title: Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus.
abstract: BACKGROUND
  Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1α levels, which may be a resistance mechanism for bevacizumab.
  
  
  METHODS
  We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus.
  
  
  RESULTS
  The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting ≥ 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD ≥ 6 months in 1/8 (13%) patients (total = 3/8, (38%)).
  
  
  CONCLUSIONS
  The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development.
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Kambrick
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Blumenschein
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Bonnie S
authors.initials: BS
authors.lastname: Glisson
authors.affiliation: Department of Thoracic/Head & Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Merrill S
authors.initials: MS
authors.lastname: Kies
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ralph G
authors.initials: RG
authors.lastname: Zinner
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Division of Hematology and Oncology, University of California San Diego, Moores Cancer Center, San Diego, CA, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D000068818:Cetuximab / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D015996:Survival Rate
chemical_list: D000068258:Bevacizumab; C401859:temsirolimus; D000068818:Cetuximab; D020123:Sirolimus
keywords: bevacizumab; cetuximab; solid tumors; temsirolimus