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 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.
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 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: Julie R Brahmer; Christina Lacchetti; Bryan J Schneider; Michael B Atkins; Kelly J Brassil; Jeffrey M Caterino; Ian Chau; Marc S Ernstoff; Jennifer M Gardner; Pamela Ginex; Sigrun Hallmeyer; Jennifer Holter Chakrabarty; Natasha B Leighl; Jennifer S Mammen; David F McDermott; Aung Naing; Loretta J Nastoupil; Tanyanika Phillips; Laura D Porter; Igor Puzanov; Cristina A Reichner; Bianca D Santomasso; Carole Seigel; Alexander Spira; Maria E Suarez-Almazor; Yinghong Wang; Jeffrey S Weber; Jedd D Wolchok; John A Thompson Journal: J Clin Oncol Date: 2018-02-14 Impact factor: 44.544
Authors: David A Reardon; Gordon Freeman; Catherine Wu; E Antonio Chiocca; Kai W Wucherpfennig; Patrick Y Wen; Edward F Fritsch; William T Curry; John H Sampson; Glenn Dranoff Journal: Neuro Oncol Date: 2014-09-04 Impact factor: 12.300
Authors: Arsen Osipov; Su Jin Lim; Aleksandra Popovic; Nilofer S Azad; Daniel A Laheru; Lei Zheng; Elizabeth M Jaffee; Hao Wang; Mark Yarchoan Journal: Clin Cancer Res Date: 2020-06-25 Impact factor: 12.531
Authors: Romualdo Barroso-Sousa; William T Barry; Ana C Garrido-Castro; F Stephen Hodi; Le Min; Ian E Krop; Sara M Tolaney Journal: JAMA Oncol Date: 2018-02-01 Impact factor: 31.777
Authors: C Lebbé; J S Weber; M Maio; B Neyns; K Harmankaya; O Hamid; S J O'Day; C Konto; L Cykowski; M B McHenry; J D Wolchok Journal: Ann Oncol Date: 2014-09-10 Impact factor: 32.976