Brentuximab Vedotin Triplet Continues to Improve R/R Diffuse Large B-Cell Lymphoma Outcomes

Christopher A. Yasenchak, MD

The addition of brentuximab vedotin (Adcetris) to lenalidomide (Revlimid) and rituximab (Rituxan) significantly improved overall survival (OS), progression-free survival (PFS), and objective response rates (ORR) vs lenalidomide/rituximab alone in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received at least 2 prior lines of systemic therapy, according to data from the phase 3 ECHELON-3 study (NCT04404283) presented during the 2024 SOHO Annual Meeting.¹

As presented at the 2024 ASCO Annual Meeting, at a median follow-up of 15.5 months (95% CI, 12.2-18.1) for the brentuximab regimen (n = 112) and 18.9 months (95% CI, 12.2-23.2) for lenalidomide/rituximab alone (n = 118), the median OS was 13.8 months (95% CI, 10.3-18.8) vs 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.²

The triplet also resulted in a 47% reduction in the risk of disease progression or death vs the doublet. At a median follow-up of 11.1 months (95% CI, 8.6-14.2) for the triplet and 8.8 months (95% CI, 6.9-10.9) for the doublet, the median PFS for the respective regimens was 4.2 months (95% CI, 2.9-7.1) and 2.6 months (95% CI, 1.4-3.1; HR, 0.527; 95% CI, 0.380-0.729; log-rank P < .0001). Notably, the OS and PFS benefits achieved with the brentuximab vedotin regimen were upheld across the key subgroups analyzed.

The triplet elicited an ORR of 64.3% (95% CI, 54.7%-73.1%) vs 41.5% (95% CI, 32.5%-51.0%) with the doublet (P = .0006); the respective complete response (CR) rates were 40.2% (95% CI, 31.0%-49.9%) and 18.6% (95% CI, 12.1%-26.9%).

The ORR improvement with the addition of brentuximab vedotin was observed irrespective of CD30 expression.¹ In those who were CD30 negative (<1%), the triplet (n = 76) elicited an ORR of 60.5% (95% CI, 48.6%-71.6%) vs 37.5% (95% CI, 26.9%-49.0%) with the doublet (n = 80; P = .0063).1 In those who were CD30 positive (≥1%), the respective ORRs with the triplet (n = 36) and doublet (n = 38) were 72.2% (95% CI, 54.8%-85.8%) and 50.0% (95% CI, 33.4%-66.6%; P = .0602).

“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,” Christopher A. Yasenchak, MD, of Willamette Valley Cancer Institute and Research Center/US Oncology Research, in Eugene, Oregon, said in an oral presentation of the data.

The randomized, double-blind, placebo-controlled, multicenter, phase 3 ECHELON-3 study enrolled patients with relapsed/refractory DLBCL who had received at least 2 prior lines of therapy. These patients were at least 18 years of age; had an ECOG performance status of 0 to 2; and fluorodeoxyglucose-avid, measurable disease. They could not have been candidates for, or experienced disease relapse after, hematopoietic stem cell transplant or CAR T-cell therapy. If they had prior exposure to brentuximab vedotin or lenalidomide, active cerebral or meningeal disease, or grade 2 or higher peripheral neuropathy, they were excluded.

Study participants were randomly assigned 1:1 to receive 1.2 mg/kg of intravenous brentuximab vedotin every 3 weeks or placebo paired with 20 mg of oral lenalidomide once daily and 375 mg/m2 of IV rituximab every 3 weeks. They were stratified based on 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 trial’s primary end point was OS in the intention-to-treat (ITT) population. Secondary end points 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.

Of the total 230 patients who underwent randomization, 112 were assigned to the triplet arm and 118 were assigned to the doublet arm; 112 and 116 patients, respectively, comprise the safety population. At the time of presentation, 22 patients were still receiving the triplet and 14 patients were still receiving the doublet. The median duration of treatment with the brentuximab regimen was 3.6 months (range, 0.5-26.4) vs 2.0 months (range, 0.1-26.6) with lenalidomide/rituximab alone.

Patient characteristics were well balanced between the treatment arms, Yasenchak said. The median patient age was 74.0 years (range, 29-87) in the triplet arm vs 70.0 years (range, 21-89). Most patients were aged 65 years or older (71%; 64%) and White (48%; 47%) and about half were male (54%; 59%). Eleven percent of patients in each arm have an ECOG performance status of 2. The median number of prior lines of systemic treatment in both arms was 3 (range, 2-8), with most patients having received prior anthracyclines (98%; 97%) and anti-CD20 antibodies (96%; 97%).

Disease characteristics were also well balanced across the groups, according to Yasenchak. Slightly more than half of patients in the triplet and doublet arms had DLBCL not otherwise specified (56% vs 54%); 29% and 23% of patients, respectively, had transformed DLBCL. Regarding cell of origin in the brentuximab arm, 46% had GCB and 54% had non-GCB disease; these rates were similar in the doublet arm. In terms of CD30 status, 32% of patients in both arms had a status of 1% or higher and 68% had a status of less than 1%.

Subgroup analysis revealed that the median OS was longer with brentuximab vedotin plus lenalidomide/rituximab vs lenalidomide/rituximab alone across subgroups, including age (<65 years: HR, 088; ≥65 years: HR, 0.54), CD30 expression (<1%: HR, 0.56; ≥1%: HR, 0.83), cell of origin (GCB: HR, 0.77; non-GCB: HR, 0.55), previous CAR T-cell therapy (yes: HR, 0.38; no: HR, 0.74), baseline International Prognostic Index (IPI) score (<3: HR, 0.75; ≥3: HR, 0.55), status after last therapy (refractory: HR, 0.57; relapsed: HR, 0.76), region (North America: HR, 0.83; Europe: HR, 0.57; Asia-Pacific: HR, 0.58), and whether they had double-/triple-hit lymphoma (yes: HR, 0.49; no: HR, 0.63).

Median PFS was also longer with the triplet vs the doublet across the subgroups, including age (<65 years: HR, 0.69; ≥65 years: HR, 0.48), CD30 expression (<1%: HR, 0.57; ≥1%: HR, 0.49), cell of origin (GCB: HR, 0.55; non-GCB: HR, 0.52), prior CAR T-cell therapy (yes: HR, 0.41; no: HR, 0.58), baseline IPI score (<3: HR, 0.60; ≥3: HR, 0.49), status after last therapy (refractory: HR, 0.51; relapsed: HR, 0.29), region (North America: HR, 0.65; Europe: HR, 0.48; Asia-Pacific: HR, 0.50), and double-/triple-hit lymphoma (yes: HR, 0.36; no: HR, 0.56).

The median DOR with the triplet was 8.3 months (95% CI, 4.2-15.3) vs 3.0 months (95% CI, 2.8-5.4) with the doublet. In those who experienced a CR with the triplet or doublet, the median DOR was 18.9 months (95% CI, 11.1-not reached [NR]) and NR (95% CI, 2.8-NR), respectively. The median time to CR onset was 1.58 months (range, 1.2-7.3) with brentuximab vedotin vs 1.61 months (range, 0.7-4.6) without.

No new safety signals were observed with the addition of brentuximab vedotin to lenalidomide/rituximab, Yasenchak noted. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 97% of patients in both arms; grade 3 or higher TEAEs occurred in 88% vs 77% of patients. Grade 5 TEAEs were experienced by 12% of those who received the brentuximab regimen vs 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.

Subsequent anticancer therapies received were well balanced across the groups; 34% of those in the brentuximab vedotin arm and 47% of those in the placebo arm received subsequent treatment. The most common reason for doing so in the brentuximab vedotin arm was progressive disease (27%), followed by relapsed disease (5%) and other (4%). The most common reasons in the placebo arm were progressive disease (38%), other (7%), relapsed disease (4%), and secondary malignancies (2%). In the brentuximab vedotin arm, subsequent treatment included anti-CD20 therapy (8%), antibody-drug conjugates (6%), bispecific antibodies (4%), CAR T-cell therapy (4%), tafasitamab (Monjuvi; 4%), or other (11%); these respective rates in the placebo arm were 9%, 5%, 9%, 4%, 1%, and 23%.

References

1. Yasenchak CA, Kim J-A, Hahn U, et al. Brentuximab vedotin in combination with lenalidomide and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma: results from the phase 3 ECHELON-3 study. Presented at: 2024 SOHO Annual Meeting; September 4-7, 2024; Houston, Texas. Poster ABCL-711.
2. Kim J, Hahn U, Kim WS, et al. Brentuximab vedotin in combination with lenalidomide and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma: results from the phase 3 ECHELON-3 study. J Clin Oncol. 2024;42(suppl 16):LBA7005. doi:10.1200/JCO.2024.42.16_suppl.LBA7005