title: Pharmacodynamic trial of nimotuzumab in unresectable squamous cell carcinoma of the head and neck: a SENDO Foundation study.
abstract: OBJECTIVE
  To assess the pharmacodynamic effects of nimotuzumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody with intermediate affinity for the receptor, in skin and tumor tissues from head and neck cancer patients.
  
  
  METHODS
  Pharmacodynamic study in patients with advanced squamous cell carcinoma of the head and neck, unsuitable for chemoradiotherapy, enrolled in a single-center trial. Patients received 8 weekly infusions of nimotuzumab. The first nimotuzumab infusion was administered 1 week before starting radiation, whereas the remaining doses were administered concomitantly with irradiation. Paired biopsies were taken from skin and primary tumors, before (pretherapy) and 1 week (on single-agent therapy) after first infusion. Immunohistochemistry was conducted to assay the effects of nimotuzumab on total and phosphorylated EGFR, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), p-AKT, and proliferation (Ki-67).
  
  
  RESULTS
  Nimotuzumab was well tolerated and there was no evidence of skin rash. Objective response was achieved in 9 of 10 patients. The pharmacodynamic assays showed inhibition of p-EGFR in both skin and tumor (P = 0.042 in skin and P = 0.034 in tumor). No significant changes in p-ERK1/2, p-AKT, or Ki-67 were detected in skin. In addition, lymphocytic infiltrates, folliculitis, or perifolliculitis were not observed. In tumor samples, there was an upregulation of p-AKT (P = 0.043), a reduction in proliferation index (P = 0.012), and a nonsignificant trend toward a decrease of p-ERK1/2 (P = 0.091).
  
  
  CONCLUSIONS
  The pharmacodynamic data confirmed the ability of nimotuzumab to decrease EGFR phosphorylation. Downstream effects were observed in tumor cells but not in skin, a finding that may help to explain the lack of skin rash in patients treated with nimotuzumab.
authors.affiliation: Cancer Research Program, IMIM-Hospital del Mar, Barcelona, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.forename: Elías
authors.initials: E
authors.lastname: Gracias
authors.forename: Nadia
authors.initials: N
authors.lastname: Villena
authors.forename: Teresa
authors.initials: T
authors.lastname: Cruz
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Corominas
authors.forename: Irene
authors.initials: I
authors.lastname: Corradino
authors.forename: Mercedes
authors.initials: M
authors.lastname: Cedeño
authors.forename: Clara
authors.initials: C
authors.lastname: Campas
authors.forename: Marta
authors.initials: M
authors.lastname: Osorio
authors.forename: Normando
authors.initials: N
authors.lastname: Iznaga
authors.forename: Beatriz
authors.initials: B
authors.lastname: Bellosillo
authors.forename: Ana
authors.initials: A
authors.lastname: Rovira
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsoni
authors.forename: Pere
authors.initials: P
authors.lastname: Gascon
authors.forename: Sergio
authors.initials: S
authors.lastname: Serrano
authors.forename: Cristiana
authors.initials: C
authors.lastname: Sessa
authors.forename: Tania
authors.initials: T
authors.lastname: Crombet
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C501466:nimotuzumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3