BRECADD IS NON‐INFERIOR TO EBEACOPP IN PATIENTS WITH ADVANCED STAGE CLASSICAL HODGKIN LYMPHOMA: EFFICACY RESULTS OF THE GHSG PHASE III HD21 TRIAL (2023)

Introduction: Individualized, PET2-guided first-line treatment of patients with advanced-stage classical Hodgkin Lymphoma (AS-cHL) with eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) achieves outstanding survival outcomes, but also causes relevant treatment-related morbidity (TRMB). We hypothesized that remodeling the eBEACOPP regimen with brentuximab vedotin (BV) could decrease TRMB while maintaining its high efficacy. Here, we report the results of the HD21 study regarding non-inferiority of BrECADD (BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) as compared to eBEACOPP in terms of progression-free survival (PFS). Methods: This international open-label phase III trial included adult patients aged ≤60 with AS-cHL. Patients were randomized in a 1:1 ratio to PET2-guided 4–6 cycles of either eBEACOPP or BrECADD. PET2 and PFS events were assessed by blinded panel review. Non-inferiority of the primary efficacy endpoint PFS was defined as an absolute difference <6% at 5 years corresponding to a hazard ratio (HR) of BrECADD versus eBEACOPP <1.69. For this interim analysis at 36 months follow-up, O’Brien-Fleming method with Lan-DeMets alpha-spending function and the actual information fraction was used to calculate the significance level and HR bound for non-inferiority in the intention-to-treat (ITT) analysis set. 100 PFS events were available, resulting in a HR bound of 1.02 and a corresponding alpha level of 0.0108. The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Results: We enrolled 1,500 patients from 9 countries and 233 trial sites between July 2016 and August 2020. The ITT population comprised 1,482 patients, 740 in the eBEACOPP arm and 742 in the BrECADD arm. 44% were female, median age was 34 y (range 18–61), 47% were at high-risk (international prognostic index ≥3), baseline characteristics were well balanced between treatment arms. 59% of patients received 4 and 41% received 6 cycles of therapy. Median follow-up was 40 months. 3-year PFS was 92.3% for eBEACOPP and 94.9% for BrECADD, the corresponding point estimate for the HR was 0.63 (99% CI 0.37–1.07) and thus below the pre-specified bound. Progression or early relapse of HL ≤1 year was documented for 37 patients in the eBEACOPP arm (5%) and 16 patients in the BrECADD arm (2.2%). 3-year overall survival was 98.5% in both groups. Conclusion: This interim analysis of the GHSG HD21 trial fully establishes non-inferiority of BrECADD compared to eBEACOPP. Importantly, we observed a relevant reduction in early PFS events with BrECADD resulting in a 3-year PFS rate of 94.9%. This mature and unparalleled PFS rate suggests that individualized treatment with PET2-directed BrECADD is currently the most effective therapy for adult patients with AS-cHL. The research was funded by: Takeda Oncology Keyword: Hodgkin lymphoma Conflicts of interests pertinent to the abstract P. Borchmann Consultant or advisory role: Takeda Oncology Research funding: Takeda Oncology Honoraria: BMS Germany, MSD Oncology Research funding: MSD Oncology (Institution); Takeda (Institution)