Detailed overall survival (OS) results from the ongoing, randomized, double-blind, multicenter Phase 3 ECHELON-3 study (NCT04404283) investigating brentuximab vedotin (Adcetris®; Pfizer*/Takeda) in combination with lenalidomide (Revlimid®; Celgene Corporation, a Bristol Myers Squibb company) and rituximab (Retuxan®; Genentech/Biogen) for the treatment of patients with relapsed/refractory will be presented at the annual meeting of the American Society of Clinical Oncology (ASCO), being held May 31, June 1, 2024.

The study showed that the combination regimen containing brentuximab vedotin reduced patients’ risk of death by 37% compared to placebo in combination with lenalidomide and rituximab (HR 0.63 [95% CI: 0.445-0.891] p=0.0085). The overall survival benefit was consistent across levels of CD30 expression.

DLBCL is the most frequent type of lymphoma and is aggressive and difficult to treat.[1][2] More than 25,000 cases of DLBCL are diagnosed each year in the United States, accounting for more than 25 percent of all lymphoma cases.[2] DLBCL can develop spontaneously or as a result of diseases such as chronic lymphocytic lymphoma/small lymphocytic lymphoma, follicular lymphoma, or marginal zone lymphoma.[1] Up to 40 percent of patients relapse or have refractory disease after frontline treatment.[2]

Brentuximab vedotin, an antibody-drug conjugates or ADC, includes a CD30-directed antibody which is attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Pfizer’s proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells.

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Ongoing study
ECHELON-3 is an ongoing, randomized, double-blind, multicenter Phase 3 study evaluating ADCETRIS plus lenalidomide and rituximab versus lenalidomide and rituximab plus placebo in adult patients with relapsed/refractory DLBCL, regardless of CD30 expression, who have received two or more prior lines of therapy and are ineligible for stem cell transplant or CAR-T therapy. In this global study, 230 patients were randomized across North America, Europe and Asia-Pacific. The primary endpoint is OS in the intent to treat population, with key secondary endpoints of PFS and ORR as assessed by investigator. Other secondary endpoints include complete response rate, duration of response, safety and tolerability.

The updated study-results of ECHELON-3 trial will be presented as a late-breaker (LBA7005) in an oral session at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting along with four-year results from the Phase 3 HD21 trial in advanced classical Hodgkin lymphoma (cHL) (LBA7000).

“ECHELON-3 is one of the first randomized, placebo-controlled Phase 3 studies to demonstrate an overall survival benefit in patients with relapsed/refractory DLBCL after two or more prior lines of systemic therapy,” said principal investigator Dr. Jeung-A Kim, MD, Ph.D., College of Medicine, The Catholic University of Korea.

“The clinically meaningful improvement in survival demonstrates the potential benefit of this brentuximab vedotin regimen in relapsed/refractory DLBCL, particularly for patients whose disease has progressed after CAR-T therapy or bispecific antibody treatment or individuals who are not able to receive these treatments.”

Brentuximab vedotin is approved in the U.S. as monotherapy or in combination with chemotherapy for seven lymphomas including certain types of cHL, anaplastic large cell lymphoma and peripheral T-cell lymphoma. Seven-year survival data for a brentuximab vedotin regimen for patients with advanced stage cHL will be shared in a poster presentation (7053) at the ASCO Meeting on June 3, 2024.

“Three Phase 3 trials in three different types of lymphoma have now demonstrated that an brentuximab vedotin-containing regimen improved overall survival,” said Roger Dansey, MD, Chief Development Officer, Oncology, Pfizer.

“Brentuximab vedotin is a standard of care medicine in its approved indications today, and these impressive results from an interim analysis highlight its potential to benefit people with relapsed/refractory DLBCL regardless of CD30 expression.”

Among 230 randomized patients in the trial, the interim analysis showed that median OS in patients randomized to receive the combination of brentuximab vedotin, lenalidomide and rituximab was 13.8 months (95% CI: 10.3-18.8) compared to 8.5 months (95% CI: 5.4-11.7) in patients randomized to lenalidomide and rituximab plus placebo.

Median progression-free survival (PFS) was 4.2 months (95% CI: 2.9-7.1) in the brentuximab vedotin arm versus 2.6 months (95% CI: 1.4-3.1) in the lenalidomide and rituximab plus placebo arm (HR 0.527 [95% CI: 0.380-0.729] p<0.0001). The overall response rate for patients treated with the brentuximab vedotin regimen was 64.3% (95% CI: 54.7-73.1) versus 41.5% (95% CI: 32.5-51.0) in the lenalidomide and rituximab plus placebo arm. The complete response rate was 40.2% in brentuximab vedotin-treated patients (95% CI: 31.0%, 49.9%) compared to 18.6% (95% CI:12.1%, 26.9%) in the lenalidomide and rituximab plus placebo arm.

Adverse events
The most frequently reported treatment-emergent adverse events (TEAEs) Grade 3 or higher for the brentuximab vedotin versus placebo arms were: neutropenia (43% vs 28%), thrombocytopenia (25% vs 19%) and anemia (22% vs 21%). Peripheral sensory neuropathy was infrequent and low grade for each arm with Grade 3 events of 4% vs 0%.

To date, more than 55,000 patients have been treated with brentuximab vedotin in the U.S. since its first U.S. approval in 2011, and more than 140,000 patients have been treated with Brentuximab vedotin globally.

Note: * On December 14, 2023, Pfizer announced the completion of its acquisition of Seagen.
Clinical trials
Brentuximab Vedotin Plus Lenalidomide and Rituximab for the Treatment of Relapsed/​Refractory DLBCL (ECHELON-3). ID – NCT04404283

Highlights of prescribing information
Brentuximab vedotin (Adcetris®; Pfizer/Takeda) [Prescribing Information]
Lenalidomide (Revlimid®; Celgene Corporation, a Bristol Myers Squibb company)[Prescribing Information]
Rituximab (Retuxan®; Genentech/Biogen) [Prescribing Information]

[1]  Diffuse Large B-Cell Lymphoma.National Library of Medicine. Updated April 24, 2023. [Online] Last accesses on June 1, 2024
[2] Diffuse Large B-Cell Lymphoma (DLBCL). Leukemia & Lymphoma Society® (LLS) [Online] Last accessed on June 1, 2024

Featured image: Laboratory at Seagen;s HQ in Bothel, WA.  Photo Courtesy © 2016 – 2024 Seagen/Pfizer. Used with permission.

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