title: Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma.
abstract: OBJECTIVE
  This retrospective analysis was conducted to characterize ipilimumab exposure-response relationships for measures of efficacy and safety in patients with advanced melanoma.
  
  
  METHODS
  Data were pooled from 498 patients who received ipilimumab monotherapy at 0.3, 3, or 10 mg/kg in 1 of 4 completed phase II clinical trials. The relationships between steady-state ipilimumab trough concentration (Cminss), complete or partial tumor response (CR or PR), and safety [immune-related adverse events (irAEs)] were described by logistic regression models. The relationship between exposure and overall survival was characterized using a Cox proportional-hazards model.
  
  
  RESULTS
  The steady-state trough concentration of ipilimumab was found to be a significant predictor of a CR or PR (P < 0.001). Model-based estimates indicate that the probabilities of a CR or PR at median Cminss for the 0.3, 3, and 10 mg/kg groups were 0.6%, 4.9%, and 11.6%, respectively. Overall survival at the median Cminss for ipilimumab at 0.3 mg/kg was estimated to be 0.85- and 0.58-fold lower relative to that at the median Cminss for 3 and 10 mg/kg, respectively. Model-based estimates indicate that the probabilities of a grade 3 or more irAE at the median Cminss for the 0.3, 3, and 10 mg/kg doses were 3%, 13%, and 24%, respectively.
  
  
  CONCLUSIONS
  Higher doses of ipilimumab produce greater Cminss that may be associated with increased tumor responses, longer survival, and higher rates of irAEs. The efficacy and safety of ipilimumab at 3 versus 10 mg/kg in patients with advanced melanoma is being evaluated in an ongoing phase III trial.
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Amit
authors.initials: A
authors.lastname: Roy
authors.forename: Eric
authors.initials: E
authors.lastname: Masson
authors.forename: Tai-Tsang
authors.initials: TT
authors.lastname: Chen
authors.forename: Rachel
authors.initials: R
authors.lastname: Humphrey
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
mesh_terms: D000465:Algorithms; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy*; D008954:Models, Biological; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074324:Ipilimumab