EGFR Exon 20 Insertion Mutations: Clinicopathological Characteristics and Treatment Outcomes in Advanced Non–Small Cell Lung Cancer

• Published in: Clinical lung cancer 2021-11, Vol.22 (6), p.e859-e869
• Main Authors: Leal, Jose Luis, Alexander, Marliese, Itchins, Malinda, Wright, Gavin M., Kao, Steven, Hughes, Brett G.M., Pavlakis, Nick, Clarke, Stephen, Gill, Anthony J, Ainsworth, Hannah, Solomon, Benjamin, John, Thomas
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; EGFR Exon 20 insertion; EGFR TKI; ErbB Receptors - genetics; Exons - genetics; Female; Genetic Testing; Humans; Immune checkpoint inhibitors; Male; Middle Aged; Mutagenesis, Insertional; Non-small cell lung cancer; Polymerase Chain Reaction; TKI resistance; Young Adult
• ISSN: 1525-7304; 1938-0690
• DOI: 10.1016/j.cllc.2021.04.009

•EGFR exon 20 insertions are uncommon in non-small cell lung cancer.•Patient demographics and clinical features are similar to common EGFR mutations.•Platinum-based chemotherapy is the standard of care in advanced disease.•There is resistance to standard tyrosine kinase inhibitors, including osimertinib.•Treatment with single-agent immune checkpoint inhibitors is ineffective. Epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20-ins) mutations are an uncommon and heterogeneous group of non–small cell lung cancers (NSCLCs), resistant to conventional EGFR tyrosine kinase inhibitors (TKIs). Characteristics and outcomes of patients with EGFR ex20-ins have not been fully established; we sought to clarify them using a multinational patient database. Patients with NSCLC from six Australian institutions with EGFR exon 20 mutations (ex20-mut), excluding T790M, were retrospectively reviewed. Clinical characteristics and outcomes with systemic treatments were collected and analyzed using comparative statistics. Among 109 patients with ex20-mut, 61% were females and 75% were Caucasians. More males presented with de novo metastatic disease (84% vs. 51%; P = .002). Central nervous system (48%) and liver (24%) metastases were common within metastatic patients (n = 86). Thirty-nine patients received platinum-based chemotherapy (PBC) and achieved a 43% objective response rate (ORR), median progression-free survival (mPFS) of 6.9 months, and median overall survival (mOS) of 31.0 months. Twenty-three of the patients with ex20-ins received conventional TKIs, resulting in an ORR of 13%, mPFS of 3.4 months (95% confidence interval [CI], 1.91-6.25), and mOS of 31.0 months (95% CI, 15.09-not reached). Nine patients with S786I mutations received TKIs, resulting in an ORR of 50%, mPFS of 18.2 months (2.79-not reached), and mOS of 33.4 months (95% CI, 16.14-not reached). Twenty-three patients received immune checkpoint inhibitor monotherapy (ICIm), resulting in an ORR of 4%, mPFS of 2.6 months (95% CI, 1.91-4.83), and mOS of 30.8 months (95% CI, 17.62-41.62). Although phenotypically similar to patients with common EGFR mutations, patients with EGFR ex20-mut had worse survival, perhaps due to the lack of targeted therapies. Chemotherapy was superior to conventional EGFR TKIs in patients with EGFR ex20-ins, although there was moderate activity of TKIs in S768I mutations. ICIm was ineffective. EGFR exon 20 insertions are uncommon in non–small cell lung cancer (NSCLC) and