EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications

Summary

Lung cancer is the leading cause of cancer-related death. The identification of epidermal growth factor receptor (EGFR) somatic mutations defined a new, molecularly classified subgroup of non-small-cell lung cancer (NSCLC). Classic EGFR activating mutations, such as inframe deletions in exon 19 or the Leu858Arg (L858R) point mutation in exon 21 are associated with sensitivity to first generation quinazoline reversible EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 20 insertion mutations, which are typically located after the C-helix of the tyrosine kinase domain of EGFR, may account for up to 4% of all EGFR mutations. Preclinical models have shown that the most prevalent EGFR exon 20 insertion mutated proteins are resistant to clinically achievable doses of reversible (gefitinib, erlotinib) and irreversible (neratinib, afatinib, PF00299804) EGFR TKIs. Growing clinical experience with patients whose tumours harbour EGFR exon 20 insertions corresponds with the preclinical data; very few patients have had responses to EGFR TKIs. Despite the prevalence and biological importance of EGFR exon 20 insertions, few reports have summarised all preclinical and clinical data on these mutations. Here, we review the literature and provide an update with an emphasis on the structural, molecular, and clinical implications of EGFR exon 20 insertions.

Introduction

Lung cancer is the leading cause of cancer-related death worldwide, with more than 1·6 million cases diagnosed and 1·3 million deaths per year.¹ Therefore, even small subgroups of non-small-cell lung cancer (NSCLC) contribute to significant morbidity and mortality.

In 2004, the identification of somatic mutations in the epidermal growth factor receptor (EGFR) provided a glimpse into a clinically relevant oncogene and a new molecularly classified subgroup of NSCLC.2, 3, 4 Among the multitude of mutations found in the EGFR gene (figure 1), the most common cluster in two regions and are often termed classic activating mutations. These include inframe deletions around the LeuArgGluAla motif (residues 746–750) of exon 19 (roughly 45–50% of all EGFR mutations), and the Leu858Arg (L858R) point mutation in exon 21 (about 40–45% of EGFR mutations).5, 6, 7 Classic EGFR mutations are more common in tumours in women, Asians, never smokers, and those with adenocarcinoma histology.5, 7, 8 About 15% of all NSCLCs in western Europeans, 30% in East Asians, and 50% in never smokers are EGFR mutation-positive.5, 7, 8 Most patients with exon 19 deletions or Leu858Arg EGFR activating mutations have substantial clinical and radiographic responses to monotherapy with the reversible anilinoquinazoline, ATP-mimetic EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib.⁹ Response rates (RRs) exceed 70%, with median progression-free survival (PFS) of longer than 9 months and overall survival (OS) that reaches 24 months.9, 10, 11, 12, 13, 14, 15, 16, 17 At least three randomised phase 3 trials have shown a better RR and PFS with gefitinib or erlotinib compared with chemotherapy in patients with classic EGFR mutation-positive NSCLC.18, 19, 20, 21 Additional EGFR mutations (figure 1) have been associated with some sensitivity to gefitinib and erlotinib, although their ability to predict a radiographic and clinical response to gefitinib or erlotinib is less striking than that of classic EGFR mutations.²² These include point mutations in position Gly719 of exon 18 (Gly719Ala, Cys, or Ser), which account for about 3% of EGFR mutations, and a recurrent Leu861Gln mutation in exon 21 that represents about 2% of EGFR mutations.23, 24 The frequency of classic EGFR mutations in patients with different ethnic backgrounds has not been completely established; however, EGFR genotyping of large prospective cohorts of western Europeans with NSCLC shows a higher frequency of exon 19 deletions than Leu858Arg mutations,¹¹ compared with similar cohorts or clinical trials of east Asian populations where exon 19 deletions are only slightly more prevalent than Leu858Arg mutations.¹⁸

Some EGFR mutations are not often associated with radiographic responses and clinical benefit with reversible EGFR TKIs. This is the case for most exon 20 EGFR insertions reported so far.25, 26, 27 Exon 20 insertion mutations might account for up to 4% of all EGFR mutations,22, 24, 28 and therefore as many as 10 000 new yearly cases of NSCLC worldwide.¹ The latter estimate is based on data from global trends in incidence of cancer and does not address geographic and ethnic variations related to NSCLCs with EGFR mutations.