Background
Brentuximab vedotin + AVD (A+AVD, from ECHELON-1) was the frontline standard for advanced Hodgkin lymphoma. S1826 (SWOG) directly compared nivolumab + AVD (N-AVD) to A+AVD in first-line advanced cHL, testing whether PD-1 blockade improves on the ADC-based regimen.
Interventions and follow up
Arm A: BV-AVD — brentuximab vedotin 1.2 mg/kg + doxorubicin + vinblastine + dacarbazine x6 cycles q14d with G-CSF prophylaxis
Arm B: N-AVD — nivolumab 240 mg + doxorubicin + vinblastine + dacarbazine x6 cycles q14d (G-CSF not required)
Population: N=994, untreated stage III/IV cHL (age ≥12, included pediatric/adolescent)
Primary endpoint: progression-free survival
Median follow-up: 31.4 months
Arm B: N-AVD — nivolumab 240 mg + doxorubicin + vinblastine + dacarbazine x6 cycles q14d (G-CSF not required)
Population: N=994, untreated stage III/IV cHL (age ≥12, included pediatric/adolescent)
Primary endpoint: progression-free survival
Median follow-up: 31.4 months
Results
2-yr PFS: 92% (N-AVD) vs 83% (BV-AVD) (HR 0.48, 95% CI 0.27–0.86, P=.01)
OS: immature at primary analysis; few events, no significant difference
Subgroups: PFS benefit for N-AVD consistent across stage IV, IPS ≥3, ECOG PS, and age
Comparison: N-AVD superior to current frontline standard A+AVD
OS: immature at primary analysis; few events, no significant difference
Subgroups: PFS benefit for N-AVD consistent across stage IV, IPS ≥3, ECOG PS, and age
Comparison: N-AVD superior to current frontline standard A+AVD
Adverse events
Overall: Grade ≥3 AEs broadly similar across arms
Neurologic: peripheral neuropathy (Grade ≥2) 9% (N-AVD) vs 44% (BV-AVD)
Hematologic/Infections: febrile neutropenia 10% (N-AVD, no required G-CSF) vs 20% (BV-AVD)
Immune-related: irAEs ~8% with N-AVD (pneumonitis, thyroiditis)
Neurologic: peripheral neuropathy (Grade ≥2) 9% (N-AVD) vs 44% (BV-AVD)
Hematologic/Infections: febrile neutropenia 10% (N-AVD, no required G-CSF) vs 20% (BV-AVD)
Immune-related: irAEs ~8% with N-AVD (pneumonitis, thyroiditis)
Conclusions
N-AVD significantly improved PFS over A+AVD with a better tolerability profile (less neuropathy, no required G-CSF) in advanced Hodgkin lymphoma, establishing nivolumab + AVD as a new preferred frontline regimen for stage III/IV cHL.
Key Limitations
OS data immature; comparator was A+AVD only (no ABVD or PET-adapted arm); immune-related AEs require monitoring; long-term effects of PD-1 blockade on autoimmunity and secondary malignancy unknown; relatively short follow-up; access/cost of nivolumab.
Clinical Context
S1826 reshapes frontline advanced Hodgkin lymphoma for the third time in a decade (ABVD → A+AVD → N-AVD). PD-1 blockade exploits high PD-L1 expression driven by EBV and Reed-Sternberg cell biology. N-AVD's elimination of neuropathy risk and G-CSF requirement is a meaningful quality-of-life advantage; ASCO/ESMO guidance now incorporates N-AVD as a preferred frontline option for stage III/IV cHL.