Cancer Res Treat.  2024 Jul;56(3):774-784. 10.4143/crt.2023.1177.

Comparison of Clinicopathogenomic Features and Treatment Outcomes of EGFR and HER2 Exon 20 Insertion Mutations in Non–Small Cell Lung Cancer: Single-Institution Experience

• Lee SH
• Jeong H
• Kim DH
• Jang SJ
• Kim SW
• Yoon S
• Lee DH

• KMID: 2557664
• DOI: http://doi.org/10.4143/crt.2023.1177

Abstract

Purpose
Exon 20 insertion mutations (E20ins) in epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) in non–small cell lung cancer (NSCLC) patients has become more important with emergence of novel agents targeting E20ins.
Materials and Methods
Advanced/Metastatic NSCLC patients with E20ins were included. EGFR E20ins was identified by two methods, next-generation sequencing (NGS) or real-time polymerase chain reaction (PCR), while HER2 E20ins was done by NGS only.
Results
Between December 2013 and July 2021, E20ins were identified in 107 patients at Asan Medical Center; 67 EGFR E20ins and 40 HER2 E20ins. Out of 32 patients with EGFR E20ins who had tested both PCR and NGS, 17 were identified only through NGS and the other 15 through both tests, giving a discordance rate of 53.1%. There was no clinically significant difference in clinicopathologic features between EGFR and HER2 E20ins; both were observed more frequently in adenocarcinoma, female and never-smokers. Brain metastases were evident at diagnosis in 31.8% of EGFR E20ins and 27.5% of HER2 E20ins, respectively. Platinum-based doublets demonstrated objective response rates (ORR) of 13.3% with a median progression-free survival (PFS) of 4.2 months for EGFR E20ins and 35.3% with 4.7 months for HER2 E20ins, respectively. In contrast, novel EGFR E20ins-targeted agents exhibited an ORR of 46.2% with a median PFS of 5.4 months, while HER2-targeted agents showed an ORR of 50% with that of 7.0 months.
Conclusion
Identification of EGFR and HER2 E20ins is more important as their targeted therapies improved outcomes. Upfront NGS test as a comprehensive molecular approach is strongly warranted.

Keyword

Non-small-cell lung carcinoma; Exon 20 insertion; EGFR; HER2; Targeted therapy

Figure

• 

  Fig. 1. Genomic characteristics. (A) Lollipop of EGFR E20ins mutations. (B) Lollipop of HER2 E20ins mutations. E20ins, exon 20 insertion; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor gene 2.

• 

  Fig. 2. Oncoplot for most commonly mutated genes and targetable alterations in patients with EGFR and HER2 E20ins mutations. Analysis based on NGS testing of 43 patients with EGFR E20ins and 40 patients with HER2 E20ins mutations. E20ins, exon 20 insertion; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor gene 2; NA, not available; NGS, next-generation sequencing; PD-L1, programmed death-ligand 1; TMB, tumor mutational burden.

• 

  Fig. 3. Survival outcomes. (A) Overall survival to platinum-based doublets. (B) Progression-free survival to platinum-based doublets. (C) Progression-free survival to PD-1/PD-L1 inhibitors as monotherapy. (D) Progression-free survival to conventional first- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (blue line) and novel EGFR exon 20 insertion (E20ins)–targeted agents (red line) in patients with EGFR E20ins, and progression-free survival to human epidermal growth factor receptor gene 2 (HER2)-targeted agents (green line) in patients with HER2 E20ins. CI, confidence interval; NE, not evaluable; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; TKI, tyrosine kinase inhibitor.

• 

  Fig. 4. Progression-free survival to immune checkpoint inhibitors according to the programmed death-ligand 1 (SP263) expression status. (A) EGFR E20ins. (B) HER2 E20ins. CI, confidence interval; E20ins, exon 20 insertion; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor gene 2; NE, not evaluable.

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