EGFR exon 20 insertion mutations and response to osimertinib in non-small-cell lung cancer

Wenfeng Fang,Jiadi Gan,Honglin Guo,Shaodong Hong,Wenjing Wang,Yihua Huang,Li Zhang,Minghui Wang,Zhonghan Zhang,Kai Wang

doi:10.1186/s12885-019-5820-0

Abstract

BackgroundEpidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4–12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). Development of effective therapies for patients with EGFRex20ins mutant non-small-cell lung carcinoma (NSCLC) represents a great unmet need. Preclinical models have shown that osimertinib is active in NSCLC harboring EGFRex20ins, while the antitumor activity of osimertinib remains to be evaluated in patients with EGFRex20ins mutations.MethodsTumor genotyping was performed in 2316 Chinese NSCLC cases with targeted next generation sequencing (NGS) covering the whole exons of EGFR gene. The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed. Furthermore, six patients with specific EGFRexon20ins mutations and receiving osimertinib 80 mg once daily were retrospectively included to assess the antitumor activity and safety of monotherapy osimertinib.ResultsEGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%). We found that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2 months (95% confidence interval 5.0–12.9 months; range 4.9–14.6 months). The most common adverse events (AEs) were diarrhea (2/6), pruritis (2/6), stomatitis (1/6) and nausea (1/6). No grade 3 or more AEs were documented.ConclusionsThis study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.

Highlights

Epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4–12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs)
Frequency and genetic characteristics of EGFRex20ins mutations Among the 2316 unselective non-small-cell lung carcinoma (NSCLC) tumors, EGFR mutations were identified in 1095 cases (47.3%)
EGFRex20ins mutations were detected in 53 cases, contributing 2.3% of all NSCLC cases and 4.8% of EGFR-mutant tumors

Summary

Introduction

Epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4–12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). The most common cluster of mutations in EGFR gene include inframe deletions around the LeuArgGluAla motif (residues 746–750) of exon 19, and the Leu858Arg (L858R) point mutation in exon 21, each accounting for about 45% of all EGFR mutations These mutations are termed classic EGFR mutations and are more common in tumors in women, Asians, never smokers, and those with adenocarcinoma [4,5,6]. Some unclassical EGFR mutations are associated with poor responses with reversible EGFR TKIs [13, 14] Among these are most EGFR exon 20 insertion (EGFRex20ins) mutations reported as far. The genetic and clinical characteristics of NSCLCs harboring EGFRex20ins mutations in Asian populations remain unknown due to the lack of large comprehensive genomic studies

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