title: Phase II trial of everolimus in patients with refractory metastatic adenocarcinoma of the esophagus, gastroesophageal junction and stomach: possible role for predictive biomarkers.
abstract: OBJECTIVE
  Our study was designed to evaluate the efficacy and safety of everolimus in patients with pre-treated metastatic gastric and esophagus cancers in a US-based population focusing on biomarker correlation.
  
  
  METHODS
  Patients with advanced upper GI adenocarcinomas who progressed after 1-2 prior regimens received everolimus 10 mg PO daily. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression-free survival (PFS), toxicity, overall survival (OS) and biomarker correlatives of the mTOR pathway. Target accrual was 50 patients based on one-sided type I error of 10 % and power of 90 %.
  
  
  RESULTS
  Forty-five patients were evaluable, 21 gastric, 11 esophagus and 13 from the GEJ. The median age was 64 (range 38-73); all patients had an ECOG of 0 or 1; and 18 patients (40 %) had only 1 prior regimen. The most common grade 3-4 adverse events included fatigue (24 %) and thrombocytopenia (22 %). We observed 1 partial response with 39 % of evaluable patients having stable disease. Median OS was 3.4 months (95 % CI 2.7-5.6 months), and PFS was 1.8 months (95 % CI 1.7-2.2 months). There was a strong correlation between ≥2 + IHC staining for p-S6 in tumor samples with better PFS (p < 0.0001) and DCR (p = 0.0001).
  
  
  CONCLUSIONS
  Our clinical outcomes were inferior to the Asian studies, which may be explained by disease heterogeneity. However, there was a similar strong correlation between clinical benefit and tumor high pS6. Testing this biomarker in patient samples from the randomized phase III Granite trial may lead to a positive predictive marker.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA, USA, zwainberg@mednet.ucla.edu.
authors.forename: Zev A
authors.initials: ZA
authors.lastname: Wainberg
authors.forename: Heloisa P
authors.initials: HP
authors.lastname: Soares
authors.forename: Ravi
authors.initials: R
authors.lastname: Patel
authors.forename: Brian
authors.initials: B
authors.lastname: DiCarlo
authors.forename: David J
authors.initials: DJ
authors.lastname: Park
authors.forename: Andre
authors.initials: A
authors.lastname: Liem
authors.forename: He-jing
authors.initials: HJ
authors.lastname: Wang
authors.forename: Lisa
authors.initials: L
authors.lastname: Yonemoto
authors.forename: Diego
authors.initials: D
authors.lastname: Martinez
authors.forename: Isett
authors.initials: I
authors.lastname: Laux
authors.forename: Meghan
authors.initials: M
authors.lastname: Brennan
authors.forename: J Randolph
authors.initials: JR
authors.lastname: Hecht
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004943:Esophagogastric Junction / Q000378:metabolism / Q000473:pathology*; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000068338:Everolimus; D020123:Sirolimus