title: Phase I/II Study of HSP90 Inhibitor AUY922 and Erlotinib for EGFR-Mutant Lung Cancer With Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.
abstract: OBJECTIVE
  AUY922 is an HSP90 inhibitor that causes degradation of HSP chaperones and their client proteins, including epidermal growth factor receptor. We conducted a phase I/II trial to evaluate AUY922 and erlotinib for patients with EGFR-mutant lung cancer and disease progression during erlotinib treatment.
  
  
  METHODS
  All patients had developed acquired resistance after treatment with erlotinib and underwent repeat tumor biopsies before study entry to assess for EGFR T790M. In phase I, 18 patients were treated with AUY922 intravenously once per week and erlotinib once per day in 28-day cycles using a 3 + 3 dose-escalation design. In phase II, 19 additional patients were treated at the maximum-tolerated dose. The primary end point of the phase II trial was complete plus partial response rate.
  
  
  RESULTS
  In phase I (n = 18), three patients were treated in each cohort, except the highest-dose cohort (AUY922 70 mg and erlotinib 150 mg), which expanded to six patients because of a dose-limiting toxicity (ie, junctional cardiac rhythm). Common drug-related adverse events were diarrhea, skin rash, hyperglycemia, and night blindness. All patients treated at maximum-tolerated dose (n = 25) were evaluable for response. The partial response rate was 16% (four of 25 patients; 95% CI, 5% to 36%) and was independent of tumor T790M status.
  
  
  CONCLUSIONS
  Partial responses were observed, but the duration of treatment with AUY922 and erlotinib was limited by toxicities, especially night blindness. This phase II study of AUY922 and erlotinib did not meet its primary end point.
authors: Melissa L. Johnson, Jyoti D. Patel, Eric M. Hart, Bing Bing Weitner, and Alfred W. Rademaker, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL; and Helena A. Yu, Mark G. Kris, and Gregory J. Riely, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY. meljohn22@hotmail.com.
authors: Melissa L
authors: ML
authors: Johnson
authors: Melissa L. Johnson, Jyoti D. Patel, Eric M. Hart, Bing Bing Weitner, and Alfred W. Rademaker, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL; and Helena A. Yu, Mark G. Kris, and Gregory J. Riely, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
authors: Helena A
authors: HA
authors: Yu
authors: Melissa L. Johnson, Jyoti D. Patel, Eric M. Hart, Bing Bing Weitner, and Alfred W. Rademaker, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL; and Helena A. Yu, Mark G. Kris, and Gregory J. Riely, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
authors: Eric M
authors: EM
authors: Hart
authors: Melissa L. Johnson, Jyoti D. Patel, Eric M. Hart, Bing Bing Weitner, and Alfred W. Rademaker, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL; and Helena A. Yu, Mark G. Kris, and Gregory J. Riely, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
authors: Bing Bing
authors: BB
authors: Weitner
authors: Melissa L. Johnson, Jyoti D. Patel, Eric M. Hart, Bing Bing Weitner, and Alfred W. Rademaker, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL; and Helena A. Yu, Mark G. Kris, and Gregory J. Riely, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
authors: Alfred W
authors: AW
authors: Rademaker
authors: Melissa L. Johnson, Jyoti D. Patel, Eric M. Hart, Bing Bing Weitner, and Alfred W. Rademaker, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL; and Helena A. Yu, Mark G. Kris, and Gregory J. Riely, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
authors: Jyoti D
authors: JD
authors: Patel
authors: Melissa L. Johnson, Jyoti D. Patel, Eric M. Hart, Bing Bing Weitner, and Alfred W. Rademaker, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL; and Helena A. Yu, Mark G. Kris, and Gregory J. Riely, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
authors: Mark G
authors: MG
authors: Kris
authors: Melissa L. Johnson, Jyoti D. Patel, Eric M. Hart, Bing Bing Weitner, and Alfred W. Rademaker, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL; and Helena A. Yu, Mark G. Kris, and Gregory J. Riely, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
authors: Gregory J
authors: GJ
authors: Riely
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001706:Biopsy; D015331:Cohort Studies; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018832:Molecular Chaperones / Q000737:chemistry; D009154:Mutation; D011799:Quinazolines / Q000008:administration & dosage*; D012118:Resorcinols / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D018832:Molecular Chaperones; D011799:Quinazolines; D012118:Resorcinols; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors