EGFR-positive NSCLC.

Conclusions: EGFR exon 20 insertion mutations are rare in NSCLC. There is a high unmet need in patients with exon 20 insertions, including effective therapies. Prospective cohort studies are needed to better clinically characterise these patients.

Fig. 1

EGFR exon 20 insertion mutations in NSCLC [14]. Prevalence estimates originate from: ^aStella et al. J Cancer Res Clin Oncol 2013; 139:1327–1335; ^bLocatelli-Sanchez et al. Lung 2013;191:491–499; ^cKerner et al. PLoS One 2013;8:e70346. Exon 19 deletions and L858R exon 21 mutations are considered common EGFR mutations. Figure source: Vyse S. et al Signal Transduct Target Ther. 2019;4:1–10. Adapted based on evidence identified by the pragmatic literature review. EGFR epidermal growth factor receptor, NSCLC non-small-cell lung cancer

Fig. 2

PRISMA diagram. Due to the large volume of evidence identified throughout the review, a prioritisation strategy was implemented in order to synthesise evidence and draw conclusions of the highest possible utility. The deprioritised evidence included: studies with specific patient populations, such as patients with specific conditions (e.g. HIV, Li-Fraumeni syndrome) or patients selected based on having specific mutations (e.g. METex14, ALK translocations, MAP2K1, HER2, BRAF). ALK anaplastic lymphoma kinase, BRAF v-raf murine sarcoma viral oncogene homolog B1, EGFR epidermal growth factor receptor, HER2 human epidermal growth factor 2, HIV human immunodeficiency virus, MAP2K1 mitogen-activated protein kinase 1, METex14 mesenchymal-epithelial transition gene exon 14, PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Fig. 3

Estimated frequency from the meta-analysis and PLR of exon 20 insertion mutations in any stage and advanced/metastatic NSCLC. ^aDoes not include T790M. The figures present a summary of the pooled results from the random effects meta-analyses overlayed with the range of results from the PLR. Full forest plots for the individual meta-analyses are presented in the supplementary materials. The outcome for the exon 20 insertion mutation frequency in advanced/metastatic NSCLC is based on findings of the one study. CI confidence interval, EGFR epidermal growth factor receptor, exon 20i exon 20 insertion mutations, NSCLC non-small-cell lung cancer, PLR pragmatic literature review, RE random effects

Fig. 4

Frequency of exon 20 insertion mutations in any stage NSCLC and advanced/metastatic NSCLC per year and method of data collection. ‘Multiple’ = direct sequencing, fragment analysis, pyrosequencing and HRM. Bubble size represents the number of patients with NSCLC in each study. Numbers in square brackets represent the article citation. EGFR epidermal growth factor receptor, HRM high-resolution melt, NGS next-generation sequencing, NSCLC non-small-cell lung cancer