The U.S. Food and Drug Administration (FDA) has granted approval to brentuximab vedotin (Adcetris), in combination with lenalidomide (Revlimid) and rituximab (Rituxan), for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (LBCL). This approval is specifically for patients who have undergone two or more lines of systemic therapy and are ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) or chimeric antigen receptor (CAR) T-cell therapy. This decision provides a new therapeutic option for a challenging patient population with limited alternatives.
The approval is based on the results of the Phase 3 ECHELON-3 clinical trial (NCT04404283), a randomized, double-blind, placebo-controlled study involving 230 adult patients with relapsed or refractory LBCL. The trial compared the combination of brentuximab vedotin, lenalidomide, and rituximab against placebo plus lenalidomide and rituximab. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and objective response rate (ORR).
ECHELON-3 Trial Results
At a median follow-up of 16.4 months, the brentuximab vedotin combination demonstrated a statistically significant improvement in OS compared to the placebo arm. The median OS was 13.8 months (95% CI: 10.3-18.8) for the brentuximab vedotin arm versus 8.5 months (95% CI: 5.4-11.7) for the placebo arm (HR 0.629; 95% CI: 0.445-0.891; P = .0085). The median PFS was also significantly improved, at 4.2 months (95% CI: 2.9-7.1) for the brentuximab vedotin arm compared to 2.6 months (95% CI: 1.4-3.1) for the placebo arm (HR .527; 95% CI: 0.380-0.729; P < .0001).
The ORR was 64.3% (95% CI: 54.7-73.1) in the brentuximab vedotin arm and 41.5% (95% CI: 32.5-51.0) in the placebo arm (P = .0006). These results highlight the clinical benefit of adding brentuximab vedotin to lenalidomide and rituximab in this patient population.
Safety and Tolerability
The most common adverse events (AEs), excluding laboratory abnormalities, in the brentuximab vedotin arm included fatigue, diarrhea, peripheral neuropathy, rash, pneumonia, and COVID-19 infection. Grade 3 or higher treatment-emergent AEs included neutropenia (46% vs 32%), anemia (29% vs 27%), and diarrhea (31% vs 23%) in the brentuximab vedotin and placebo groups, respectively. Peripheral neuropathy of any grade was reported in 31% of patients in the brentuximab vedotin arm and 24% in the placebo arm, with grade 3 events occurring in 6% and 2% of patients, respectively.
Impact on Clinical Practice
This approval provides a valuable new option for patients with relapsed or refractory LBCL who are not candidates for auto-HSCT or CAR T-cell therapy. LBCL, a type of non-Hodgkin lymphoma, affects immune cells called B lymphocytes. Diffuse large B-cell lymphoma (DLBCL) is the most common, aggressive, and difficult-to-treat form of LBCL, with over 25,000 cases diagnosed annually in the United States. Up to 40% of patients relapse or have refractory disease after frontline treatment, underscoring the need for effective therapies in later lines of treatment.
According to Dr. Craig Portell, Associate Professor at the University of Virginia and principal investigator of the trial, "For patients who have previously faced setbacks with other therapies, Adcetris provides a new therapeutic option with outpatient administration and proven safety and efficacy."
Dosing and Administration
The recommended dose of brentuximab vedotin is 1.2 mg/kg (up to a maximum of 120 mg) in combination with lenalidomide and rituximab, administered intravenously every 3 weeks until disease progression or unacceptable toxicity.
