Exposure-Response Relationships of the Efficacy and Safety of Ipilimumab in Patients with Advanced Melanoma
A partir de données portant sur 498 patients atteints d'un mélanome de stade avancé et inclus dans un essai d'évaluation de l'ipilimumab en monothérapie, cette étude rétrospective analyse les relations entre différents dosages du traitement , la réponse tumorale, la survie globale et le taux d'événements indésirables
Purpose: This retrospective analysis was conducted to characterize ipilimumab exposure-response relationships for measures of efficacy and safety in patients with advanced melanoma. Experimental Design: Data were pooled from 498 patients who received ipilimumab monotherapy at 0.3, 3 or 10 mg/kg in one of four 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 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 vs. 10 mg/kg in patients with advanced melanoma is being evaluated in an ongoing phase III trial.