title: Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab.
  
  
  METHODS
  Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913.
  
  
  RESULTS
  In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7.1 months (95% CI 5.7-9.0) and 4.1 months (2.8-4.4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0.704 vs 0.386, p=0.036 and 0.949 vs 0.332, p=0.036, respectively) and tumour shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 patients with available tissue.
  
  
  CONCLUSIONS
  The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA; University of Chicago Cancer Research Center, Chicago, IL, USA.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.forename: Darren W
authors.initials: DW
authors.lastname: Davis
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Karrison
authors.forename: Tanguy Y
authors.initials: TY
authors.lastname: Seiwert
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Wong
authors.forename: Sreenivasa
authors.initials: S
authors.lastname: Nattam
authors.forename: Mark F
authors.initials: MF
authors.lastname: Kozloff
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Clark
authors.forename: Duen-Hwa
authors.initials: DH
authors.lastname: Yan
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Carolyn
authors.initials: C
authors.lastname: Pierce
authors.forename: Janet E
authors.initials: JE
authors.lastname: Dancey
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stenson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blair
authors.forename: Allison
authors.initials: A
authors.lastname: Dekker
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000401:mortality; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D012044:Regression Analysis; D016211:Transforming Growth Factor alpha / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; D016211:Transforming Growth Factor alpha; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2