Exposure-Response and Subgroup Analyses to Support Body Weight-Based Dosing of Brentuximab Vedotin in Children and Young Adults with Newly Diagnosed High-risk Classical Hodgkin Lymphoma.
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PURPOSE: The purpose of the study was to evaluate the relationships between brentuximab vedotin (BV) pharmacokinetics, age, and body weight (BW) with efficacy and safety in pediatric and young adult patients with previously untreated, high-risk classical Hodgkin lymphoma in the phase III AHOD1331 study. EXPERIMENTAL DESIGN: Overall, 296 patients (age 2-21 years) in the overall population were randomized to and received BV + chemotherapy; the pharmacokinetic subpopulation comprised 24 patients (age <13 years). Age- and/or BW-based (pharmacokinetic surrogates) subgroup analyses of efficacy and safety were conducted for the overall population. Exposure-response analyses were limited to the pharmacokinetic subpopulation. RESULTS: There were no visible trends in disease characteristics across pediatric age subgroups, whereas BW increased with age. Observed antibody-drug conjugate exposures in patients ages <12 years were lower than those in adults administered BV 1.8 mg/kg every 3 weeks, as exposure increased with BW. Nevertheless, no detrimental impact on event-free survival was seen in younger subgroups: 3-year event-free survival rates were 96.2% (2-<12 years) and 92.0% (12-<18 years), with no events observed in those ages <6 years. Neither early response nor lack of need for radiation therapy was associated with high pharmacokinetic exposure. No evidence of exposure-driven grade ≥2 or ≥3 peripheral neuropathy or grade ≥3 neutropenia was seen in exposure-safety and BW-based subgroup analyses; the incidence of these safety events was comparable across pediatric age subgroups, despite lower exposure in younger children. CONCLUSIONS: No further adjustments based on age or BW are required for the BV dosage (1.8 mg/kg every 3 weeks) approved in children.