Pediatric model ‐based dose optimization using a pooled exposure‐response safety analysis for nivolumab and nivolumab plus ipilimumab combination in melanoma

AbstractAn exposure –response (E-R) safety analysis was conducted across adult and pediatric (<18  years) studies to evaluate the potential impact of higher nivolumab and/or ipilimumab exposures in adolescents (≥12 to<18  years ) versus adults with melanoma using the approved adult dosing regimens for nivolumab alone or in combination with ipilimumab. Data from 3507 patients across 15 studies were used to examine the relationship between nivolumab–ipilimumab daily average exposure (Cavg) and time to grade 2+ immune-mediated adverse events (gr2+ IMAEs). Results from the E-R safety model showed ipilimumab, but not nivolumab, exposure to be a statistically significant predictor of gr2+ IMAEs. Significant covariates included sex (41% higher risk for women than men), line of therapy (19% higher for first-line than later-line), and treatment setting (26% lower for adjuvant than advanced melanoma). Younger age and lower body weight (BW) were each associated with a lower risk of gr2+ IMAEs (hazard ratio, 0.830 for 15-year-olds versus 60-year-olds and 0.84 for BW 52 kg versus 75 kg). For adolescents with melanoma treated with nivolumab in the advanced or adjuvant settings, these results are supportive of nivolumab flat dosing regimens for adolescents ≥40 kg and BW-based dosing for adolescents<40 kg. These results also support adult weight-based dosing regimens for nivolumab plus ipilimumab in adolescents with advanced melanoma. This analysis suggests that although...
Source: CPT: Pharmacometrics and Systems Pharmacology - Category: Drugs & Pharmacology Authors: Tags: ARTICLE Source Type: research