title: Phase II trial of dasatinib for patients with acquired resistance to treatment with the epidermal growth factor receptor tyrosine kinase inhibitors erlotinib or gefitinib.
abstract: BACKGROUND
  Dual inhibition of SRC- and EGFR-dependent pathways may overcome acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for patients with lung adenocarcinoma with EGFR mutations. The SRC inhibitor dasatinib demonstrates antitumor activity in gefitinib-resistant cells lines and xenografts. Dasatinib is tolerable for patients with advanced non-small cell lung cancer, and in combination with erlotinib.
  
  
  METHODS
  We conducted this phase II study of dasatinib 70 mg twice daily in patients with EGFR-mutant lung adenocarcinoma and acquired resistance to EGFR-TKIs. After a protocol amendment based on evolving data about both drugs, patients received dasatinib at a dose of 100 mg daily with continued erlotinib after developing acquired resistance. Enrolled patients either harbored an activating mutation in EGFR or experienced clinical benefit with single-agent erlotinib or gefitinib, followed by RECIST documented progression while being treated with an EGFR-TKI.
  
  
  RESULTS
  Twenty-one patients were enrolled, 9 under the original trial design and 12 after the protocol amendments. We observed no complete or partial responses (0% observed rate, 95% confidence interval: 0-18%). The median time to progression was 0.5 months (range, 0.2-1.8 months) in patients treated with dasatinib and 0.9 months (range, 0.4-5 months) for patients treated with dasatinib and erlotinib in combination. Pleural effusions and dyspnea were frequent toxicities.
  
  
  CONCLUSIONS
  Dasatinib has no activity in patients with EGFR-mutant lung adenocarcinoma with acquired resistance to erlotinib and gefitinib.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. melissa-johnson@northwestern.edu
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Johnson
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Naiyer A
authors.initials: NA
authors.lastname: Rizvi
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Azzoli
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Camelia S
authors.initials: CS
authors.lastname: Sima
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Ginsberg
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage; D013844:Thiazoles / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D013844:Thiazoles; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000069439:Dasatinib; D000077156:Gefitinib