Association of ERBB Mutations With Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients With Lung Squamous Cell Carcinoma Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trial

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dc.contributor.authorGoss, Glenwood D.
dc.contributor.authorFelip, Enriqueta
dc.contributor.authorCobo, Manuel
dc.contributor.authorLu, Shun
dc.contributor.authorSyrigos, Konstantinos
dc.contributor.authorLee, Ki Hyeong
dc.contributor.authorGoker, Erdem
dc.contributor.authorGeorgoulias, Vassilis
dc.contributor.authorLi, Wei
dc.contributor.authorGuclu, Salih
dc.contributor.authorIsla, Dolores
dc.contributor.authorMin, Young Joo
dc.contributor.authorMorabito, Alessandro
dc.contributor.authorArdizzoni, Andrea
dc.contributor.authorGadgeel, Shirish M.
dc.contributor.authorFueloep, Andrea
dc.contributor.authorBuehnemann, Claudia
dc.contributor.authorGibson, Neil
dc.contributor.authorKraemer, Nicole
dc.contributor.authorSolca, Flavio
dc.contributor.authorCseh, Agnieszka
dc.contributor.authorEhrnrooth, Eva
dc.contributor.authorSoria, Jean-Charles
dc.date.accessioned2019-10-27T10:02:48Z
dc.date.available2019-10-27T10:02:48Z
dc.date.issued2018
dc.departmentEge Üniversitesien_US
dc.description.abstractIMPORTANCE Treatment choice for lung squamous cell carcinoma could be aided by identifying predictive biomarkers. OBJECTIVE To assess whether patient outcomes in the LUX-Lung 8 trial were associated with ERBB gene family member aberrations in tumor specimens. DESIGN, SETTING, AND PARTICIPANTS Ad hoc secondary analysis of the LUX-Lung 8 trial conducted at 183 centers in 23 countries from March 30, 2012, to January 30, 2014. Eligible patients had stage IIIB or IV lung squamous cell carcinoma with progressive disease after 4 or more cycles of platinum-based chemotherapy. Tumor genetic analysis (TGA) was performed using next-generation sequencing in a cohort enriched for patients with progression-free survival (PFS) of more than 2 months. Epidermal growth factor receptor (EGFR) expression levels were assessed by immunohistochemistry in a separate cohort of patients from the LUX-Lung 8 population. Associations of PFS and overall survival (OS) with ERBB gene alterations and EGFR expression levels were assessed. This analysis was conducted from February 26, 2015, to June 12, 2017. INTERVENTIONS Patients were randomized 1:1 to treatment with afatinib dimaleate (40mg/d; n = 398) or erlotinib hydrochloride (150mg/d; n = 397). MAIN OUTCOMES AND MEASURES Overall survival, PFS, pooled and individual ERBB gene mutations, ERBB copy number alterations, and EGFR expression. RESULTS Tumor specimens from 245 patients were eligible for next-generation sequencing (TGA subset: 132 patients treated with afatinib; 113 patients treated with erlotinib). In this population, outcomes were improved with afatinib vs erlotinib treatment (PFS: median, 3.5 vs 2.5 months; hazard ratio [HR], 0.69; 95% CI, 0.51-0.92; P = .01; OS: median, 8.4 vs 6.6 months; HR, 0.81; 95% CI, 0.62-1.05; P = .12). Of 245 patients in the TGA subset, 53 (21.6%) had tumors with 1 or more ERBB mutations. Among afatinib-treated patients, PFS (median, 4.9 vs 3.0 months; HR, 0.62; 95% CI, 0.37-1.02; P = .06) and OS (median, 10.6 vs 8.1 months; HR, 0.75; 95% CI, 0.47-1.17; P = .21) were longer among those with ERBB mutation-positive disease than among those without. The presence of HER2 mutations was associated with favorable PFS and OS following afatinib vs erlotinib treatment. There was no apparent association between copy number alteration or EGFR expression level and outcome. CONCLUSIONS AND RELEVANCE Next-generation sequencingmay help identify patients with lung squamous cell carcinoma who would derive additional benefit from treatment with afatinib. The role of ERBB mutations, particularly HER2 mutations, as predictive biomarkers for afatinib treatment in this setting warrants further evaluation.en_US
dc.description.sponsorshipBoehringer IngelheimBoehringer Ingelheimen_US
dc.description.sponsorshipThis study was funded by Boehringer Ingelheim.en_US
dc.identifier.doi10.1001/jamaoncol.2018.0775en_US
dc.identifier.endpage1197en_US
dc.identifier.issn2374-2437
dc.identifier.issn2374-2445
dc.identifier.issue9en_US
dc.identifier.pmid29902295en_US
dc.identifier.startpage1189en_US
dc.identifier.urihttps://doi.org/10.1001/jamaoncol.2018.0775
dc.identifier.urihttps://hdl.handle.net/11454/30039
dc.identifier.volume4en_US
dc.identifier.wosWOS:000444765300010en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAmer Medical Assocen_US
dc.relation.ispartofJama Oncologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleAssociation of ERBB Mutations With Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients With Lung Squamous Cell Carcinoma Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trialen_US
dc.typeArticleen_US

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