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CHICAGO -- A triplet combination consisting of the antibody-drug conjugate brentuximab vedotin (BV; Adcetris) plus lenalidomide (Revlimid) and rituximab for diffuse large B-cell lymphoma (DLBCL) improved survival in the third-line setting over lenalidomide-rituximab alone, an interim analysis of the phase III ECHELON-3 trial demonstrated.

Among more than 200 patients receiving lenalidomide-rituximab, median overall survival (OS) improved from 8.5 months with placebo to 13.8 months with the addition of BV, representing a 37% reduction in the risk for death (HR 0.63, 95% CI 0.45-0.89, P=0.0085), reported Jeong-A Kim, MD, of the Catholic University of Korea in Suwon, at the American Society of Clinical Oncology meeting here.

The promising OS benefit with the triplet has the potential to address a high unmet need for patients with relapsed/refractory DLBCL, Kim said. Notably, the trial enrolled patients who were either ineligible for or had relapsed after CAR T-cell therapy or hematopoietic stem-cell transplantation (HSCT).

Secondary endpoints showed improved progression-free survival (PFS) with the addition of BV (4.2 vs 2.6 months with placebo; HR 0.53, 95% CI 0.38-0.73, P<0.0001) as well as significantly greater overall response rates (64% vs 42%) and complete response (CR) rates (40% vs 19%).

BV plus lenalidomide-rituximab may represent an encouraging treatment for patients who are ineligible for CAR-T, transplant, or bispecific antibodies due to things like access issues, comorbidities, and prior treatment exposure, said session discussant Peter Riedell, MD, of the University of Chicago.

He noted that while CAR T-cell therapy and HSCT are potent therapies in the relapsed/refractory setting, these treatments can often be challenging for a variety of reasons, including patient-, disease-, and logistic-related factors. Furthermore, for patients who do receive CAR-T, approximately 60% experience treatment failure and outcomes with subsequent lines of therapy are often rather poor, he said.

Importantly, Riedell pointed out, responses to the triplet regimen in ECHELON-3 were observed in CD30-positive and CD30-negative disease, and the OS benefit was shown in meaningful high-risk disease subsets, such as those with a high International Prognostic Index (IPI) score, advanced age, non-germinal center B-cell (GCB) phenotype, and those with prior exposure to CAR-T.

The regimen was not without toxicity, he said. "We saw a higher incidence of grade 3 or greater treatment-emergent adverse events [AEs]. There was additionally a higher burden of hematologic toxicity, even despite the requirement for growth-factor support, and also a higher incidence of any-grade peripheral neuropathy."

In March, BV's drugmaker Pfizer said it was in about an indication in DLBCL based on the results of the current study. The CD30-directed antibody already carries multiple indications in lymphoma, including for classical Hodgkin's lymphoma, systemic anaplastic large cell lymphoma, and other CD30-expressing peripheral T-cell lymphomas.

Kim presented an interim analysis of the phase III trial, which included 230 patients with relapsed/refractory DLBCL who had failed at least two prior lines of therapy. Patients were randomized 1:1 to lenalidomide-rituximab plus either BV or placebo. Patients were excluded if they had previously received lenalidomide or BV.

The participants enrolled in the trial were reflective of real-world clinical practice, said Riedell. They had a median age of 70-74, 56% were men, a little more than half were white, and about a fourth were Asian. A majority had primary refractory disease, 54% had non-GCB disease, 32% were CD30-negative, and 60% had an IPI score ≥3 at enrollment.

In terms of prior treatment, patients had a median of three prior lines of therapy, with nearly all having previously received anthracyclines and an anti-CD20 antibody. Nearly 30% had received CAR T-cell therapy, 15% had been treated with a bispecific antibody, and 12% had a prior HSCT.

In the CD30-negative subgroup, 61% of patients responded to the BV-containing regimen as compared with 38% with lenalidomide-rituximab alone, including CRs in 41% and 15%, respectively. In the CD30-positive subgroup, 72% of patients responded to the BV-containing regimen versus 50% with lenalidomide-rituximab alone, including CRs in 39% and 26%.

Overall, the median duration of response reached 8.3 months with the triplet regimen versus 3 months with lenalidomide-rituximab alone.

Kim noted that no new safety signals were detected.

Grade ≥3 AEs occurred more frequently in the triplet arm (88% vs 77%), as did peripheral neuropathy of any grade (31% vs 24%). AE-related deaths occurred in 12% of patients who received the BV-containing regimen (primarily due to neurotoxicity and infections due to bone marrow suppression, including COVID-19) and 8% of those who received lenalidomide-rituximab alone.

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