Data from Exposure–Response Relationships of the Efficacy and Safety of Ipilimumab in Patients with Advanced Melanoma

Abstract

<div>Abstract<p><b>Purpose:</b> This retrospective analysis was conducted to characterize ipilimumab exposure–response relationships for measures of efficacy and safety in patients with advanced melanoma.</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> The steady-state trough concentration of ipilimumab was found to be a significant predictor of a CR or PR (<i>P</i> < 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.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 19(14); 3977–86. ©2013 AACR</i>.</p></div>