EGFR Exon 20 Insertion in Metastatic Non-Small-Cell Lung Cancer: Survival and Clinical Efficacy of EGFR Tyrosine-Kinase Inhibitor and Chemotherapy

Abstract

EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs). In this paper, we describe the clinical characteristics, efficacy of EFGR TKIs and chemotherapy, and resulting survival in this population. We retrospectively collected patients with EGFR exon 20 insertions (Exon20ins) from 11 French genetic platforms and paired them (1:2 ratio) with classic Exon 19/21 EGFR mutation patients (controls). Between 2012 and 2017, 35 Exon20ins patients were included. These patients were younger at diagnosis than the controls. All Exon20ins patients who were treated with first-line EGFR TKIs (n = 6) showed progressive disease as the best tumor response. There was no significant difference in the tumor response or the disease control rate with first-line platinum-based chemotherapy between the two groups. A trend towards shorter overall survival was observed in Exon20ins vs. controls (17 months (14—not reach(NR) 95% confidence interval(CI) vs. 29 months (17–NR 95%CI), p = 0.09), respectively. A significant heterogeneity in amino acid insertion in EGFR exon 20 was observed. EGFR exon 20 insertions are heterogeneous molecular alterations in NSCLC that are resistant to classic EGFR TKIs, which contraindicates their use as a first-line treatment.

Non–Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology

“…188 First-line platinumbased chemotherapy is typically recommended for most patients with EGFR exon 20 insertion-positive metastatic NSCLC (eg, carboplatin/[pemetrexed or paclitaxel]). 189,190 The response rates (0%-25%) to immunotherapy regimens vary, depending on the specific EGFR exon 20 insertion mutation. 191,192 Response rates to classic subsequent therapy regimens, such as docetaxel, are low (14%) in patients with metastatic NSCLC and disease progression after first-line therapy.…”

Targeting exon 20 insertion mutations in lung cancer

“…First and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors According to current data, most EGFR exon 20 insertion mutations were resistant to first and secondgeneration EGFR-TKIs except EGFR p.A763_ Y764insFQEA [23,24]. Retrospective data confirmed the generally of unsatisfactory outcomes of patients with EGFR exon 20 insertions: the objective response rates (ORRs) were between 0% and 28% and the median progression-free survival (PFS) of majority researches did not reach 4 months [11,[25][26][27][28][29][30]. The pooled analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 revealed afatinib only achieved an ORR of 8.7%, with a PFS of 2.7 months in 23 NSCLC patients with EGFR exon 20 insertions [31].…”

Long-term survival after stereotactic body radiotherapy combined with immunotherapy plus anti-angiogenesis therapy in patients with advanced non-small cell lung cancer and EGFR exon 20 insertion mutation: a report of two cases

“…Based on this, these two drugs have been included into the NCCN guidelines as second-line treatment options for patients who have failed chemotherapy. In addition, the clinical outcomes of targeted drugs including furmonertinib, osimertinib, afatinib, sunvozertinib, and poziotinib have also been reported ( 24 , 27 , 29 - 37 ) ( Table 1 ).…”