title: First-line treatment of EGFR-mutated nonsmall cell lung cancer: critical review on study methodology.
abstract: Recent advances in understanding the mechanisms of nonsmall cell lung cancer (NSCLC) has led to the development of targeted treatments, including the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib, and the irreversible ErbB family blocker afatinib. Several important activating EGFR mutations have now been identified, which correlate strongly with response to treatment with these agents. Multiple randomised controlled trials have confirmed the association between the presence of activating EGFR mutations and objective response to gefitinib, erlotinib and afatinib, thus demonstrating their superiority over platinum-based chemotherapy as first-line treatment for NSCLC patients with EGFR mutation-positive tumours, and resulting in approval of these agents for use in this setting. It can be tempting to compare outcome data across multiple clinical trials and agents; however, substantial differences in methodology between studies, including investigator versus independent assessment and differences in patient eligibility, makes such comparisons fraught with difficulty. This critical review provides an overview of the evolution of the methodology used in eight phase III trials investigating first-line targeted treatment of NSCLC, identifies key differences in methodology and reporting, and critically assesses how these differences should be taken into account when interpreting the findings from such trials.
authors.affiliation: Dept of Hematology/Oncology, University Hospital Frankfurt, Frankfurt, 2 Hematology, Oncology, Infectious Diseases, Aerzteforum Seestrasse, Medizinisches Versorgungszentrum, Berlin, and 3 LungClinic Grosshansdorf, Member of the German Centre for Lung Research (DZL), Grosshansdorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Sebastian
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmittel
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019317:Evidence-Based Medicine; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D058990:Molecular Targeted Therapy; D009154:Mutation; D018579:Patient Selection; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D012107:Research Design; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors