title: A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study.
abstract: BACKGROUND
  The aim of the present study was to evaluate the clinical activity of imatinib mesylate in patients with recurrent and refractory c-kit-expressing small-cell lung cancer.
  
  
  METHODS
  Patients with c-kit-expressing SCLC (> or =1+ by immunohistochemistry) were enrolled in two groups. Arm A included patients with disease progression <3 months and arm B included patients with disease progression > or =3 months after previous treatment. Imatinib was administered at a dose of 400 mg b.i.d. continuously, with a cycle length of 28 days. A single stage Simon design with a planned interim analysis was used to evaluate the 16-week progression free rate in each arm.
  
  
  RESULTS
  A total of 29 evaluable patients were entered into the study (seven in arm A, median age 68; 22 in arm B, median age 64.5). Median number of treatment cycles was one in both arms. Grade 3+ non-hematologic adverse events were seen in 15 (52%) patients, with nausea, vomiting, dyspnea, fatigue, anorexia and dehydration each occurring in at least 10% of patients. Median survival was 3.9 and 5.3 months and median time to progression was 1 and 1.1 months for arms A and B, respectively. Enrollment to arm A was temporarily suspended prior to reaching interim analysis due to striking early disease progression (29%), early deaths (29%) and patient refusal (42%). No objective responses and no confirmed stable disease > or =6 weeks were seen in either arm. Accrual was permanently terminated to both arms as only one patient was progression-free at 16 weeks.
  
  
  CONCLUSIONS
  Imatinib failed to demonstrate any clinical activity in spite of patient selection for c-kit-expressing SCLC. Our results strengthen the collective evidence that prediction of efficacy of novel therapeutic agents based on target expression, rather than pathway activation (for example, through activating mutations), may not be a valid paradigm for drug development.
authors.affiliation: Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
authors.forename: G K
authors.initials: GK
authors.lastname: Dy
authors.forename: A A
authors.initials: AA
authors.lastname: Miller
authors.forename: S J
authors.initials: SJ
authors.lastname: Mandrekar
authors.forename: M-C
authors.initials: MC
authors.lastname: Aubry
authors.forename: R M
authors.initials: RM
authors.lastname: Langdon
authors.forename: R F
authors.initials: RF
authors.lastname: Morton
authors.forename: S E
authors.initials: SE
authors.lastname: Schild
authors.forename: J R
authors.initials: JR
authors.lastname: Jett
authors.forename: A A
authors.initials: AA
authors.lastname: Adjei
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D011446:Prospective Studies; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use*; D016879:Salvage Therapy; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit