title: Rationale and study design of the IRENE-trial (NVALT-16): a phase II trial to evaluate iressa rechallenge in advanced NSCLC patients with an activating EGFR mutation who responded to an EGFR-TKI used as first-line or previous treatment.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown improved progression-free survival (PFS) and overall survival (OS) over chemotherapy in a molecularly defined subgroup of advanced non-small-cell lung cancer (NSCLC) patients (ie, patients with an activating mutation in the EGFR gene). Nevertheless, all EGFR-mutated NSCLC patients develop TKI resistance eventually and there is no registered treatment or therapeutic strategy available for these patients. Several retrospective or small cohort studies have described patients who re-responded to EGFR-TKI treatment after a TKI-free interval ('drug holiday'). To date, no large prospective evaluation of the clinical effects of EGFR-TKI rechallenge in EGFR-mutated NSCLC patients has been performed.
  
  
  METHODS
  The IRENE (Iressa RE-challenge in advanced, EGFR-mutated NSCLC patients who responded to an EGFR-TKI used as first-line or previous treatment) (Dutch association for pulmonologists [NVALT]-16) trial is a multicenter, open-label, single-arm, single-stage, phase II study to evaluate gefitinib rechallenge in EGFR-mutated NSCLC patients who were previously treated with a TKI followed by a subsequent line of treatment (excluding EGFR-TKIs). The primary objective is disease control rate according to Response Evaluation Criteria in Solid Tumors criteria. Secondary objectives are objective response rate, PFS, OS, mutation characterization of sequential biopsies, VeriStrat correlation to PFS and OS, analysis of tumor-derived RNA in blood platelets and analysis of cell-free DNA in blood plasma.
  
  
  RESULTS
  The IRENE (NVALT-16) trial will evaluate the safety, efficacy, and feasibility of readministration of gefitinib after an EGFR-TKI-free interval in EGFR-mutated NSCLC patients.
  
  
  CONCLUSIONS
  The study will evaluate gefitinib re-challenge in EGFR-mutated NSCLC patients. The study will also provide more insight into the dynamic development of molecular characteristics of EGFR-mutated NSCLC along the course of the disease.
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: jl.kuiper@vumc.nl.
authors.forename: Justine L
authors.initials: JL
authors.lastname: Kuiper
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Danielle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; ThromboDX BV, Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Würdinger
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Katrien
authors.initials: K
authors.lastname: Grünberg
authors.affiliation: Department of Pulmonary Diseases, University Medical Center of Groningen, Groningen, The Netherlands.
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
mesh_terms: D024221:Antineoplastic Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D009154:Mutation / Q000235:genetics; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D012107:Research Design; D016019:Survival Analysis; D028761:Withholding Treatment
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Drug holiday; EGFR; NSCLC; TKI; TKI-resistance