Is nivolumab (PD‑1 inhibitor) plus AVD superior to brentuximab‑vedotin plus AVD as frontline therapy for newly diagnosed advanced‑stage (stage III‑IV) classical Hodgkin lymphoma in patients aged ≥12 years?

Nivolumab-AVD is Superior to Brentuximab Vedotin-AVD for Advanced-Stage Hodgkin Lymphoma

Based on the landmark S1826 phase III randomized trial, nivolumab-AVD (N-AVD) is definitively superior to brentuximab vedotin-AVD (BV-AVD) as frontline therapy for newly diagnosed advanced-stage (stage III-IV) classical Hodgkin lymphoma in patients aged ≥12 years, demonstrating significantly improved progression-free survival, overall survival, and a markedly better toxicity profile. 1

Evidence from the Pivotal S1826 Trial

The S1826 trial provides the highest-quality, most recent evidence directly comparing these two regimens:

Efficacy Outcomes

• N-AVD achieved 2-year progression-free survival of 92% compared to 83% with BV-AVD (hazard ratio 0.45; 95% CI 0.30-0.65), representing a 55% reduction in risk of disease progression or death 1

• The efficacy advantage of N-AVD was consistent across all age groups, including:

  • Adolescents (12-17 years): 3-year PFS of 93% with N-AVD versus 82% with BV-AVD (hazard ratio 0.37; 95% CI 0.17-0.80) 2
  • Older adults (≥60 years): 2-year PFS of 89% with N-AVD versus 64% with BV-AVD (hazard ratio 0.24; 95% CI 0.09-0.63) 3

• Overall survival was also superior with N-AVD in older patients: 96% versus 85% at 2 years (hazard ratio 0.16; 95% CI 0.03-0.75) 3

Critical Toxicity Differences

The toxicity profile strongly favors N-AVD over BV-AVD:

• Treatment completion rates: 69% completed 6 cycles without dose reduction on N-AVD versus only 26% on BV-AVD 3

• Treatment discontinuation: 55% discontinued brentuximab vedotin versus only 14% discontinued nivolumab due to adverse events 3

• Non-relapse mortality was 16% with BV-AVD compared to 6% with N-AVD in older patients, highlighting the substantial safety advantage 3

• Peripheral neuropathy (grade ≥2) occurred in 14% with BV-AVD versus 7% with N-AVD in adolescents 2

• Febrile neutropenia, sepsis, and infections were all higher with BV-AVD despite more neutropenia with N-AVD, indicating that the clinical consequences of toxicity favor N-AVD 3

• Immune-related adverse events with nivolumab were infrequent and manageable, with thyroid dysfunction (7%) being the most common, all grade 1-2 and not requiring high-dose corticosteroids 2, 4

Radiation Therapy Avoidance

• Minimal use of consolidative radiation therapy: only 7 patients across the entire S1826 trial received protocol-specified radiotherapy (1 with N-AVD and 2 with BV-AVD in adolescents), demonstrating that N-AVD achieves excellent disease control without radiation 1, 2

• This is particularly important for long-term quality of life, as radiation therapy is associated with increased risks of secondary malignancies and cardiovascular disease 5

Comparison to BrECADD

The question mentions BrECADD, but this regimen is not directly comparable:

• BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone) was studied only in a phase II trial of 104 patients with 18-month PFS of 89% 6

• BrECADD was designed as a BEACOPP-alternative regimen to reduce toxicity compared to escalated BEACOPP, not as a competitor to AVD-based regimens 6

• No phase III data exist comparing BrECADD to N-AVD or BV-AVD, and the phase II BrECADD data predate the S1826 results by nearly a decade 6

• BrECADD contains more intensive chemotherapy (including cyclophosphamide and etoposide) and would be expected to have greater toxicity than AVD-based regimens 6

Clinical Implementation Algorithm

For newly diagnosed advanced-stage (III-IV) classical Hodgkin lymphoma in patients ≥12 years:

1. First-line therapy: Nivolumab 240 mg IV every 2 weeks + AVD (doxorubicin, vinblastine, dacarbazine) for 6 cycles 1

2. PET-CT assessment after completion of therapy 1

3. Radiotherapy only for residual metabolically active lesions ≥2.5 cm (rarely needed with N-AVD) 1, 5

4. Monitor for manageable toxicities:

   • Thyroid function (7% develop dysfunction, all grade 1-2) 2
   • Neutropenia (more common than BV-AVD but with fewer infectious complications) 3
   • Rare immune-related adverse events (do not require routine high-dose corticosteroids) 4

Common Pitfalls to Avoid

• Do not use BV-AVD based on older data: The S1826 trial definitively established N-AVD as superior 1

• Do not withhold N-AVD in older patients due to age concerns: The benefit was actually greatest in patients ≥60 years, with dramatic improvements in both PFS and OS 3

• Do not routinely plan consolidative radiation: The high complete response rates with N-AVD make radiation unnecessary in most patients 1, 2

• Do not confuse BrECADD with BV-AVD: BrECADD is a different, more intensive regimen without phase III validation 6