title: Should Tyrosine Kinase Inhibitors Be Considered for Advanced Non-Small-Cell Lung Cancer Patients With Wild Type EGFR? Two Systematic Reviews and Meta-Analyses of Randomized Trials.
abstract: Guidance concerning tyrosine kinase inhibitors (TKIs) for patients with wild type epidermal growth factor receptor (EGFR) and advanced non-small-cell lung cancer (NSCLC) after first-line treatment is unclear. We assessed the effect of TKIs as second-line therapy and maintenance therapy after first-line chemotherapy in two systematic reviews and meta-analyses, focusing on patients without EGFR mutations. Systematic searches were completed and data extracted from eligible randomized controlled trials. Three analytical approaches were used to maximize available data. Fourteen trials of second-line treatment (4388 patients) were included. Results showed the effect of TKIs on progression-free survival (PFS) depended on EGFR status (interaction hazard ratio [HR], 2.69; P = .004). Chemotherapy benefited patients with wild type EGFR (HR, 1.31; P < .0001), TKIs benefited patients with mutations (HR, 0.34; P = .0002). Based on 12 trials (85% of randomized patients) the benefits of TKIs on PFS decreased with increasing proportions of patients with wild type EGFR (P = .014). Six trials of maintenance therapy (2697 patients) were included. Results showed that although the effect of TKIs on PFS depended on EGFR status (interaction HR, 3.58; P < .0001), all benefited from TKIs (wild type EGFR: HR, 0.82; P = .01; mutated EGFR: HR, 0.24; P < .0001). There was a suggestion that benefits of TKIs on PFS decreased with increasing proportions of patients with wild type EGFR (P = .11). Chemotherapy should be standard second-line treatment for patients with advanced NSCLC and wild type EGFR. TKIs might be unsuitable for unselected patients. TKIs appear to benefit all patients compared with no active treatment as maintenance treatment, however, direct comparisons with chemotherapy are needed.
authors.affiliation: MRC Clinical Trials Unit at UCL, London, United Kingdom. Electronic address: Claire.Vale@ucl.ac.uk.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Vale
authors.affiliation: MRC Clinical Trials Unit at UCL, London, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Burdett
authors.affiliation: MRC Clinical Trials Unit at UCL, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Fisher
authors.affiliation: Department of Thoracic Medicine, University College London Hospital, London, United Kingdom.
authors.forename: Neal
authors.initials: N
authors.lastname: Navani
authors.affiliation: MRC Clinical Trials Unit at UCL, London, United Kingdom.
authors.forename: Mahesh K B
authors.initials: MK
authors.lastname: Parmar
authors.affiliation: MRC Clinical Trials Unit at UCL, London, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Copas
authors.affiliation: MRC Clinical Trials Unit at UCL, London, United Kingdom.
authors.forename: Jayne F
authors.initials: JF
authors.lastname: Tierney
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases
keywords: Chemotherapy; Meta-analysis; NSCLC; RCT; TKI