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Triplet Notches Survival Win in Heavily Pretreated DLBCL

— Benefit with BV plus lenalidomide-rituximab seen in those who relapsed after CAR-T or transplant

Last Updated June 3, 2024
MedpageToday

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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    Ian Ingram is Managing Editor at 鶹ý and helps cover oncology for the site.

Disclosures

Kim reported no disclosures.

Riedell disclosed relationships (including institutional research funding) with Abbvie, ADC Therapeutics, BeiGene, Bristol Myers Squibb/Celgene, Calibr, Cellectis, CRISPR Therapeutics, CVS, Fate Therapeutics, Genentech/Roche, Genmab, Intellia Therapeutics, Kite/Gilead, Nektar, Novartis, Pharmacyclics/Janssen, Sana Biotechnology, Tessa Therapeutics, and Xencor.

Primary Source

American Society of Clinical Oncology

Kim JA "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" ASCO 2024; Abstract LBA7005.