Potential treatment strategy for the rare osimertinib resistant mutation EGFR L718Q

Abstract

Epidermal growth factor receptor (EGFR) L718Q is a rare resistant mutation which independently leads to third-generation tyrosine kinase inhibitor (TKI) resistance. Although a few studies have examined its resistance mechanisms, no effective treatment strategy has yet been proposed for patients with this mutation. Here, we report an effective treatment strategy for the rare EGFR L718Q mutation for the first time. A 44-year-old Chinese male patient initially presented with the sensitizing EGFR L858R mutation, and the progression-free survival (PFS) time after initial icotinib treatment was 9 months. When the progression of the disease (PD) and the EGFR T790M mutation were identified, he did not respond to the osimertinib treatment. Through comprehensive next-generation sequencing (NGS) of the surgical specimen, the rare EGFR L718Q mutation was eventually identified as having a frequency of 68.84%, together with an EGFR amplification with a copy number of 11.54. The previous treatment response was retrospectively explained, and the patient faced the challenge of not being able to benefit from any targeted therapy. Following chemotherapy with a personalized regimen which effectively modified the proportion of sensitive and resistant cells, significant response to osimertinib re-challenge was observed, and another PFS of 4.7 months was achieved. Unfortunately, four EGFR mutations, EGFR L858, T790M, L718Q, and C797S, were simultaneously detected in his late stage, and led to further progression of disease.

Case Report: Dacomitinib Overcomes Osimertinib Resistance in NSCLC Patient Harboring L718Q Mutation: A Case Report

“…In China, approximately 50% of all non-small cell lung cancers (NSCLCs) have an epidermal growth factor receptor (EGFR) mutation ( 1 ). It is well known that advanced NSCLC harboring EGFR mutations has been successfully treated with tyrosine kinase inhibitors (TKIs).…”

“…Unfortunately, although uncommon, resistance to the third-generation TKI osimertinib can be difficult to overcome in a small subset of patients and has been attributed to secondary resistant mutations. The EGFR L718Q mutation, identified in 8% of Chinese osimertinib-resistant NSCLC patients, has been found to independently lead to osimertinib resistance by stabilizing its non-reactive conformation, but an effective treatment directed at this rare mutation has yet to be identified ( 1 ). Several reports have shown that second-generation EGFR TKIs can overcome osimertinib resistance due to concomitant EGFR L858R/L718Q mutations ( 1 , 2 ).…”

Successful sequential tyrosine kinase inhibitors to overcome a rare compound of EGFR exon 18–18 and EGFR amplification: A case report

“…Indeed, these patients will present different subpopulations of cancer cells with heterogeneous mutations, which can be potentially insensitive to EGFR-TKI. The prescription of chemotherapy following EGFR-TKI would make it possible to target all subpopulations and thus reduce the proportion of resistant clones and then to restore sensitivity to TKI by promoting the re-emergence of clones with a targetable mutation (20). This principle was well described in the study by Ichihara et al who retrospectively studied the rechallenge of osimertinib after chemotherapy treatment in 15 patients who relapsed after osimertinib.…”

Tracking and tackling the tumor dynamics clonal evolution: osimertinib rechallenge after interval therapy might be an effective treatment approach in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC)

“…Recently, a case report was published in 2020 in Journal of Thoracic Disease by Song et al which best exemplified the latter concept (12). It reported on an EGFR exon 21 L858R-mutated patient who benefitted from osimertinib administered following the sequence of the EGFR-TKI icotinib and platinum-doublet chemotherapy.…”