Background: Incorporation of brentuximab vedotin (BV) into frontline therapy of advanced stage (AS) classic Hodgkin lymphoma (cHL) has improved outcomes in pediatric and adult patients (pts). We hypothesized that introducing PD-1 blockade with nivolumab in combination with doxorubicin, vinblastine, and dacarbazine (N-AVD) would improve progression-free survival (PFS) over BV-AVD in AS cHL and evaluated this approach in the randomized, phase 3 S1826 study. Early results demonstrated a PFS advantage with N-AVD; here, we present updated data with a median follow-up of 2 years (y).
Methods: Eligible pts were ≥12y with stage 3-4 cHL. Pts were randomized 1:1 to 6 cycles of N-AVD or BV-AVD, stratified by age, international prognostic score (IPS), and intent to use radiation (RT). G-CSF was required with BV-AVD; it was optional with N-AVD. RT to residually metabolically active lesions on end of treatment PET was allowed in pre-specified patients. Response and disease progression were assessed by investigators using 2014 Lugano Classification. The primary endpoint was PFS; secondary endpoints included safety, event-free survival (EFS), patient-reported outcomes, and overall survival.
Results: 994 pts were enrolled from 7/9/19 to 10/5/22 and randomized to N-AVD (n=496) or BV-AVD (n=498). 970 were eligible and comprised the modified intent-to-treat cohort. Median age was 27y (range, 12-83y), 56% of pts were male, 76% were white, 12% were black, and 13% were Hispanic. 24% of pts were < 18y, 10% were > 60y, and 32% had IPS 4-7. Only 7 (0.7%) pts across arms received RT. With 2.1y median follow-up, the PFS advantage with N-AVD was sustained (HR 0.45, 95% CI 0.3-0.65, two-sided p<0.001), with 2y PFS of 92% after N-AVD compared to 83% after BV-AVD. The PFS benefit was consistent across all age, stage, IPS subgroups. EFS was also improved after N-AVD. There were 14 deaths observed after BV-AVD compared to 7 after N-AVD. Nearly all adverse events except neutropenia and arthralgia were more frequent after BV-AVD, including peripheral sensory neuropathy (any grade, 29% N vs 56% BV). Rates of febrile neutropenia and infection were similar between arms, as were rates of pneumonitis, colitis, gastritis, and rash.
Conclusions: N-AVD was better tolerated and improved PFS versus BV-AVD in adolescent and adult pts with AS cHL. Longer follow-up confirmed the PFS benefit with N-AVD at 2y, including pre-specified subgroups. N-AVD is a new standard of care for treatment of AS cHL.
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