EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs

Kobayashi, Yoshihisa; Togashi, Yosuke; Yatabe, Yasushi; Mizuuchi, Hiroshi; Jangchul, Park; Kondo, Chiaki; Shimoji, Masaki; Sato, Katsuaki; Suda, Kenichi; Tomizawa, Kenji; Takemoto, Toshiki; Hida, Toyoaki; Nishio, Kazuto; Mitsudomi, Tetsuya

doi:10.1158/1078-0432.ccr-15-1046

Cited by 183 publications

(191 citation statements)

References 35 publications

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“…Then, we had a total of 134 G719X patients, of which 47 patients responded to 1st generation EGFR-TKIs (Table I). The average RR is 35.1% (47/134), indicating that G719X is a mutation of intermediate sensitivity, which is in accordance with previous reviews (16,44–46) (Table II). …”

Section: Current Studies Of the G719x Mutation In Egfr In Nsclcsupporting

confidence: 92%

“…In addition, Yang et al reviewed patients with the G719X mutation who were treated with afatinib in the LUX-LUNG trial series and found that the overall response rate was 77.8% (14/18) (78). In laboratory studies, the G719A mutation exhibited higher sensitivity than Del19 in terms of both kinase activity and cell viability (16). …”

Section: Discussionmentioning

confidence: 99%

“…To be more quantitative, the 50% inhibiting concentration (IC 50 ) of gefitinib in various mutants was further measured in series of studies. The IC50 of gefitinib in G719S mutants was between that of gefitinib in wild-type cells and Del19/L858R mutants, implying an intermediate sensitivity of G719S (16,52,54,55,57,63). …”

Section: Current Studies Of the G719x Mutation In Egfr In Nsclcmentioning

confidence: 91%

“…Four reviews concerned responses of G719X to TKIs, with response rates of 50–66.7% (16,44–46) (Table II). Still, in these reviews, the numbers of cases were too small to be convincing.…”

Section: Current Studies Of the G719x Mutation In Egfr In Nsclcmentioning

confidence: 99%

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Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution

Yang

Liang

et al. 2017

Oncology Reports

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Mutations in epidermal growth factor receptor (EGFR) play critical roles in the pathogenesis of non-small cell lung cancer (NSCLC), and they are highly associated with sensitivity to tyrosine kinase inhibitors (TKIs). While the pathogenic and pharmacological characteristics of common mutations in EGFR have been thoroughly investigated, those of uncommon mutations remain to be elucidated. Traditional approaches to study common mutations by randomized controlled trials are not feasible for uncommon mutations owing to their rarity. Therefore, by systematically reviewing laboratory and clinical studies of the G719X mutation, one of the uncommon mutations, we concluded that the G719X mutation was intermediately sensitive to TKIs, with an average response rate of 35.1% (47/134). Moreover, accordingly, we proposed a comprehensive model to investigate uncommon mutations in EGFR. The model involves both basic and clinical components, composed of structural analyses, functional alterations, cell viabilities and animal models with various types of clinical studies. In this review, we systematically reviewed studies of the G719X mutation and put forward a research model that could be generalized to explore uncommon mutations in diseases associated with gene mutations.

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Section: Current Studies Of the G719x Mutation In Egfr In Nsclcsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Current Studies Of the G719x Mutation In Egfr In Nsclcmentioning

confidence: 91%

Section: Current Studies Of the G719x Mutation In Egfr In Nsclcmentioning

confidence: 99%

See 2 more Smart Citations

Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution

Yang

Liang

et al. 2017

Oncology Reports

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“…for EGFR exon 18 mutations (20). Indeed, the ORRs to afatinib 40 mg/day seem to be higher than 55% for tumors harboring EGFR-G719X, L861Q or S768I mutations (17).…”

mentioning

confidence: 96%

Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

Costa¹

2016

Transl. Lung Cancer Res.

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Epidermal growth factor receptor (EGFR) mutations were first identified as driver oncogenes in non-small-cell lung cancers (NSCLCs) in 2004 by three separate independent groups (1-3), and originally thought to consistent of only inframe deletions, insertions (i.e., indels) or point mutations within exons 18 to 21 of the kinase domain of EGFR (4). The most abundant EGFR mutations are deletions/indels (around amino-acid residues 747 to 752) of exon 19 (these account for ~45% of all EGFR mutations, with the most common delE746_A750) and the exon 21 point mutation L858R mutation (~35% of all EGFR mutations). Inhibition of mutant EGFR in preclinical models through tyrosine kinase inhibitors (TKIs) unsettles the intracellular signaling cascade, generating cell cycle arrest and apoptosis (5). In the clinic, the 1 st generation EGFR TKIs gefitinib and erlotinib, both reversible ATP mimetics with a favorable therapeutic window in relation to the wild-type (WT) EGFR (4,6), induce overall response rate (ORR), EditorialKinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements that comprehensive molecular profiling may be necessary to maximize the identification of all cases that can benefit from precision oncology.

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Variability of EGFR exon 20 insertions in 24 468 Chinese lung cancer patients and their divergent responses to EGFR inhibitors

Qin

Hong

Tong³

et al. 2020

Molecular Oncology

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EGFR exon 20 insertions (EGFR e20ins) account for up to 10% of EGFR mutations in lung cancer; however, tumors with EGFR e20ins had poor response rates to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, afatinib, and osimertinib, and the heterogeneity of EGFR e20ins further complicates the clinical studies. Here, we retrospectively screened next-generation sequencing (NGS) data from 24 468 lung cancer patients, and a total of 85 unique EGFR e20ins variants were identified in 547 cases (2.24%), with p.A767_V769dup (25.1%) and p.S768_D770dup (17.6%) being the most prevalent ones. Comprehensive genomic profiling revealed that TP53 mutations frequently coexisted with p.H773dup (77.8%, P = 0.0558) and p.A767_V769dup (62.8%, P = 0.0325), while RB1 mutations usually co-occurred with p.H773_V774insAH (33.3%, P = 0.0551), implying that different EGFR e20ins variants might require distinct genomic context for tumorigenesis and/or maintenance. Despite that treatment regimens were highly diverse for EGFR e20ins-positive patients, we observed an overall response rate of 14% and a disease control rate (DCR) of 38.4% in 65 patients who received at least one EGFR TKI. The progression-free survival (PFS) differs significantly in six representative EGFR e20ins variants (P = 0.017), and EGFR p.A763_Y764insF-QEA was associated with better PFS than other EGFR e20ins when treating with various EGFR TKIs. Some EGFR e20ins variants showed at least partial response to first-generation EGFR TKIs, including p.A767_V769dup, p.S768_D770dup, p.N771_H773dup, p.A763_Y764insF-QEA, and p.D770_N771insG. Poziotinib achieved higher DCR for p.S768_D770dup than for p.A767_V769dup, whereas osimertinib showed limited effects for these two insertions when used as the first-line treatment. Overall, our results demonstrated that EGFR e20ins were highly diversified in terms of insertion patterns and co-occurring mutations and these EGFR e20ins variants showed different clinical responses to various EGFR TKIs,

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EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs

Cited by 183 publications

References 35 publications

Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution

Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution

Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

Variability of EGFR exon 20 insertions in 24 468 Chinese lung cancer patients and their divergent responses to EGFR inhibitors

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