Brentuximab Vedotin Combo Adds Another Targeted Option Beyond CD19/CD20 in R/R LBCL

Grzegorz S. Nowakowski, MD

The treatment landscape for relapsed/refractory large B-cell lymphoma (LBCL) has evolved with the development of various therapies targeting CD19 and CD20; now, the CD30-targeted antibody-drug conjugate brentuximab vedotin (Adcetris) offers another targeted therapy approach for this patient population, according to Grzegorz S. Nowakowski, MD.

In February 2025, the FDA approved brentuximab vedotin in combination with lenalidomide (Revlimid) and rituximab (Rituxan) for adult patients with relapsed or refractory 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 or CAR T-cell therapy.

This approval is based on findings from the phase 3 ECHELON-3 trial (NCT04404283), which demonstrated that the combination (n = 112) generated 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 placebo plus lenalidomide and rituximab (n = 118; HR, 0.63; 95% CI, 0.45-0.89; P = .0085).

“With all these new treatments in LBCL, sequencing of therapies will be very important, and we'll learn over time how to best sequence those therapies,” Nowakowski explained. “However, right now, with the exhaustion of some of the CD20- and CD19-targeting treatments, [brentuximab vedotin plus lenalidomide and rituximab] is important because it provides a different way of targeting the tumor. More therapies like this targeting different antigens will probably be seen in the future.”

In the interview with OncLive®, Nowakowski discussed the FDA approval of brentuximab vedotin plus lenalidomide and rituximab; expanded on the data that supported the approval; and explained where this regimen could fit into clinical practice.

Nowakowski is a professor of medicine and a professor of oncology; a consultant in the Division of Hematology of the Department of Internal Medicine; and the enterprise deputy director of Clinical Research at Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota.

OncLive: What is the significance of the FDA approval of brentuximab vedotin in combination with lenalidomide and rituximab for patients with relapsed/refractory LBCL?

Nowakowski: We have seen significant changes in the landscape of therapy of LBCL, particularly in the relapsed/refractory setting where we have [recently had] a number of new treatments approved. [The brentuximab vedotin combination] is important because it provides a new way of treating LBCL in the relapsed/refractory setting by targeting CD30 [via brentuximab vedotin] in combination with lenalidomide and rituximab. Many currently approved treatments target CD19 or CD20. Targeting a different antigen [with CD30] using a different mode of action provides a new opportunity for our patients.

What was the rationale for conducting the ECHELON-3 trial, and which patient populations were included in the study?

The rationale was built on an initial phase 1/2 study [NCT02086604], which was developed by Nancy L. Bartlett, MD, of the University of Washington, as an investigator-initiated trial. This [phase 1/2] trial showed that this combination could be active in patients with relapsed/refractory aggressive lymphomas, and this led to development of this [phase 3 trial], which focused on patients who were ineligible for high-dose chemotherapy or [autologous] stem cell transplantation and had [received] at least 2 prior lines of therapy.

A lot of patients in the study [relapsed] after transplant or CAR T-cell therapy, which is currently a huge unmet need. Despite the progress of cellular therapies, unfortunately, the majority of patients will still relapse after CAR T-cell therapy. In [ECHELON-3], patients were randomly assigned to treatment with brentuximab vedotin [plus] lenalidomide and rituximab vs lenalidomide and rituximab alone.

The primary end point [of the study] was OS, and this study showed that the addition of brentuximab vedotin resulted in improvement in OS, [along with] secondary end points of [overall] response rate [ORR] and progression-free survival [PFS].

What efficacy and safety data from this trial contributed to the FDA approval of this treatment?

[OS] was significantly improved from a median of 8.5 months in the control arm to 13.8 months in the experimental arm. [This is] a significant separation of OS curves. If you look at the secondary end points, ORR was also significantly improved [at 64.3% (95% CI, 54.7%-73.1%) in the experimental arm vs 41.5% (95% CI, 32.5%51.0%) in the control arm]. This improvement in OS was building on improvement in both ORR and PFS.

What's also important about this combination was that it was very well tolerated overall. The [observed] toxicity was primarily hematological associated with myeloid suppression, but overall, patients were able to tolerate this combination quite well.

What guidance would you offer to clinicians on incorporating this combination into their clinical practice?

With new treatments, the question is, ‘Where does this regimen fit into the treatment [paradigm]?’ I would consider [brentuximab vedotin plus lenalidomide and rituximab] for patients who relapse after CAR T-cell therapy or transplant, or for patients who are not eligible for those therapies in the third line.

[Brentuximab vedotin plus lenalidomide and rituximab] will be positioned somewhere in between bispecific antibodies and the other CD19-targeting therapies approved in this space, like loncastuximab tesirine [Zynlonta] or tafasitamab [Monjuvi] plus lenalidomide. The importance here is that [brentuximab vedotin] targets a different antigen than currently approved therapies, including bispecific antibodies, which are targeting C20.

[This approval] provides an option for those patients outside of those 2 other major targets [CD19 and CD20] that are currently used in clinical practice.

I would also mention that although brentuximab vedotin targets CD30, activity is seen in both patients with CD30-negative and CD30-positive disease. The ORR is somewhat higher in patients with CD30-positive [disease], but it is still very high, approaching 60%, in patients with CD30-negative disease. This is based on the fact that CD30 is expressed in a tumor microenvironment. Therefore, [when] selecting patients for this treatment in clinical practice, we do not need to assess CD30 expression. Essentially, all patients with aggressive lymphoma are eligible for this combination [if it is indicated].

Reference

1. FDA approves brentuximab vedotin with lenalidomide and rituximab for relapsed or refractory large B-cell lymphoma. FDA. February 12, 2025. Accessed March 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brentuximab-vedotin-lenalidomide-and-rituximab-relapsed-or-refractory-large-b-cell