Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy

Ann Oncol. 2016 Mar;27(3):519-25. doi: 10.1093/annonc/mdv595. Epub 2016 Jan 11.


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.

Patients and 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.

Keywords: breast cancer; everolimus; pancreatic neuroendocrine tumors; renal cell carcinoma; stomatitis; tuberous sclerosis complex.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Disease-Free Survival
  • Everolimus / adverse effects*
  • Everolimus / therapeutic use
  • Humans
  • Immunosuppressive Agents / adverse effects*
  • Immunosuppressive Agents / therapeutic use
  • Mucous Membrane / pathology*
  • Neoplasms / drug therapy
  • Stomatitis / chemically induced*
  • Stomatitis / epidemiology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Tuberous Sclerosis / drug therapy


  • Antineoplastic Agents
  • Immunosuppressive Agents
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases