title: Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer.
abstract: BACKGROUND
  Concurrent signal transduction inhibition with the epidermal growth factor receptor (EGFR) inhibitor gefitinib and the mammalian target-of-rapamycin inhibitor everolimus has been hypothesized to result in enhanced antitumor activity in patients with non-small cell lung cancer (NSCLC). This phase II trial assessed the efficacy of the combination of gefitinib and everolimus in patients with advanced NSCLC.
  
  
  METHODS
  Two cohorts of 31 patients with measurable stage IIIB/IV NSCLC were enrolled: (1) no prior chemotherapy and (2) previously treated with cisplatin or carboplatin and docetaxel or pemetrexed. All patients received daily everolimus 5 mg and gefitinib 250 mg. Response was assessed after 1 month and then every 2 months. Pretreatment tumor specimens were collected for mutation testing.
  
  
  RESULTS
  Sixty-two patients were enrolled (median age: 66 years, 50% women, 98% stage IV, all current/former smokers, and 85% adenocarcinoma). Partial responses were seen in 8 of 62 patients (response rate: 13%; 95% confidence interval: 5-21%); five responders had received no prior chemotherapy. Three partial responders had an EGFR mutation. Both patients with a KRAS (G12F) mutation responded. The median time to progression was 4 months. Median overall survival was 12 months, 27 months for no prior chemotherapy patients, and 11 months for patients previously treated with chemotherapy.
  
  
  CONCLUSIONS
  The 13% partial response rate observed did not meet the prespecified response threshold to pursue further study of the combination of gefitinib and everolimus. The response rate in patients with non-EGFR mutant tumors was 8%, likely reflecting activity of everolimus. Further investigation of mammalian target-of-rapamycin inhibitors in patients with NSCLC with KRAS G12F-mutated tumors is warranted.
authors.affiliation: Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York City, New York, USA.
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Price
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Azzoli
authors.forename: Lee M
authors.initials: LM
authors.lastname: Krug
authors.forename: Maria C
authors.initials: MC
authors.lastname: Pietanza
authors.forename: Naiyer A
authors.initials: NA
authors.lastname: Rizvi
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Robert T
authors.initials: RT
authors.lastname: Heelan
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017321:Clinical Trials, Phase I as Topic; D015331:Cohort Studies; D066246:ErbB Receptors / Q000235:genetics; D000068338:Everolimus; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage; D016879:Salvage Therapy; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D015996:Survival Rate; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000068338:Everolimus; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib; D020123:Sirolimus