FDA Approves Brentuximab Vedotin, Lenalidomide, Rituximab Triplet for R/R LBCL

The triplet therapy of brentuximab vedotin (Adcetris; Seagen), lenalidomide, and a rituximab product was approved late yesterday by the FDA to treat relapsed or refractory large B-cell lymphoma (LBCL), including diffuse LBCL (DLBCL) not otherwise specified (NOS), DLBCL arising from indolent lymphoma, or high-grade BCL.¹

Adult patients may qualify for the treatment if they have failed 2 or more prior systemic therapies and are ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) or chimeric antigen receptor (CAR) T-cell therapy, according to the announcement.

Interim data from ECHELON-3 previously showed this triplet to improve overall survival among patients who have relapsed or refractory large B-cell lymphoma. | Image Credit: © wladimir1804 - stock.adobe.com

This approval was based on results seen in the ongoing phase 3 ECHELON-3 (NCT04404283) trial of 230 patients living with relapsed/refractory LBCL from the US, Australia, Belgium, Canada, Czechia, Denmark, France, Germany, Italy, Republic of Korea, Netherlands, Poland, Spain, Switzerland, Taiwan, and the United Kingdom.² The expected primary completion date of the study is May 31, 2025, and the estimated study completion date is April 30, 2027. Participants were randomized 1:1 to receive brentuximab vedotin/lenalidomide/rituximab or placebo/lenalidomide/rituximab until disease progression or unacceptable toxicity.

The primary study outcome is overall survival (OS), and secondary outcomes are progression-free survival (PFS) and objective response rate (ORR) per 2014 Lugano Criteria, which is used to evaluate findings seen with a fluorodeoxyglucose PET/CT for lymphoma.^3,4

The OS improvement was considered statistically significant, at a median of 13.8 months (95% CI, 10.3-18.8) among the patients who received brentuximab vedotin/lenalidomide/rituximab compared with 8.5 months (95% CI, 5.4-11.7) seen in those who received placebo/lenalidomide/rituximab.¹ This translates to a 37% reduced risk of death (HR, 0.63; 95% CI, 0.45, 0.89; P = .0085) for those who received the triplet.

For the secondary outcomes of PFS and ORR, the triplet treatment again bested the placebo-based regimen, with a 47% reduced risk of death (HR, 0.53, 95% CI, 0.38-0.73; P < .0001):

• Brentuximab vedotin/lenalidomide/rituximab:
  • PFS: 4.2 months (95% CI, 2.9-7.1)
  • ORR: 64.3% (95% CI, 54.7%-73.1%)
• Placebo/lenalidomide/rituximab:
  • PFS: 2.6 months (95% CI, 1.4-3.1)
  • ORR: 41.5% (95% CI, 32.5%-51.0%)

In ECHELON-3, common (≥20%) adverse events were fatigue, diarrhea, peripheral neuropathy, rash, pneumonia, and COVID-19 infection. Grade 3/4 lab abnormalities (> 10%) were decreased neutrophils, lymphocytes, platelets, and hemoglobin. During the study, 6% of patients switched to a reduced dose of brentuximab vedotin and 4.5% discontinued treatment after developing or experiencing a worsening of peripheral neuropathy.

The current recommended dose of brentuximab vedotin is 1.2 mg/kg when combined with lenalidomide and rituximab; it is administered every 3 weeks until disease progression or unacceptable toxicity.

Interim data from ECHELON-3, published earlier this year, showed a statistically significant survival advantage and acceptable safety profile of brentuximab vedotin/lenalidomide/rituximab vs placebo/lenalidomide/rituximab in heavily pretreated patients living with R/R DLBCL⁵:

• Median OS was 13.8 (95% CI, 10.3-18.8) vs 8.5 (95% CI, 5.4-11.7) months, for a 37% reduced risk of death (HR, 0.63; 95% CI, 0.45-0.89; P = .009)
• Median PFS was 4.2 (95% CI, 2.9-7.1) vs 2.6 (95% CI, 1.4-3.1) months, for a 47% reduced risk of death (HR, 0.53; 95% CI, 0.38-0.73; P <.001)
• ORR was 64% (95% CI, 55%-73%; P <.001) vs 42% (95% CI, 33%-51%)
• Complete response (CR) rates were 40% and 19%, respectively, with corresponding median CRs of 18.9 months (95% CI, 11.1-not evaluable [NE]) and NE (95% CI, 2.8 months-NE)
• Median duration of response was 8.3 (95% CI, 4.2-15.3) vs 3.0 (95% CI, 2.8-5.4) months

Brentuximab vedotin is also indicated for use in patients with Hodgkin lymphoma who failed autologous stem cell transplant (ASCT) or those who failed at least 2 previous multi-agent chemotherapy regiments and are not candidates for ASCT.⁶ It was first approved for use in the US in 2011.⁷

References

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

2. Brentuximab vedotin plus lenalidomide and rituximab for the treatment of relapsed/refractory DLBCL (ECHELON-3). ClinicalTrials.gov. Updated November 13, 2024. Accessed February 12, 2025. https://clinicaltrials.gov/study/NCT04404283

3. Van Heertum RL, Scarimbolo R, Wolodzko JG, et al. Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma: an operational approach for clinical trials. Drug Des Devel Ther. 2017;11:1719-1728. doi:10.2147/DDDT.S136988

4. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068. doi:10.1200/JCO.2013.54.8800

5. Cortese T. Brentuximab vedotin combination improves survival in pretreated R/R DLBCL. CancerNetwork^®. January 17, 2025. Accessed February 12, 2025. https://www.cancernetwork.com/view/brentuximab-vedotin-combination-improves-survival-in-pretreated-r-r-dlbcl

6. Adcetris. Prescribing information. Seattle Genetics; 2014. Accessed February 12, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125388_s056s078lbl.pdf

7. Leach B. FDA approves brentuximab vedotin for 2 types of lymphoma. OncLive^®. August 19, 2011. Accessed February 12, 2025. https://www.onclive.com/view/fda-approves-brentuximab-for-2-types-of-lymphoma