Impact of EBV Status and Histology on Patient Outcomes with Nivolumab-AVD vs BV-AVD in Advanced Classic Hodgkin Lymphoma (S1826)

Classic Hodgkin lymphoma (cHL) associated with Epstein‐Barr virus (EBV) positive status as well as nonnodular sclerosis (non‐NS) histologic subtypes has demonstrated poorer outcomes compared with EBV‐ and NS tumors. We report a prespecified subset analysis of patients enrolled in the phase 3 SWOG S1826 trial to evaluate outcomes based on EBV status and histologic subtype in patients treated with N‐AVD (nivolumab‐AVD) or BV‐AVD (brentuximab vedotin‐AVD). In the phase 3 SWOG S1826 trial, patients with stage III to IV cHL were randomized to N‐AVD or BV‐AVD treatment. Of 970 eligible patients, 522 had known EBV status. N‐AVD improved 3‐year progression‐free survival (PFS) in patients who were EBV+ (91% vs 70%; hazard ratio [HR], 0.30; P = .01) and EBV‐ (90% vs 84%; HR, 0.64; P = .09). Among 664 patients with slides available for histology review, 102 (15.4%) had non‐NS histologic subtypes. N‐AVD prolonged 3‐year PFS in patients with non‐NS histologic subtype (86% vs 63%; HR, 0.33; P = .006) and NS histologic subtype (93% vs 86%; HR, 0.53; P = .01). Non‐NS histologic subtype was independently associated with inferior outcomes (HR, 2.54; P< .0001) after adjusting for treatment in the entire cohort. However, N‐AVD treatment still had favorable PFS within this high‐risk group. In addition, patients with EBV+ status or non‐NS histologic subtype cHL treated with BV‐AVD had significantly worse PFS (HR, 1.97; P = .03 for EBV and HR, 3.08; P< .0001 for histology). N‐AVD substantially abrogated the historically poor prognosis associated with EBV+ status and non‐NS histologic subtype in advanced‐stage cHL. These results support N‐AVD as a frontline standard of care, particularly in high‐risk biologic subgroups. This trial was registered at www.clinicaltrials.gov as NCT03907488.