SUMMARY: The FDA on March 20, 2026, approved Nivolumab (OPDIVO®) with Doxorubicin, Vinblastine, and Dacarbazine (AVD) for adult and pediatric patients 12 years and older with previously untreated, Stage III or IV classical Hodgkin lymphoma (cHL).
The American Cancer Society estimates that in the United States for 2026, about 8920 new cases of Hodgkin Lymphoma will be diagnosed, and about 1100 patients will die of the disease. Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted, subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin Lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS).
For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. Advanced stage (Stage III-IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.
Brentuximab Vedotin (ADCETRIS®) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. In the ECHELON-1 study, frontline treatment with Brentuximab Vedotin (BV) in combination with Doxorubicin, Vinblastine and Dacarbazine (AVD) resulted in a significant improvement both in Progression Free Survival as well as Overall Survival, after a median follow up of 6 years. However, frontline BV adds toxicity, and 7-20% of patients still develop Relapsed/Refractory Hodgkin Lymphoma.
The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2, with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells, as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells.
Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells.
SWOG S1826 was an open-label, randomized Phase III trial conducted to compare the combination of Nivolumab plus AVD, to Brentuximab Vedotin plus AVD, in adolescent and adult patients with previously untreated advanced-stage classical Hodgkin Lymphoma (cHL). In this study, 976 newly diagnosed Stage III or IV cHL patients (N=976) were randomly assigned 1:1 to receive either 6 cycles of Nivolumab at 240 mg IV on days 1 and 15 (N=489) or Brentuximab Vedotin 1.2 mg/kg IV on days 1 and 15 (N=487). Both treatment groups also received AVD (Doxorubicin, Vinblastine, Dacarbazine ) IV on days 1 and 15, and treatment was repeated every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Granulocyte-Colony Stimulating Factor (G-CSF) Pegfilgrastim SC on days 2 and 16, or Filgrastim SC on days 6-10 and 21-25 was optional in the Nivolumab group (N-AVD) but was required in the Brentuximab Vedotin group (BV-AVD). Approximately 54% in the N-AVD group received G-CSF compared to 95% in the BV-AVD group. After completion of cycle 6, patients could receive radiation therapy at the discretion of the treating physician, to metabolically active residual lesions noted on the end of treatment PET. Less than 1% of patients across both treatment groups had received radiotherapy. Patients were stratified by age, International Prognostic Score (IPS) and intent to use radiation therapy. The median age was 27 years, 24% of patients were less than 18 yrs, 76% were Caucasian, 55% were men, 64% had Stage IV disease and 32% had IPS of 4-7. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Event-Free Survival (EFS), Patient-Reported Outcomes (PROs), and Safety.
Sustained Progression-Free Survival Benefit at 3 Years
With a median follow-up of 3.1 years, updated data continue to reinforce the clinical advantage of N-AVD over BV-AVD in patients with advanced-stage classical Hodgkin lymphoma (cHL). The 3-year PFS rate reached 91% with N-AVD, compared with 82% with BV-AVD, translating to a 52% reduction in the risk of progression or death (HR 0.48; P< 0.0001).
Consistent Benefit Across Key Patient Subgroups
The PFS advantage with N-AVD was maintained irrespective of age, disease stage, or baseline risk, as defined by the International Prognostic Score (IPS):
- Adolescents (12–17 years): 93% vs 82%
- Adults (18–60 years): 91% vs 85%
- Older patients (>60 years): 82% vs 58%
- Stage III disease: 93% vs 86%
- Stage IV disease: 89% vs 80%
- IPS 0–3: 92% vs 84%
- IPS 4–7: 87% vs 77%
Notably, outcomes in Stage IV disease with N-AVD approached those seen in Stage III, highlighting the regimen’s efficacy even in higher disease burden settings. These findings further support current guideline positioning of N-AVD as a preferred frontline treatment approach in advanced-stage disease.
Event-Free and Overall Survival Trends
Beyond PFS, N-AVD also demonstrated a statistically significant improvement in EFS (HR 0.56; P =0.0004). While OS data remain immature, an encouraging trend favoring N-AVD has emerged:
- 3-year OS: 98% (N-AVD) vs 97% (BV-AVD)
- Deaths observed: 8 vs 15, respectively
Longer follow-up will be essential to determine whether this early signal translates into a definitive survival advantage.
Safety Profile: Favorable and Manageable
No new safety signals were identified with extended follow-up, reinforcing the tolerability of the N-AVD regimen. Key safety observations include Lower incidence of second malignancies with N-AVD (1.2% vs 2.3%) with BV-AVD. Immune-related adverse events were generally infrequent and peripheral neuropathy was less frequent with N-AVD (7% vs 14%), reflecting reduced neurotoxicity compared with BV-containing therapy. Higher rates of grade ≥3 events occurred with N-AVD (48.4% vs 30.5%), but was not associated with increased infectious complications. G-CSF use was mandatory with BV-AVD but optional with N-AVD, influencing observed rates.
Unique Trial Design: Inclusion of Adolescent Patients
This study represents a landmark effort in Hodgkin lymphoma research, as it is the first large-scale trial to enroll both adolescents and adults in the frontline setting, and adolescents in this trial constituted the largest cohort in which a checkpoint inhibitor has been evaluated as part of initial therapy, providing important insights into younger patient populations.
Clinical Implications and Future Directions
These long-term results confirm that the integration of immune checkpoint blockade into frontline therapy yields durable disease control with a manageable safety profile.
Nivolumab plus AVD:
- Provides sustained remission benefits
- Demonstrates consistent efficacy across risk groups
- Reduces certain long-term toxicities, including neuropathy and second cancers
Collectively, the data support N-AVD as a new standard of care for patients with advanced-stage cHL. Ongoing follow-up will further clarify Long-term overall survival outcomes, Late toxicities and Patient-reported outcomes
Key Takeaways
- N-AVD significantly improves 3-year PFS vs BV-AVD (91% vs 82%)
- Benefit is consistent across age, stage, and risk categories
- EFS is significantly improved; OS data are trending positive
- Safety profile is favorable, with reduced neuropathy and fewer second malignancies
- Findings reinforce N-AVD as a preferred frontline regimen in advanced-stage cHL
3-year follow-up of the S1826 study confirms improved progression-free survival with nivolumab-AVD compared to brentuximab vedotin-AVD in advanced stage classic Hodgkin lymphoma. Herrera A, Leblanc M, Castellino S, et al. Blood (2025) 146 (Supplement 1):151. doi: 10.1182/blood-2025-151.
