L718Q/V mutation in exon 18 of EGFR mediates resistance to osimertinib: clinical features and treatment

Li, Meihui; Qin, Jing; Xie, Fajun; Gong, Lei; Han, Na; Lu, Hongyang

doi:10.1007/s12672-022-00537-7

Cited by 5 publications

(3 citation statements)

References 24 publications

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“…This result is in line with a previous report that L718Q causes osimertinib resistance in NSCLC regardless of the presence of T790M, possibly due to spatial restrictions and reduced hydrophobic interactions of EGFR with osimertinib 49 . Our finding is also compatible with another previous report that afatinib can be a possible treatment option with modest efficacy in patients harboring the L718Q mutation 15,50 .…”

Section: Maintextsupporting

confidence: 93%

Saturation resistance profiling of EGFR variants against tyrosine kinase inhibitors using prime editing

Kim,

Oh,

Lee

et al. 2023

Preprint

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Variants of uncertain significance (VUS) hamper the clinical application of genetic information. For example, in treating lung cancer with tyrosine kinase inhibitors (TKIs), many epidermal growth factor receptor (EGFR) variants remain classified as VUS with respect to TKI sensitivity1,2. Such incomplete resistance profiles hinder clinicians from selecting optimal therapeutic agents3,4. A high-throughput approach that can evaluate the functional effects of single nucleotide variants (SNVs) could reduce the number of VUS. Here we introduce SynPrime, a method based on prime editing that enabled the generation and functional evaluation of 2,476 SNVs in theEGFRgene, including 99% of all possible variants in the canonical tyrosine kinase domain (exons 18 to 21). We determined resistance profiles of 95% (= 1,726/1,817) of all possible EGFR protein variants encoded in the whole tyrosine kinase domain (exons 18 to 24) against afatinib, osimertinib, and osimertinib in the presence of the co-occurring mutation T790M, in PC-9 cells. SynPrime, which uses direct sequencing of endogenous regions to identify SNVs, provided more accurate functional evaluations than a guide RNA abundance-based approach. Our study has the potential to substantially improve the precision of therapeutic choices in clinical settings and contribute to addressing the issue of VUS by being applied to other genes.

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Section: Maintextsupporting

confidence: 93%

Saturation resistance profiling of EGFR variants against tyrosine kinase inhibitors using prime editing

Kim,

Oh,

Lee

et al. 2023

Preprint

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“…Of note, immunotherapy and TKIs other than afatinib were ineffective in patients with L718Q or L718V and acquired resistance to osimertinib. 22 Another retrospective analysis showed similar results in patients with G724S. In 23 patients treated with afatinib (n = 8) or other treatments (alternative EGFR TKI, chemotherapy, or best supportive care [n = 15]), PFS was significantly higher in the afatinib group (median: 4.5 vs 1.7 months; P = 0.037) including in those patients who previously received osimertinib (median: 6.2 vs 1.0 months; P = 0.005).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Patients with EGFR Mutation-Positive NSCLC Following Emergence of the Osimertinib Resistance Mutations, L718Q or G724S: A Multicenter Retrospective Observational Study in France

Sanchis-Borja,

Guisier,

Swalduz

et al. 2024

OTT

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Purpose The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is an effective first-line therapy for patients with common EGFR mutation-positive non-small cell lung cancer (NSCLC). However, almost all patients become resistant to treatment. In some patients, emergence of tertiary EGFR mutations is implicated as a resistance mechanism. This study describes patients with NSCLC who acquired the rare EGFR mutations, L718Q or G724S, following EGFR TKI treatment. Patients and Methods This was a retrospective, observational study undertaken in France from Feb–Nov 2021, in patients with EGFR mutation-positive NSCLC with an acquired L718Q or G724S mutation. Primary objectives were description of tumor characteristics, progression, and progression under treatment. Results Nine eligible patients were identified. Acquired resistance to initial EGFR TKI treatment was associated with T790M emergence in six patients, who then received osimertinib monotherapy. Overall, eight patients received osimertinib monotherapy treatment at some point (average treatment duration: 18.3 months). Following the emergence of L718Q or G724S, patients received chemotherapy (n = 4; two of whom subsequently received afatinib), nivolumab (n = 2), afatinib (n = 2), or immunochemotherapy (n = 1). In the four patients who received afatinib after identification of L718Q or G724S, 2 achieved a partial response, one had stable disease and one had progressive disease. Treatment duration was 1.6–31.7 months. In patients with controlled disease (n = 3), progression-free survival was 6.1–31.7 months. Two of these patients had previously received osimertinib. Conclusion Currently, there is no consensus regarding the treatment of EGFR mutation-positive NSCLC following emergence of the osimertinib resistance mutations, L718Q or G724S. Afatinib appears to be a promising treatment option in this setting.

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“…One study also included a total of 14 lung cancer patients with the EGFR L718Q/V mutation following osimertinib therapy, 7 of whom received afatinib therapy. Patients receiving afatinib experienced a DCR of 85.7% and an ORR of 42.9% [ 56 ]. This underlines once more how well afatinib works for those with lung cancer who have established osimertinib resistance because of the L718Q/V mutation.…”

Section: Afatinib’s Effectiveness In Curing Various Uncommon Egfr Mut...mentioning

confidence: 99%

Afatinib for the Treatment of NSCLC with Uncommon EGFR Mutations: A Narrative Review

et al. 2023

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Afatinib, the world’s first irreversible ErbB family (containing four different cancer cell epidermal growth factor receptors, including EGFR, HER2, ErbB3, and ErbB4) inhibitor, is a second-generation oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It can be used as a first-line treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) with an EGFR-sensitive mutation or for patients with locally advanced or metastatic squamous lung cancer whose disease progresses during or after platinum-containing chemotherapy. Currently, with the use of third-generation EGFR-TKIs, afatinib is no longer clinically indicated as the first choice for patients with NSCLC who have EGFR-sensitive mutations. However, afatinib showed a considerable inhibitory effect in NSCLC patients with uncommon EGFR mutations (G719X, S768I, and L861Q) according to a combined post hoc analysis of the LUX-Lung2/3/6 trials. With the development of genetic testing technology, the detection rate of uncommon EGFR mutations is increasing. The aim of this paper is to describe in detail the sensitivity of rare EGFR mutations to afatinib and to provide information and a reference for those suffering from advanced NSCLC who have uncommon EGFR mutations.

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L718Q/V mutation in exon 18 of EGFR mediates resistance to osimertinib: clinical features and treatment

Cited by 5 publications

References 24 publications

Saturation resistance profiling of EGFR variants against tyrosine kinase inhibitors using prime editing

Saturation resistance profiling of EGFR variants against tyrosine kinase inhibitors using prime editing

Characterization of Patients with EGFR Mutation-Positive NSCLC Following Emergence of the Osimertinib Resistance Mutations, L718Q or G724S: A Multicenter Retrospective Observational Study in France

Afatinib for the Treatment of NSCLC with Uncommon EGFR Mutations: A Narrative Review

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