On November 10, the U.S. Food and Drug Administration (FDA) approved the CD30-directed antibody-drug conjugate brentuximab vedotin (Adcetris) in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide for pediatric patients aged 2 years and older with previously untreated high-risk classical Hodgkin lymphoma. This is the first pediatric approval for brentuximab vedotin.
Efficacy was evaluated in the phase III AHOD1331 study (ClinicalTrials.gov identifier: NCT02166463), a randomized, open-label, actively controlled trial. High risk was identified as Ann Arbor stage IIB with bulky disease, stage IIIB, stage IVA, and stage IVB. Of the 600 total patients randomly assigned, 300 received brentuximab vedotin plus doxorubicin (A), vincristine (V), etoposide (E), prednisone (P), and cyclophosphamide (C) (brentuximab vedotin plus AVEPC arm), and 300 patients were randomly assigned to doxorubicin plus bleomycin (B), vincristine, etoposide, prednisode, and cyclophosphamide (ABVE-PC arm). Patients in each treatment arm received up to five cycles of the following:
- Brentuximab vedotin + AVEPC arm: brentuximab vedotin at 1.8 mg/kg over 30 minutes (day 1), doxorubicin at 25 mg/m2 (days 1 and 2), vincristine at 1.4 mg/m2 (day 8), etoposide at 125 mg/m2 (days 1–3), prednisone at 20 mg/m2 twice daily (days 1–7), and cyclophosphamide at 600 mg/m2 (days 1 and 2)
- ABVE-PC arm: doxorubicin at 25 mg/m2 (days 1 and 2), bleomycin at 5 units/m2 (day 1) and 10 units/m2 (day 8), vincristine at 1.4 mg/m2 (days 1 and 8), etoposide at 125 mg/m2 (days 1–3), prednisone at 20 mg/m2 twice daily (days 1–7), and cyclophosphamide at 600 mg/m2 (days 1 and 2).
The main efficacy outcome measure was event-free survival, defined as the time from random assignment to disease progression or relapse, second malignancy, or death due to any cause, whichever occurred earliest.
Median event-free survival was not reached in either arm. There were 23 events (8%) in the brentuximab vedotin plus AVEPC arm and 52 events (17%) in the ABVE-PC arm, with a corresponding hazard ratio of 0.41 (95% confidence interval = 0.25–0.67, P = .0002).
The most common grade ≥ 3 adverse reactions (≥ 5%) in pediatric patients treated with brentuximab vedotin in combination with AVEPC were neutropenia, anemia, thrombocytopenia, febrile neutropenia, stomatitis, and infection.
The recommended brentuximab vedotin dose for pediatric patients aged 2 years and older is 1.8 mg/kg up to a maximum of 180 mg in combination with AVEPC every 3 weeks for a maximum of five doses.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Priority Review. Brentuximab vedotin has Orphan Drug designation for the treatment of Hodgkin lymphoma.
