The addition of brentuximab vedotin (Adcetris) to lenalidomide (Revlimid) and rituximab (Rituxan) has demonstrated significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have undergone at least two prior lines of systemic therapy. These findings come from the phase 3 ECHELON-3 study (NCT04404283), recently presented at the 2024 SOHO Annual Meeting.
At a median follow-up of 15.5 months for the brentuximab regimen (n = 112) and 18.9 months for lenalidomide/rituximab alone (n = 118), the median OS was 13.8 months (95% CI, 10.3-18.8) versus 8.5 months (95% CI, 5.4-11.7), respectively (HR, 0.629; 95% CI, 0.445-0.891; log-rank P = .0085), meeting the trial’s primary end point.
The triplet regimen also resulted in a 47% reduction in the risk of disease progression or death compared to the doublet. With median follow-ups of 11.1 months and 8.8 months for the triplet and doublet, respectively, the median PFS was 4.2 months (95% CI, 2.9-7.1) versus 2.6 months (95% CI, 1.4-3.1; HR, 0.527; 95% CI, 0.380-0.729; log-rank P < .0001).
The triplet therapy elicited an ORR of 64.3% (95% CI, 54.7%-73.1%) compared to 41.5% (95% CI, 32.5%-51.0%) with the doublet (P = .0006). Complete response (CR) rates were 40.2% (95% CI, 31.0%-49.9%) and 18.6% (95% CI, 12.1%-26.9%), respectively.
Impact Across CD30 Expression Levels
Notably, the improvement in ORR with the addition of brentuximab vedotin was observed regardless of CD30 expression levels. In patients with CD30 negative tumors (<1%), the triplet (n = 76) achieved an ORR of 60.5% (95% CI, 48.6%-71.6%) compared to 37.5% (95% CI, 26.9%-49.0%) with the doublet (n = 80; P = .0063). For those with CD30 positive tumors (≥1%), the ORRs were 72.2% (95% CI, 54.8%-85.8%) and 50.0% (95% CI, 33.4%-66.6%; P = .0602) for the triplet and doublet, respectively.
Expert Commentary
"This triplet combination, with its promising OS benefit, has the potential to address the high unmet need of patients with relapsed/refractory DLBCL, particularly those who are not able to receive CAR T-cell therapy or bispecific antibodies or who have relapsed/refractory disease following these treatments," said Christopher A. Yasenchak, MD, of Willamette Valley Cancer Institute and Research Center/US Oncology Research.
Study Design and Patient Population
The ECHELON-3 study was a randomized, double-blind, placebo-controlled, multicenter phase 3 trial. It enrolled patients with relapsed/refractory DLBCL who had received at least two prior lines of therapy. Key inclusion criteria included age of 18 years or older, an ECOG performance status of 0 to 2, and fluorodeoxyglucose-avid, measurable disease. Patients who were candidates for or had relapsed after hematopoietic stem cell transplant or CAR T-cell therapy were excluded. Patients with prior exposure to brentuximab vedotin or lenalidomide, active cerebral or meningeal disease, or grade 2 or higher peripheral neuropathy were also excluded.
Participants were randomized 1:1 to receive either 1.2 mg/kg of intravenous brentuximab vedotin every three weeks or placebo, combined with 20 mg of oral lenalidomide once daily and 375 mg/m2 of IV rituximab every three weeks. Stratification factors included CD30 status (≥1% vs <1%), cell of origin (germinal center B cell [GCB] vs non-GCB), previous CAR T-cell therapy (yes vs no), and prior stem cell transplant (yes vs no).
The primary endpoint of the trial was OS in the intention-to-treat (ITT) population. Secondary endpoints included investigator-assessed PFS and ORR per Lugano 2014 criteria in the ITT population, investigator-assessed CR rate, investigator-assessed duration of response (DOR), OS in the CD30-positive population, and safety and tolerability.
Safety Profile
No new safety signals were observed with the addition of brentuximab vedotin to lenalidomide/rituximab. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 97% of patients in both arms; grade 3 or higher TEAEs occurred in 88% versus 77% of patients. Grade 5 TEAEs were experienced by 12% of those who received the brentuximab regimen versus 8% of those given the placebo arm.
The most common TEAEs reported in the triplet and doublet arms were neutropenia, thrombocytopenia, diarrhea, anemia, fatigue, COVID-19, asthenia, constipation, reduced appetite, pneumonia, cough, pyrexia, nausea, and pruritus. Any-grade peripheral neuropathy occurred in 31% of those given the brentuximab triplet and 24% of those given the doublet.
"AEs were manageable with dose modifications and consistent with the known safety profile of each individual drug," Yasenchak said.
