title: A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma.
abstract: OBJECTIVE
  The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy.
  
  
  METHODS
  Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0-2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines.
  
  
  RESULTS
  Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ≥ 3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression.
  
  
  CONCLUSIONS
  The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted.
authors: Department of Internal Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh, PA, USA. baumanje@upmc.edu
authors: Julie E
authors: JE
authors: Bauman
authors: Hugo
authors: H
authors: Arias-Pulido
authors: Sang-Joon
authors: SJ
authors: Lee
authors: M Houman
authors: MH
authors: Fekrazad
authors: Hiroyuki
authors: H
authors: Ozawa
authors: Elana
authors: E
authors: Fertig
authors: Jason
authors: J
authors: Howard
authors: Justin
authors: J
authors: Bishop
authors: Hao
authors: H
authors: Wang
authors: Garth T
authors: GT
authors: Olson
authors: Michael J
authors: MJ
authors: Spafford
authors: Dennie V
authors: DV
authors: Jones
authors: Christine H
authors: CH
authors: Chung
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000556:secondary; D058534:Class I Phosphatidylinositol 3-Kinases; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D051058:Oncogene Protein v-akt / Q000032:analysis; D051059:PTEN Phosphohydrolase / Q000032:analysis; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis / Q000235:genetics; D010984:Platinum; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D019893:Ribosomal Protein S6 Kinases / Q000032:analysis; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D025521:Tumor Suppressor Proteins / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016207:Cytokines; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010984:Platinum; D047428:Protein Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C401859:temsirolimus; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C494929:PTEN protein, human; C501009:HRAS protein, human
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