Introduction: The randomized phase 3 S1826 study demonstrated that, in adolescent and adult patients (pts) with previously untreated advanced stage (AS) classic Hodgkin lymphoma (cHL), PD-1 blockade with nivolumab in combination with doxorubicin, vinblastine, and dacarbazine (N-AVD) prolonged progression-free survival (PFS) compared with standard brentuximab vedotin (BV) combined with AVD at a median follow-up of 2 years. The PFS benefit was consistent across patient subgroups, N-AVD was better tolerated than BV-AVD, and radiation (RT) was rarely utilized. Herein, we evaluate durability of these results with a median follow-up of 3 years (y).

Methods: Eligible pts were ≥12y with stage 3-4 cHL. Pts were randomized in a 1:1 ratio to receive either 6 cycles of N-AVD or BV-AVD. Pts were stratified by age, international prognostic score (IPS), and intent to use RT. G-CSF prophylaxis was mandatory with BV-AVD; it was optional with N-AVD. RT (30 Gy) to residually metabolically active lesions at the end of treatment was allowed according to pre-specified criteria. Pathology was centrally reviewed, patients without confirmation of cHL were ineligible for modified intent-to-treat (mITT) analysis. 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 (OS). The database was locked for analysis on July 1, 2025.

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 (98%) were eligible and comprised the mITT 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 3.1y of median follow-up (range, 0-5.5y), the PFS advantage with N-AVD was sustained (HR 0.48, 95%CI 0.34-0.69, one-sided p<0.0001), with 3y PFS of 91% after N-AVD compared to 82% after BV-AVD. As previously, the PFS benefit was significant across all age, stage, and IPS subgroups. Among pts ages 18-60y, 3y PFS in pts who received N-AVD was 91% compared to 85% in pts treated with BV-AVD (HR 0.61, 95% CI 0.38-0.96). Among adolescent pts ages 12-17y, 3y PFS in pts who received N-AVD was 93% vs 82% after BV-AVD (HR 0.36, 95% CI 0.17-0.79). In pts older than 60y, 3y PFS was 82% after N-AVD vs 58% after BV-AVD (HR 0.33, 95% CI 0.14 – 0.77). Pts with Stage IV cHL who received N-AVD had 3y PFS 89% compared to 80% after BV-AVD (HR 0.55, 95% CI 0.36-0.83), and had similar PFS to pts with stage III cHL who received N-AVD (3y PFS 93% vs 86% with BV-AVD, HR 0.42, 95% CI 0.22-0.81). Likewise, N-AVD led to improved PFS among pts with IPS scores of 4-7 (3y PFS 87% vs 77% with BV-AVD, HR 0.57, 95% CI 0.33-0.97). Pts with IPS 0-3 had longer PFS with N-AVD (3y PFS 92%) than with BV-AVD (3y PFS 84%, HR 0.45, 95% CI 0.28-0.72). EFS was also improved after N-AVD (HR 0.56, 95% CI 0.41-0.78, p=0.0004). There were 15 deaths observed after BV-AVD (3y OS 97%) compared to 8 after N-AVD (3y OS 98%, HR 0.48, 95% CI 0.20-1.15, p=0.092). No new safety signals were observed. Second cancers were observed in 6 (1.2%) pts after N-AVD (4 non-Hodgkin lymphomas [NHL], 1 skin cancer, 1 solid tumor) vs 11 (2.3%) pts after BV-AVD (3 NHL, 1 multiple myeloma, 7 solid tumors).

Conclusions: The benefit of N-AVD compared to BV-AVD in adolescent and adult pts with AS cHL is sustained with 3y follow-up, including all pre-specified age, stage, and IPS risk subgroups. This update demonstrates the durability of remissions with N-AVD over time without any new safety signals, and enables benchmarking with other modern cHL trials. Follow-up will continue to evaluate for late toxicities, OS, and PROs. These results validate guidelines recommending N-AVD as a preferred frontline treatment regimen in patients with AS cHL, including high-risk patients.

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2025
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