title: Bexarotene and erlotinib for aerodigestive tract cancer.
abstract: OBJECTIVE
  The epidermal growth factor receptor (EGFR) and cyclin D1 are overexpressed in lung carcinogenesis. The rexinoid, bexarotene, represses cyclin D1 and EGFR expression in vitro. It was hypothesized that combining bexarotene with the EGFR inhibitor, erlotinib, would augment clinical activity.
  
  
  METHODS
  In vitro studies and a phase I clinical trial were performed. Twenty-four patients with advanced aerodigestive tract cancers were enrolled; 79% had non-small-cell lung cancer (NSCLC). The primary objective was to determine the maximum-tolerated dose. Clinical activity was a secondary objective.
  
  
  RESULTS
  Combining erlotinib with bexarotene enhanced growth suppression in vitro compared with each single-agent treatment. This cooperatively repressed cyclin D1 expression. Clinically, the most frequent toxicities were mild hypertriglyceridemia and skin rash. Two serious treatment-related adverse events occurred (creatine phosphokinase elevation attributed to antilipid therapy and a case of generalized pain). Five objective responses (four partial and one minor) were observed in NSCLC patients. Responses were observed in males and smokers. EGFR sequence analyses did not reveal activating mutations in tumors from assessable responding patients. Median time to progression was 2.0 months; overall survival time was 14.1 months; and 1-year survival rate was 73.8%.
  
  
  CONCLUSIONS
  The recommended phase II doses are erlotinib 150 mg/d and bexarotene 400 mg/m2/d orally. These agents can be administered in combination at the recommended single-agent doses without added toxicity. Overall survival and clinical features of responding patients differ from prior reports of single-agent erlotinib treatment. These findings are encouraging and warrant further investigation of this regimen.
authors.affiliation: Hematology/Oncology Section, Department of Medicine, Norris Cotton Cancer Center, Lebanon, NH, USA.
authors.forename: Konstantin H
authors.initials: KH
authors.lastname: Dragnev
authors.forename: W Jeffrey
authors.initials: WJ
authors.lastname: Petty
authors.forename: Sumit
authors.initials: S
authors.lastname: Shah
authors.forename: Adrian
authors.initials: A
authors.lastname: Biddle
authors.forename: Neil B
authors.initials: NB
authors.lastname: Desai
authors.forename: Vincent
authors.initials: V
authors.lastname: Memoli
authors.forename: James R
authors.initials: JR
authors.lastname: Rigas
authors.forename: Ethan
authors.initials: E
authors.lastname: Dmitrovsky
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000077610:Bexarotene; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis; D004067:Digestive System Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D015228:Hypertriglyceridemia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D017422:Sequence Analysis, DNA; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013764:Tetrahydronaphthalenes; D019938:Cyclin D1; D000077610:Bexarotene; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors