title: Phase II clinical and exploratory biomarker study of dacomitinib in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck.
abstract: OBJECTIVE
  The goals of this study were to investigate the clinical activity, safety, and biomarkers of dacomitinib, an irreversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, in recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN).
  
  
  METHODS
  Patients were eligible if the diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, and were treated with dacomitinib 45 mg/day. The primary endpoint was objective response rate by RECISTv1.1. Exploratory analysis included the characterization of somatic mutation, gene copy number, gene expression, p16(INK4A) expression by IHC, and investigation of their relationship with clinical outcomes.
  
  
  RESULTS
  Forty-eight patients were evaluable for efficacy and toxicity. Ten patients (20.8%) had partial responses and 31 patients (65%) had stable diseases. The median progression-free survival (PFS) and overall survival (OS) were 3.9 months [95% confidence interval (CI), 2.9-5.0] and 6.6 months (95% CI, 5.4-10.3). Adverse events were mostly grade 1-2. Mutations in the PI3K pathway (PIK3CA, PTEN) and high expression of inflammatory cytokines (IL6, IL8, IL1A, IL1B, IL4, and TNF) were significantly associated with shorter PFS (2.9 vs. 4.9 months without mutations, P = 0.013; 2.8 vs. 9.9 months with low expression, P = 0.004). Those harboring PI3K pathway mutations or high inflammatory cytokine expression had shorter median OS (6.1 vs. 12.5 months lacking PI3K pathway mutations and with low inflammatory cytokine expression, P = 0.005).
  
  
  CONCLUSIONS
  Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-SCCHN patients. Screening of PI3K pathway mutation and inflammatory cytokine expression may help identify which R/M-SCCHN patients are likely to gain benefit from dacomitinib.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Seoul, Korea. Department of Pharmacology, Pharmacogenomic Research Center for Membrane Transporters, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea.
authors.forename: Han Sang
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyeong Ju
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Department of Biostatistics, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Inkyung
authors.initials: I
authors.lastname: Jung
authors.affiliation: JE UK Institute for Cancer Research, Gumi City, Kyungbuk, Korea.
authors.forename: Mi Ran
authors.initials: MR
authors.lastname: Yun
authors.affiliation: Samsung Medical Center, Seoul, Korea.
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
authors.affiliation: Kyungpook National University Hospital, Daegu, Korea.
authors.forename: Byung Woog
authors.initials: BW
authors.lastname: Kang
authors.affiliation: Samsung Medical Center, Seoul, Korea.
authors.forename: Jong-Mu
authors.initials: JM
authors.lastname: Sun
authors.affiliation: Asan Medical Center, Seoul, Korea.
authors.forename: Sung Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Asan Medical Center, Seoul, Korea.
authors.forename: Dok-Hyun
authors.initials: DH
authors.lastname: Yoon
authors.affiliation: Keimyung University, Daegu, Korea.
authors.forename: Keon Uk
authors.initials: KU
authors.lastname: Park
authors.affiliation: Seoul National University Hospital, Seoul, Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Yoon Woo
authors.initials: YW
authors.lastname: Koh
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Se Hun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Eun Chang
authors.initials: EC
authors.lastname: Choi
authors.affiliation: Division of Hematology/Oncology, Kangbuk Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Dong Hoe
authors.initials: DH
authors.lastname: Koo
authors.affiliation: Department of Pathology, Kangbuk Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Sohn
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
authors.forename: Bomi
authors.initials: B
authors.lastname: Kim
authors.affiliation: Macrogen Inc., Seoul, Korea.
authors.forename: Nak-Jung
authors.initials: NJ
authors.lastname: Kwon
authors.affiliation: Department of Hematology-Oncology, Chungnam National University, Daejeon, Korea.
authors.forename: Hwan Jung
authors.initials: HJ
authors.lastname: Yun
authors.affiliation: Department of Pharmacology, Pharmacogenomic Research Center for Membrane Transporters, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea.
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.affiliation: Department of Oral Biology, College of Dentistry, Yonsei University, Seoul, Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Tae-Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Seoul, Korea.
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Seoul, Korea.
authors.forename: Joo Hang
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Pathology NSABP, Pittsburgh, Pennsylvania. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Soonmyung
authors.initials: S
authors.lastname: Paik
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Seoul, Korea. cbc1971@yuhs.ac.
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D016000:Cluster Analysis; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D052999:Quinazolinones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019233:Retreatment; D012307:Risk Factors; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D052999:Quinazolinones; C525726:dacomitinib