title: Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily.
  
  
  RESULTS
  One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib.
  
  
  CONCLUSIONS
  Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants.
authors: Winship Cancer Institute, Emory University, 1365 Clifton Rd NE, Suite C-3090, Atlanta, GA 30322, USA. suresh.ramalingam@emory.edu
authors: Suresh S
authors: SS
authors: Ramalingam
authors: Fiona
authors: F
authors: Blackhall
authors: Maciej
authors: M
authors: Krzakowski
authors: Carlos H
authors: CH
authors: Barrios
authors: Keunchil
authors: K
authors: Park
authors: Isabel
authors: I
authors: Bover
authors: Dae
authors: D
authors: Seog Heo
authors: Rafael
authors: R
authors: Rosell
authors: Denis C
authors: DC
authors: Talbot
authors: Richard
authors: R
authors: Frank
authors: Stephen P
authors: SP
authors: Letrent
authors: Ana
authors: A
authors: Ruiz-Garcia
authors: Ian
authors: I
authors: Taylor
authors: Jane Q
authors: JQ
authors: Liang
authors: Alicyn K
authors: AK
authors: Campbell
authors: Joseph
authors: J
authors: O'Connell
authors: Michael
authors: M
authors: Boyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D052999:Quinazolinones / Q000009:adverse effects / Q000627:therapeutic use*; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D052999:Quinazolinones; C525726:dacomitinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins