Treatment of uncommon EGFR mutations in non-small cell lung cancer: new evidence and treatment

Abstract

Sensitizing mutations in epidermal growth factor receptor (EGFR) are associated with positive responses to anti-EGFR-targeted therapy, leading to a new era of treatment for non-small cell lung cancer (NSCLC). Exon 19 deletions and exon 21 L858R substitutions are the most common mutations, accounting for approximately 90% mutations in NSCLC; these are termed classic mutations and result in high sensitivity to tyrosine kinase inhibitors (TKIs). Other EGFR mutations are termed uncommon EGFR mutations, of which G719X, S768I, L861Q, exon 20 insertions, and complex mutations are the most frequent. G719X, S768I, and L861Q are point mutations and those that exist with complex mutations are sensitive to firstgeneration TKIs. A prospective analysis demonstrated that afatinib, a second-generation TKI, led to a better prognosis in some patients with NSCLC compared to first-generation TKIs. Chemotherapy used to be the traditional choice for patients carrying exon 20 insertions; however, with the development of novel targeted drugs, the role of chemotherapy is changing. Tremendous progress has also been made in clinical trials on immunotherapy treatment of uncommon EGFR mutations. The treatment for patients with NSCLC harboring uncommon EGFR mutations remains a subject of debate and the sensitivity of uncommon EGFR mutations to TKIs is still unclear. Here, we summarized recent data in the literature and provide an overview of the clinical characteristics, incidence, and outcomes of patients harboring G719X, S768I, L861Q, exon 20 insertions, and complex mutations who were treated with TKIs, chemotherapy, or immunotherapy.

The effectiveness of afatinib in patients with lung adenocarcinoma harboring complex epidermal growth factor receptor mutation

“…In contrast, the first-generation EGFR TKIs gefitinib and erlotinib have shown inconsistent responses in patients with uncommon EGFR mutations. 32 – 35 In in vitro studies, afatinib had a lower half-maximal inhibitory concentration (IC 50 ) in Ba/F3 cell lines transfected with S768I or G719X mutations than first-generation EGFR TKIs. 36 , 37 Afatinib also had a lower IC 50 in Ba/F3 cells transfected with the complex EGFR mutations L858R + L747P, L858R + D761Y, and L858R + T854A than gefitinib and erlotinib.…”

The Role of c-Met as a Biomarker and Player in Innate and Acquired Resistance in Non-Small-Cell Lung Cancer: Two New Mutations Warrant Further Studies

“…With regards to EGFR-targeted agents, exon 19 deletions and exon 21 L858R substitutions, termed classic mutations, represent the most common genetic alterations, accounting for approximately 90% mutations in NSCLC adenocarcinomas and resulting in a high sensitivity to the first generation of EGFR-TKIs [1]. Conversely, other uncommon EGFR mutations, including G719X, S768I, L861Q, exon 20 insertions and complex mutations, are able to determine more efficient responses to second-and third-generation TKIs compared to first-generation ones and have been the target of various drugs (i.e., poziotinib) [32,33].…”

Excellent response to erlotinib in breast carcinoma with rare EGFR mutation—a case report

“…As a last resort, RTPCR for EGFR mutation analysis was carried out and it showed Exon 21 L861Q mutation positivity. The case could be narrowed down to two close differential diagnoses that is, either a metastatic breast carcinoma or a second primary in the lung as Exon 21 L861Q is also a well-known, but uncommon lung cancer mutation that confers sensitivity to TKIs [12]. Exon 21 L861Q mutation is known to activate the receptor tyrosine kinase and growth factor signalling pathway.…”