The U.S. Food and Drug Administration (FDA) has approved brentuximab vedotin (Adcetris) in combination with lenalidomide and a rituximab product for adult patients with relapsed or refractory large B-cell lymphoma (LBCL)—including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from indolent lymphoma, or high-grade B-cell lymphoma—after two or more lines of systemic therapy who are ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) or chimeric antigen receptor (CAR) T-cell therapy.
ECHELON-3
Approval was based on ECHELON-3 (ClinicalTrials.gov identifier NCT04404283), a randomized, double-blind, placebo-controlled trial which enrolled 230 adult patients with relapsed or refractory LBCL who were ineligible to receive auto-HSCT or CAR T-cell therapy. Patients were randomly assigned 1:1 to receive brentuximab vedotin plus lenalidomide and rituximab (BV+R2) or placebo plus lenalidomide and rituximab (Pbo+R2) until disease progression or unacceptable toxicity.
The major efficacy outcome measure was overall survival; additional efficacy outcome measures included progression-free survival and objective response rate per 2014 Lugano Criteria. The trial demonstrated a statistically significant overall survival improvement, with a median overall survival of 13.8 months (95% confidence interval [CI] = 10.3–18.8 months) in the BV+R2 arm and 8.5 months (95% CI = 5.4–11.7 months) in the Pbo+R2 arm (hazard ratio [HR] = 0.63, 95% CI = 0.45–0.89; P = .0085). The trial also demonstrated a statistically significant improvement in progression-free survival and objective response rate. Median progression-free survival was 4.2 months (95% CI = 2.9–7.1 months) with BV+R2 and 2.6 months (95% CI = 1.4–3.1 months) with Pbo+R2 (HR = 0.53, 95% CI = 0.38–0.73; P < .0001). The objective response rate was 64.3% (95% CI = 54.7%–73.1%) and 41.5% (95% CI = 32.5%–51.0%), respectively.
Adverse Reactions
The most common adverse reactions (occurring in ≥ 20% of patients)—excluding laboratory abnormalities in the BV+R2 arm—were fatigue, diarrhea, peripheral neuropathy, rash, pneumonia, and COVID-19 infection. Grade 3 to 4 laboratory abnormalities occurring in more than 10% of patients were decreased neutrophils, decreased lymphocytes, decreased platelets, and decreased hemoglobin. Peripheral neuropathy developed or worsened in 27% of patients, was predominantly sensory, and led to brentuximab vedotin dose reduction in 6% and discontinuation in 4.5%.
The recommended brentuximab vedotin dose is 1.2 mg/kg up to a maximum of 120 mg in combination with lenalidomide and rituximab administered every 3 weeks until disease progression or unacceptable toxicity.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
