title: Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction.
abstract: BACKGROUND
  Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.
  
  
  METHODS
  Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150 mg erlotinib+300 mg dovitinib) and cohort -1 (150 mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.
  
  
  RESULTS
  Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308±698 ng/ml and AUC 0-24 41,030±15,577 ng×h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration.
  
  
  CONCLUSIONS
  This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.
authors.affiliation: Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA; VA Palo Alto Health Care System, Palo Alto, CA.
authors.forename: Millie
authors.initials: M
authors.lastname: Das
authors.affiliation: Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA.
authors.forename: Sukhmani K
authors.initials: SK
authors.lastname: Padda
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, CA.
authors.forename: Adam
authors.initials: A
authors.lastname: Frymoyer
authors.affiliation: Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis School of Medicine, Sacramento, CA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Riess
authors.affiliation: Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA.
authors.forename: Joel W
authors.initials: JW
authors.lastname: Neal
authors.affiliation: Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA. Electronic address: hwakelee@stanford.edu.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Wakelee
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D015363:Quinolones / Q000008:administration & dosage; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D001562:Benzimidazoles; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D000069347:Erlotinib Hydrochloride; D040262:Receptors, Vascular Endothelial Growth Factor; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Dovitinib; Epidermal growth factor receptor (EGFR); Erlotinib; NSCLC; TKI 258