FDA Approves Brentuximab Vedotin Combination for Relapsed or Refractory Large B-Cell Lymphoma

On February 11, 2025, the U.S. Food and Drug Administration (FDA) granted approval for the use of brentuximab vedotin (marketed as Adcetris by Seagen Inc., a subsidiary of Pfizer) in combination with lenalidomide and rituximab for adult patients suffering from relapsed or refractory large B-cell lymphoma (LBCL). This approval extends to various forms of LBCL, including diffuse large B-cell lymphoma (DLBCL) that is not otherwise specified, DLBCL originating from indolent lymphoma, and high-grade B-cell lymphoma (HGBL). The treatment targets those patients who have undergone two or more lines of systemic therapy and are not eligible for autologous hematopoietic stem cell transplantation (auto-HSCT) or CAR T-cell therapy. Complete prescribing details for Adcetris will be available on Drugs@FDA.

The approval was significantly influenced by results from the ECHELON-3 clinical trial (NCT04404283), a randomized, double-blind, placebo-controlled study. This trial involved 230 adult participants with relapsed or refractory LBCL who were not candidates for auto-HSCT or CAR T-cell therapy. Participants were randomly assigned to receive either the combination of brentuximab vedotin, lenalidomide, and rituximab (BV+R2) or a placebo combined with lenalidomide and rituximab (Pbo+R2). Treatment continued until there was either disease progression or unacceptable levels of toxicity.

The primary measure of efficacy within the trial was overall survival (OS). Additional efficacy endpoints included progression-free survival (PFS) and objective response rate (ORR) as per the 2014 Lugano Criteria. Findings from the trial indicated a significant improvement in overall survival for the BV+R2 group, which had a median OS of 13.8 months compared to 8.5 months for the Pbo+R2 group. The hazard ratio (HR) was calculated at 0.63, with a 95% confidence interval (CI) ranging from 0.45 to 0.89, and a p-value of 0.0085, indicating statistical significance.

Moreover, the trial demonstrated notable improvements in both progression-free survival and the objective response rate. Median progression-free survival was recorded at 4.2 months for the BV+R2 group compared to 2.6 months for the placebo group. The hazard ratio for this comparison was 0.53, with a 95% CI of 0.38 to 0.73 and a highly significant p-value of less than 0.0001. The objective response rate stood at 64.3% for the BV+R2 arm, while the placebo group had an ORR of 41.5%.

In terms of safety, the most frequently observed adverse reactions in the BV+R2 group, excluding laboratory abnormalities, included fatigue, diarrhea, peripheral neuropathy, rash, pneumonia, and COVID-19 infection. Grade 3 to 4 laboratory abnormalities occurring in over 10% of patients included decreased levels of neutrophils, lymphocytes, platelets, and hemoglobin. Peripheral neuropathy, mainly of a sensory nature, developed or worsened in 27% of patients, necessitating a dose reduction of brentuximab vedotin in 6% of cases and discontinuation in 4.5%.

The recommended dosage for brentuximab vedotin is 1.2 mg/kg, with a maximum dose of 120 mg, in combination with lenalidomide and rituximab. This regimen is to be administered every three weeks until either disease progression or unacceptable toxicity occurs.

The FDA's review process included the use of the Assessment Aid, a voluntary submission from the applicant aimed at facilitating the assessment. Healthcare professionals are encouraged to report any serious adverse events potentially linked to the use of medicines and devices to the FDA's MedWatch Reporting System.