title: Safety and efficacy of dacomitinib in korean patients with KRAS wild-type advanced non-small-cell lung cancer refractory to chemotherapy and erlotinib or gefitinib: a phase I/II trial.
abstract: BACKGROUND
  Dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor ([HER]-1/EGFR, HER-2, and HER-4) tyrosine kinase inhibitor, demonstrated antitumor activity in Western patients with non-small-cell lung cancer (NSCLC) at a dose of 45 mg once daily. We report data from a phase I/II, multicenter, open-label study of Korean patients with refractory KRAS wild-type adenocarcinoma NSCLC (defined as patients with evidence of disease progression during or within 6 months of treatment with chemotherapy and gefitinib or erlotinib).
  
  
  METHODS
  The phase I dose-finding portion identified the recommended phase II dose (RP2D) in Korean patients, evaluated safety, and characterized the pharmacokinetics of dacomitinib. In the phase II portion, patients received dacomitinib at the RP2D. The primary end point was progression-free survival at 4 months (PFS4m).
  
  
  RESULTS
  Twelve patients enrolled in phase I, and 43 patients enrolled in phase II at the RP2D of 45 mg once daily. In phase II, PFS4m was 47.2% (95% confidence interval [CI], 31.6-61.3; one-sided p-value = 0.0007). Median PFS was 15.4 weeks (95% CI, 9.7-17.6); median overall survival was 46.3 weeks (95% CI, 32.7-not reached); and the objective response rate was 17.1% (95% CI, 7.2-32.1). Common treatment-related adverse events were dermatitis acneiform, diarrhea, and paronychia; there were no treatment-related grade 4 or 5 adverse events. Pharmacokinetic parameters of dacomitinib in Korean patients were similar to those reported in Western patients. By patient report, NSCLC symptoms "cough" and "pain" showed improvement within 3 weeks of initiating treatment.
  
  
  CONCLUSIONS
  Dacomitinib was well tolerated and had antitumor activity in Korean patients with NSCLC who had previously progressed on chemotherapy and an epidermal growth factor receptor tyrosine kinase inhibitor.
authors.affiliation: *Division of Hematology & Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; †Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea; ‡Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; §Pfizer Korea, Seoul, Republic of Korea; ‖Pfizer Oncology, Groton, Connecticut; ¶Pfizer (China) Research & Development Co. Ltd, Shanghai, China; #Pfizer Oncology, La Jolla, California; and **Pfizer Oncology, New York, New York.
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.forename: Byoung C
authors.initials: BC
authors.lastname: Cho
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
authors.forename: Sang-Yoon
authors.initials: SY
authors.lastname: Lee
authors.forename: Diana
authors.initials: D
authors.lastname: Gernhardt
authors.forename: Ian
authors.initials: I
authors.lastname: Taylor
authors.forename: Alicyn K
authors.initials: AK
authors.lastname: Campbell
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Nagdeep
authors.initials: N
authors.lastname: Giri
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Letrent
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Connell
authors.forename: Dae S
authors.initials: DS
authors.lastname: Heo
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / 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 / Q000494:pharmacology; D052999:Quinazolinones / Q000009:adverse effects / Q000627:therapeutic use*; D056910:Republic of Korea; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D054316:Biomarkers, Pharmacological; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D052999:Quinazolinones; C525726:dacomitinib; D000069347:Erlotinib Hydrochloride; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib