title: Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy.
abstract: BACKGROUND
  Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta-analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety.
  
  
  METHODS
  Data were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately.
  
  
  RESULTS
  The rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62-1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66-1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)].
  
  
  CONCLUSIONS
  Stomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines.
authors.affiliation: University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco hope.rugo@ucsf.edu.
authors.forename: H S
authors.initials: HS
authors.lastname: Rugo
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: G N
authors.initials: GN
authors.lastname: Hortobagyi
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yao
authors.affiliation: Charité Universitätsmedizin Berlin/Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pavel
authors.affiliation: Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France.
authors.forename: A
authors.initials: A
authors.lastname: Ravaud
authors.affiliation: University of Cincinnati College of Medicine, Cincinnati, USA.
authors.forename: D
authors.initials: D
authors.lastname: Franz
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Ringeisen
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Gallo
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Rouyrre
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: O
authors.initials: O
authors.lastname: Anak
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: R
authors.initials: R
authors.lastname: Motzer
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D018572:Disease-Free Survival; D000068338:Everolimus / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D009092:Mucous Membrane / Q000473:pathology*; D009369:Neoplasms / Q000188:drug therapy; D013280:Stomatitis / Q000139:chemically induced* / Q000453:epidemiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014402:Tuberous Sclerosis / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: breast cancer; everolimus; pancreatic neuroendocrine tumors; renal cell carcinoma; stomatitis; tuberous sclerosis complex