title: Everolimus and erlotinib as second- or third-line therapy in patients with advanced non-small-cell lung cancer.
abstract: BACKGROUND
  The epidermal growth factor receptor inhibitor erlotinib is an approved treatment for chemotherapy-refractory advanced non-small-cell lung cancer (NSCLC). Because activated epidermal growth factor receptor signals through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, adding the oral mTOR inhibitor everolimus to erlotinib may improve efficacy by blocking multiple components of the same pathway. We conducted a phase I study to determine feasible dosages of combination therapy with erlotinib and everolimus for previously treated metastatic or unresectable NSCLC.
  
  
  METHODS
  Participants had advanced NSCLC progressing after two or less previous chemotherapy regimens. Feasibility of daily/weekly everolimus plus daily erlotinib was determined using a 6 + 6 dose-escalation design based on the rate of dose-limiting toxicities. Antitumor activity was assessed by the Response Evaluation Criteria In Solid Tumors study.
  
  
  RESULTS
  Of the 94 patients enrolled, 90% had stage IV NSCLC, 19% never smoked, and 15% were current smokers. Eighty-nine patients experienced one or more adverse events possibly related to any study medication. The most common dose-limiting toxicities were stomatitis (n = 5), rash (n = 4), and diarrhea (n = 3). Maximum tolerated doses were everolimus 5 mg per day or 50 mg per week plus erlotinib 150 mg per day. In daily everolimus cohorts (n = 74), nine patients achieved a complete/partial response and 28 had stable disease (median duration disease control, 9.3 months). In weekly everolimus cohorts (n = 20), no tumor response was observed; seven patients had stable disease (median duration, 9.6 months).
  
  
  CONCLUSIONS
  Combination therapy with everolimus 5 mg per day or 50 mg per week and erlotinib 150 mg per day provided acceptable tolerability and disease control. A randomized phase II study evaluating this combination in comparison with erlotinib alone is complete and is being analyzed.
authors.affiliation: University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA. vpapadim@ mdanderson.org
authors.forename: Vassiliki A
authors.initials: VA
authors.lastname: Papadimitrakopoulou
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Annette
authors.initials: A
authors.lastname: Jappe
authors.forename: Valentine
authors.initials: V
authors.lastname: Jehl
authors.forename: Judith
authors.initials: J
authors.lastname: Klimovsky
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018287:Carcinoma, Large Cell / Q000188:drug therapy* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D015331:Cohort Studies; D000069347:Erlotinib Hydrochloride; D000068338:Everolimus; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D014018:Tissue Distribution
chemical_list: D011799:Quinazolines; D000068338:Everolimus; D000069347:Erlotinib Hydrochloride; D020123:Sirolimus