Brentuximab Vedotin in Combination with Lenalidomide and Rituximab Approved for Relapsed or Refractory Large B-Cell Lymphoma
Expert Perspectives · Lyn Brook · 2025-02-18
The FDA has granted approval to a promising new treatment regimen for patients with relapsed or refractory large B-cell lymphoma (LBCL). Brentuximab vedotin (Adcetris®, Seagen Inc., a subsidiary of Pfizer) in combination with lenalidomide and rituximab is now an option for adults who have undergone two or more lines of systemic therapy and are ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) or CAR T-cell therapy. This indication includes patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma (HGBL).
Why This Approval Matters
For clinicians managing patients with relapsed or refractory LBCL, treatment options can be limited, particularly for those who cannot undergo curative-intent therapies such as auto-HSCT or CAR T-cell therapy. The introduction of this novel combination provides a much-needed alternative, offering improved survival and response rates in this high-risk population.
Breaking Down the ECHELON-3 Trial
The approval was based on results from ECHELON-3 (NCT04404283), a pivotal phase 3, randomized, double-blind, placebo-controlled trial. The study enrolled 230 adult patients with relapsed or refractory LBCL who were ineligible to receive auto-HSCT or CAR T-cell therapy. Patients were randomized 1:1 to receive either brentuximab vedotin plus lenalidomide and rituximab (BV+R2) or a placebo-based regimen (Pbo+R2) until disease progression or unacceptable toxicity.
Key efficacy end points included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), assessed using the 2014 Lugano Criteria.
The results were compelling:
- Median OS was 13.8 months in the BV+R2 arm versus 8.5 months in the control arm
- Median PFS was significantly improved at 4.2 months with BV+R2 versus 2.6 months in the control arm
- ORR reached 64.3% in the BV+R2 group compared with 41.5% in the control arm, reinforcing its superior efficacy
Managing Adverse Events
While the combination therapy demonstrated clear benefits, clinicians must be aware of potential side effects. The most frequently reported adverse events experienced in ≥20% of patients included fatigue, diarrhea, peripheral neuropathy, rash, pneumonia, and COVID-19 infection. Grade 3 to 4 laboratory abnormalities occurring in more than 10% of patients included reductions in neutrophils, lymphocytes, platelets, and hemoglobin.
Peripheral neuropathy, a known concern with brentuximab vedotin, developed or worsened in 27% of patients. While predominantly sensory, this led to dose reductions in 6% and treatment discontinuation in 4.5% of cases.
Clinical Implications and Future Outlook
“Treatment with BV+R2 triplet, compared to R2, demonstrated statistically significant and clinically meaningful improvements in all key efficacy outcomes including OS in high-risk subgroups, with manageable safety,” wrote Jeong Kim, MD, an Oncologist at The Catholic University of Korea St. Vincent’s Hospital, South Korea, and colleagues, in their published results of the ECHELON-3 study. “This triplet regimen represents a novel treatment option for patients with heavily pretreated relapsed or refractory DLBCL.”
This approval marks a significant step forward for relapsed or refractory LBCL patients who previously had few viable treatment alternatives. With growing evidence supporting antibody-drug conjugates and immunomodulatory agents in lymphoma, ongoing research may further refine treatment strategies, improve tolerability, and expand indications.
Dosing and Administration
Brentuximab vedotin is administered at 1.2 mg/kg, up to a maximum of 120 mg, every three weeks in combination with lenalidomide and rituximab, until disease progression or unacceptable toxicity.