title: Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma.
abstract: BACKGROUND
  Enhanced phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key adaptive changes accounting for epidermal growth factor receptor (EGFR) inhibitor-resistant growth in head and neck squamous cell carcinoma (HNSCC). We designed a phase II clinical trial of EGFR tyrosine kinase inhibitor (TKI), erlotinib, in association with the mTOR inhibitor, everolimus, based on the hypothesis that the downstream effects of Akt through inhibition of mTOR may enhance the effectiveness of the EGFR-TKI in patients with recurrent/metastatic HNSCC.
  
  
  METHODS
  Patients with histologically or cytologically confirmed platinum-resistant HNSCC received everolimus 5 mg and erlotinib 150 mg daily orally until disease progression, intolerable toxicity, investigator or patient decision. Cytokines and angiogenic factors profile, limited mutation analysis and p16 immunohistochemistry status were included in the biomarker analysis.
  
  
  RESULTS
  Of the 35 assessable patients, 3 (8%) achieved partial response at 4 weeks, 1 confirmed at 12 weeks; overall response rate at 12 weeks was 2.8%. Twenty-seven (77%) patients achieved disease stabilization at 4 weeks, 11 (31%) confirmed at 12 weeks. Twelve-week progression-free survival (PFS) was 49%, median PFS 11.9 weeks and median overall survival (OS) 10.25 months. High neutrophil gelatinase lipocalin (P = 0.01) and vascular endothelial growth factor (VEGF) (P = 0.04) plasma levels were significantly associated with worse OS.
  
  
  CONCLUSIONS
  The combination of erlotinib and everolimus did not show significant benefit in unselected patients with platinum-resistant metastatic HNSCC despite a manageable toxicity profile. Markers of tumor invasion and hypoxia identify a group of patients with particularly poor prognosis.
  
  
  BACKGROUND
  NCT00942734.
authors.affiliation: Departments of Thoracic Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: E
authors.initials: E
authors.lastname: Massarelli
authors.affiliation: Biostatistics, Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: H
authors.initials: H
authors.lastname: Lin
authors.affiliation: Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Ginsberg
authors.affiliation: Departments of Thoracic Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: H T
authors.initials: HT
authors.lastname: Tran
authors.affiliation: Biostatistics, Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Canales
authors.affiliation: Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Williams
authors.affiliation: Departments of Thoracic Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Blumenschein
authors.affiliation: Departments of Thoracic Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lu
authors.affiliation: Departments of Thoracic Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: J V
authors.initials: JV
authors.lastname: Heymach
authors.affiliation: Departments of Thoracic Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Kies
authors.affiliation: Departments of Thoracic Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, USA vpapadim@mdanderson.org.
authors.forename: V
authors.initials: V
authors.lastname: Papadimitrakopoulou
mesh_terms: D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D000068338:Everolimus / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D010984:Platinum / Q000008:administration & dosage; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate
chemical_list: D010984:Platinum; D000068338:Everolimus; D000069347:Erlotinib Hydrochloride
keywords: EGFR inhibitors; HNSCC; erlotinib; everolimus; mTOR inhibitors