FDA Approves Brentuximab Vedotin Plus Lenalidomide/Rituximab for R/R LBCL

The FDA has approved brentuximab vedotin (Adcetris) in combination with lenalidomide (Revlimid) and rituximab (Rituxan) 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 2 or more lines of systemic therapy who are ineligible for autologous hematopoietic stem cell transplantation (HSCT) or CAR T-cell therapy.1

The regulatory decision was supported by data from the phase 3 ECHELON-3 trial (NCT04404283), which demonstrated that patients treated with the combination (n = 112) experienced a median overall survival (OS) of 13.8 months (95% CI, 10.3-18.8) compared with 8.5 months (95% CI, 5.4-11.7) for those given placebo plus lenalidomide and rituximab (n = 118; HR, 0.63; 95% CI, 0.45-0.89; P = .0085).1,2

Brentuximab vedotin plus lenalidomide and rituximab also generated a median progression-free survival (PFS) of 4.2 months (95% CI, 2.9-7.1) vs 2.6 months (95% CI, 1.4-3.1) for placebo plus lenalidomide and rituximab (HR, 0.53; 95% CI, 0.38-0.73; P < .0001).1

The overall response rate (ORR) was 64.3% (95% CI, 54.7%-73.1%) for the experimental arm vs 41.5% (95% CI, 32.5%-51.0%) for the control arm.

ECHELON-3 was a randomized, double-blind, placebo-controlled, active-comparator, multicenter trial that enrolled patients with eligible subtypes of relapsed/refractory DLBCL, including transformed DLBCL, who received at least 2 prior lines of systemic therapy; were ineligible for HSCT or CAR T-cell therapy; and had an ECOG performance status of 2 or less.2

Patients were randomly assigned 1:1 to receive brentuximab vedotin at 1.2 mg/kg or placebo once every 3 weeks. All patients received lenalidomide at 20 mg once per day and rituximab at 375 mg/m2 once every 3 weeks. Notably, subcutaneous rituximab at 1400 mg was allowed starting in cycle 2 and thereafter.

OS served as the trial's primary end point. Secondary end points consisted of PFS, ORR, complete response rate, duration of response, and safety.

Additional data published in the Journal of Clinical Oncology demonstrated that patients in the experimental arm achieved a median DOR of 8.3 months (95% CI, 4.2-15.3) compared with 3.0 months (95% CI, 2.8-5.4) for those in the placebo arm.

The CR rate was 40% for the brentuximab vedotin regimen vs 19% for the placebo regimen. The median duration of CR was 18.9 months (95% CI, 11.1-not evaluable [NE]) vs NE (95% CI, 2.8-NE), respectively; the median time to CR was 1.58 months (range, 1.2-7.3) and 1.61 months (range, 0.7-4.6), respectively.

Thirty patients in the experimental arm were still ongoing treatment at data cutoff compared with 16 patients in the placebo arm. All 3 study drugs were still being administered to 16 and 13 patients, respectively, including those receiving reduced doses of brentuximab vedotin or lenalidomide.

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) were reported in 97% of patients in the experimental arm vs 97% of patients in the placebo arm. The rates of grade 3 or higher TEAEs were 88% and 77%, respectively.

TEAEs led to death in 12% of patients in the brentuximab vedotin group vs 8% of patients in the placebo group. COVID-19–related TEAEs were the most common to lead to death in both the experimental arm (4%) and placebo arm (3%).

The most common AEs reported in at least 20% of patients in the experimental arm, excluding laboratory abnormalities, included fatigue, diarrhea, peripheral neuropathy, rash, pneumonia, and COVID-19.1 Grade 3 to 4 laboratory abnormalities reported in more than 10% comprised decreased neutrophil count, decreased lymphocyte count, decreased platelet count, and decreased hemoglobin level.

The recommended dose of brentuximab vedotin is 1.2 mg/kg, up to a maximum of 120 mg, in combination with lenalidomide and rituximab once every 3 weeks until disease progression or unacceptable toxicity.

References

1. FDA approves brentuximab vedotin with lenalidomide and rituximab for relapsed or refractory large B-cell lymphoma. FDA. February 12, 2025. Accessed February 12, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brentuximab-vedotin-lenalidomide-and-rituximab-relapsed-or-refractory-large-b-cell
2. Bartlett NL, Hahn U, Kim WS, et al. Brentuximab Vedotin Combination for Relapsed Diffuse Large B-Cell Lymphoma. J Clin Oncol. Published online January 7, 2025. doi:10.1200/JCO-24-02242