The United States (US) Food and Drug Administration (FDA) has approved brentuximab vedotin (BV) in combination with lenalidomide and a rituximab product (Len + R) for adults with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after two or more systemic therapies, including those with diffuse LBCL (DLBCL) not otherwise specified (NOS), DLBCL arising from indolent lymphoma, or high-grade B-cell lymphoma (HGBL), who are ineligible for autologous stem cell transplantation (auto-HSCT) or CAR T-cell therapy.¹ This approval was based on results from the phase 3 ECHELON-3 trial, which demonstrated a clinically meaningful improvement in overall survival (OS), as well as progression-free survival (PFS) and overall response rate (ORR).^1-3

DLBCL is the most common type of non-Hodgkin lymphoma (NHL), accounting for 30% of all lymphoma cases.³ In the US, the age-standardized incidence of DLBCL is approximately 7.2 per 100,000, with rates increasing with age and higher in males than females.⁴ Despite treatment advances, around 40% of patients experience R/R disease after frontline therapy.³ For patients who fail two prior lines of therapy, treatment options have been limited.³ Despite recent advances in targeted therapies, there remains an urgent need for effective, outpatient-administered treatments that improve survival outcomes in this challenging patient population.³

BV is a CD30-directed antibody-drug conjugate (ADC) composed of a monoclonal antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker.^3,5 This linker system is designed to remain stable in the bloodstream and release MMAE upon internalization into CD30-positive tumor cells.⁵

ECHELON-3 trial is a phase 3, randomized, double-blind, multicenter study comparing BV with a placebo, in combination with Len + R in adult patients with R/R DLBCL who had received at least two prior lines of therapy.^1-3 The trial demonstrated a 37% reduction in the risk of death (HR=0.63; 95% CI: 0.45-0.89; p=0.009), representing a statistically significant and clinically meaningful improvement in OS.3 Notably, the survival benefit was observed across all levels of CD30 expression, expanding the potential patient population that may benefit from this therapy.³ Additionally, the BV regimen demonstrated statistically significant improvements in key secondary endpoints, including higher ORR (64% vs. 42%; p<0.001) and a 47% reduction in the risk of disease progression or death (HR=0.53; 95% CI: 0.38-0.73; p<0.001).^2,3

The safety profile of BV in ECHELON-3 was consistent with previous clinical data.3 The most common grade 3 or higher treatment-emergent adverse events (TEAEs) associated with the BV combination included neutropenia (43% vs. 28% in the placebo group), thrombocytopenia (25% vs. 19%), anemia (22% vs. 21%).³ Peripheral sensory neuropathy was infrequent and remained low-grade, with grade 3 events occurring in 4% of patients in the BV arm and 0% in the placebo group.³ While myelosuppression remains a concern, the BV regimen provides a manageable safety profile in heavily pretreated patients with R/R DLBCL.^2,3

In conclusion, the FDA approval of BV in combination with Len + R for R/R DLBCL represents a critical advancement in lymphoma treatment.¹ By significantly improving OS while maintaining a manageable safety profile, this regimen offers new hope for patients with limited treatment options.^1-3 As the landscape of lymphoma therapy continues to evolve, BV is poised to play a central role in addressing the unmet needs of patients with aggressive B-cell lymphomas.³