Exposure-response and age subgroup analyses to support body-weight (BW) dosing of brentuximab vedotin (BV) in newly diagnosed high-risk classical Hodgkin lymphoma (cHL) in children and young adults (aged 2-21 years [y]): A randomized children's oncology group phase 3 trial (AHOD1331)

Introduction: High‐risk cHL in pediatric patients (pts) is typically treated with chemotherapy and radiation. BV, an antibody‐drug conjugate (ADC) directed to CD30, is approved in six adult indications including cHL and in children with previously untreated high‐risk cHL. In AHOD1331, BV was incorporated into the standard chemotherapy backbone treatment regimen of doxorubicin (Adriamycin®), bleomycin, vincristine, etoposide, prednisone & cyclophosphamide (ABVE‐PC) for cHL to replace bleomycin and its expectant toxicity. BV‐AVEPC treatment resulted in a statistically significant improvement in efficacy compared to ABVE‐PC; safety profiles were comparable. We sought to examine the exposure‐response (E‐R) relationships in this pediatric population. Methods: Pts in the BV‐AVEPC arm received 1.8 mg/kg BV (max: 180 mg) every 3 weeks (Q3W) for a max of 5 cycles. Pharmacokinetics (PK) evaluation focused on pts aged <13 y (n=26), as lower BV exposure was previously reported in pts with lower BW. Age and BW subgroup analyses were conducted on the primary efficacy endpoint, event‐free survival (EFS); key secondary efficacy endpoints included early response rate (ERR) and key AEs of interest: peripheral neuropathy (PN) and neutropenia. E‐R was evaluated in the PK population. Results: In all, 593 pts (aged 2 to 21 y) with previously untreated high‐risk cHL (Ann Arbor Stage IIB with bulk/IIIB/IVA/IVB) were randomized to ≥1 cycle of ABVE‐PC (n=297) or BV‐AVEPC (n=296). Compared to adults, BW dosing provided similar BV exposure in pts aged 12 to <18 y (median: 54 kg) but numerically lower ADC exposure (31%) in pts aged 2 to <12 y due to their lower BW (median: 21 kg). However, EFS was comparable between pts aged 2 to <12 y and 12 to <18 y in the BV‐AVEPC arm (EFS rate at 36 mo: 96.2% [91.1‐100%] vs. 92.0% [88.5‐95.7%]). Similarly, in the exploratory E‐R no trends were observed for ERR. Similar PN rates (Grade [Gr] ≥3: 5.8% vs 6.4%) and neutrophil count decrease (Gr ≥3: 53.8% vs 48.6.%) with BV‐AVEPC were observed between pts aged <12 y and 12 to <18 y. There were no apparent trends in neutropenia across BW groups but slightly elevated PN in pts with BW ≥70 kg (Gr ≥3: 11.3% vs ≤8.2%). Overall, there was no consistent evidence that PN and neutropenia were exposure or age‐driven in this pediatric population. Conclusions: Consistent efficacy was observed in pediatric pts in the BV‐AVEPC arm across age groups despite lower exposure in pts 2 to <12 y, with no evidence of exposure‐driven PN and neutropenia. For pediatric pts with previously untreated cHL,1.8 mg/kg Q3W BV + AVEPC ≤5 cycles demonstrated a favorable risk‐benefit profile. These data support the 1.8 mg/kg Q3W BV dosage and do not indicate a need for dose adjustment by age or BW subgroups. ZZ and DZ contributed equally.