Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6

Yang, James Chih‐Hsin; Sequist, Lecia V.; Geater, Sarayut Lucien; Tsai, Chun Ming; Mok, Tony; Schüler, Martin; Yamamoto, Nobuyuki; Yu, Chong Jen; Ou, Sai Hong Ignatius; Zhou, Caicun; Massey, Daniel; Zazulina, Victoria; Wu, Yi‐Long

doi:10.1016/s1470-2045(15)00026-1

Cited by 796 publications

(849 citation statements)

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“…However, these mutant EGFRs at the structural and biological level do not have a favorable therapeutic window in relation to WT EGFR. The later realization explains why gefitinib (16), erlotinib (15) and afatinib (17) have limited activity (near 0% ORRs and short PFSs) in EGFR exon 20 insertion mutated NSCLCs (14). Grippingly, near identical exon 20 insertion mutations can be found on the erb-b2 receptor tyrosine kinase 2 (ERBB2) gene and the resulting encoded proteins are also not particularly sensitive to standard dosing schemes of dual EGFR/ERBB2 TKIs (18).…”

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confidence: 99%

“…Certain other clinically-relevant kinase domain EGFR mutations, named by others as uncommon or atypical mutations, seem to be EGFR TKI sensitive in preclinical models (where they are transforming and activate the MAPK/PI3K signaling cascades) and in available published clinical reports (4,16,17). These mutations encompass EGFR-exon 18 indels/E709X (<0.5% of EGFR mutations), exon 18 G719X (~3% of EGFR mutations), exon 19 insertions (<0.5% of EGFR mutations), exon 20 A763_ Y764insFQEA (<0.5% of EGFR mutations), exon 20 S768I (<1.5% of EGFR mutations) and the exon 21 L861Q (~3% of EGFR mutations); either alone or compound with other EGFR mutations (19).…”

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confidence: 99%

“…Indeed, the ORRs to afatinib 40 mg/day seem to be higher than 55% for tumors harboring EGFR-G719X, L861Q or S768I mutations (17). Despite initial rapid and sometimes prolonged responses to gefitinib, erlotinib and afatinib for lung cancers with the aforementioned EGFR TKI-sensitizing mutations, acquired resistance to EGFR TKIs is inevitable for most tumors due to biological (on-target mutations, bypass tracks or histological transformation) and pharmacokinetic mechanisms (24).…”

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confidence: 99%

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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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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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“…Afatinib is the only compound showing a significant OS benefit in the recent pooled analysis of both LuxLung3 (LL3) and LuxLung6 (LL6) trials, even if limited to the subgroup of patients with EGFR exon 19 deletion (Yang et al, 2015a). Furthermore it is the TKI with more evidence-based activity against EGFR uncommon mutations (Yang et al, 2015c). Particularly it showed to be active against the most frequent uncommon mutations, including Gly719Xaa, Leu861Gln, and Ser768Ile, while very low activity has been demonstrated in other mutation types, such as de-novo Thr790Met mutation or insertions in exon 20.…”

Section: Indirect Comparisonsmentioning

confidence: 99%

EGFR inhibition in NSCLC: New findings…. and opened questions?

Passiglia

Listì

Castiglia

et al. 2017

Critical Reviews in Oncology/Hematology

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The targeted inhibition of epidermal growth factor receptor (EGFR) has represented a milestone in the treatment of lung cancer. Several studies convincingly and consistently demonstrated a significant superiority of EGFR-TKIs over standard platinum-chemotherapy in EGFR-mutated NSCLC patients, leading to the sequential approval of gefitinib, erlotinib and afatinib as new standard first-line clinical treatment. To date we are witnessing a second revolution in the management of EGFR-positive NSCLC thanks to the development of new treatment strategies aiming to overcome acquired resistance to TKIs and ultimately improve patients’ outcomes. In this review we summarize the most important recent findings regarding EGFR-inhibition in NSCLC, highlighting the current unsolved questions on the selection of the best TKI in first-line, which therapy can be combined with upfront EGFR-TKIs, how to overcome acquired resistance, and which are the clinical applications of liquid biopsy

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“…For patients with active EGFR mutations, TKIs produced high response rates up to 75% and improved progression-free survival (PFS) to 9-13 months as compared with chemotherapy in randomized trials (4,(9)(10)(11). However, majority of the patients developed acquired drug resistance after initial response to TKI, and the median overall survival in those patients was estimated to 30 months.…”

Section: Historical and Current Perspectives Of Epidermal Growth Factmentioning

confidence: 99%

Management of non-small cell lung cancer with EGFR mutation: the role of radiotherapy in the era of tyrosine kinase inhibitor therapy—opportunities and challenges

Xia

Zhang

2017

J. Thorac. Dis.

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In recent years, the treatment of advanced non-small cell lung cancer (NSCLC) was greatly promoted by the discovery of oncogenic drivers and the development of targeted therapies specific for these drivers. Somatic mutations in epidermal growth factor receptor (EGFR) are the most common type in patients with NSCLC. Small-molecule tyrosine kinase inhibitor (TKI) targeting EGFR produced relatively high response rate and long duration with acceptable toxicity profile. Also, the life expectancy in patients with active EGFR mutation has been significantly prolonged than the past. Additionally, evolution of advanced imaging and radiation techniques has expanded the indications for radiotherapy in complex clinical situation. All of those factors contributed to the widely use of radiotherapy for advanced NSCLC treated with TKI therapy. In this review, we will discuss how to integrate radiotherapy into the comprehensive treatment of patients with TKI therapy in order to maximize the therapeutics effect.

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Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6

Cited by 796 publications

References 64 publications

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

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

EGFR inhibition in NSCLC: New findings…. and opened questions?

Management of non-small cell lung cancer with EGFR mutation: the role of radiotherapy in the era of tyrosine kinase inhibitor therapy—opportunities and challenges

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