title: Phase II study of everolimus in metastatic urothelial cancer.
abstract: What's known on the subject? and what does the study add?: No recent advances have been made in the treatment of patients with advanced bladder cancer and, to date, targeted therapies have not resulted in an improvement in outcome. The mammalian target of rapamycin pathway has been shown to be up-regulated in bladder cancer and represents a rational target for therapeutic intervention. In the present phase II study of everolimus, one near-complete response, one partial response and several minor responses suggest that everolimus possesses biological activity in a subset of patients with bladder cancer. To maximize benefit from targeted agents such as everolimus, the preselection of patients based on molecular phenotype is required.
  
  
  OBJECTIVE
  To assess the efficacy and tolerability of everolimus in advanced urothelial carcimoma (UC).
  
  
  METHODS
  The present study comprised a single-arm, non-randomized study in which all patients received everolimus 10 mg orally once daily continuously (one cycle = 4 weeks). In total, 45 patients with metastatic UC progressing after one to four cytotoxic agents were enrolled between February 2009 and November 2010 at the Memorial Sloan-Kettering Cancer Center. The primary endpoints were 2-month progression-free survival (PFS) and the safety of everolimus, with the secondary endpoint being the response rate. A Simon minimax two-stage design tested the null hypothesis that the true two month PFS rate was ≤ 50%, as opposed to the alternative hypothesis of ≥ 70%.
  
  
  RESULTS
  The most common grade 3/4 toxicities were fatigue, infection, anaemia, lymphopaenia, hyperglycaemia and hypophosphataemia. There were two partial responses in nodal metastases, with one patient achieving a 94% decrease in target lesions and remaining on drug at 26 months. An additional 12 patients exhibited minor tumour regression. There were 23 of 45 (51%) patients who were progression-free at 2 months with a median (95% CI) PFS of 2.6 (1.8-3.5) months and a median (95% CI) overall survival of 8.3 (5.5-12.1) months. No clear association was observed between mammalian target of rapamycin pathway marker expression and 2-month PFS.
  
  
  CONCLUSIONS
  Although everolimus did not meet its primary endpoint, one partial response, one near-complete response and twelve minor regressions were observed. Everolimus possesses meaningful anti-tumour activity in a subset of patients with advanced UC. Studies aiming to define the genetic basis of everolimus activity in individual responders are ongoing.
authors.affiliation: Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. matt_milowsky@med.unc.edu
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Milowsky
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Regazzi
authors.forename: Hikmat
authors.initials: H
authors.lastname: Al-Ahmadie
authors.forename: Scott R
authors.initials: SR
authors.lastname: Gerst
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.forename: Lan L
authors.initials: LL
authors.lastname: Gellert
authors.forename: Rana
authors.initials: R
authors.lastname: Kaplan
authors.forename: Ilana R
authors.initials: IR
authors.lastname: Garcia-Grossman
authors.forename: Deepa
authors.initials: D
authors.lastname: Pendse
authors.forename: Arjun V
authors.initials: AV
authors.lastname: Balar
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Flaherty
authors.forename: Alisa
authors.initials: A
authors.lastname: Trout
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000556:secondary; D017322:Clinical Trials, Phase II as Topic; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D020123:Sirolimus
keywords: bladder cancer; everolimus; mTOR; transitional cell carcinoma; urothelial cancer
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