Brentuximab Vedotin Combination for Relapsed Diffuse Large B-Cell Lymphoma

Abstract

Purpose: In patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), brentuximab vedotin (BV) as monotherapy or combined with either lenalidomide (Len) or rituximab (R) has demonstrated efficacy with acceptable safety. We evaluated the efficacy and safety of BV + Len + R versus placebo + Len + R in patients with R/R DLBCL.

Methods: ECHELON-3 is a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial comparing BV + Len + R with placebo + Len + R in patients with R/R DLBCL. Patients received BV or placebo once every 3 weeks, Len once daily, and R once every 3 weeks. The primary end point was overall survival (OS), and secondary end points included investigator-assessed progression-free survival (PFS) and objective response rate (ORR). A prespecified interim analysis was performed after 134 OS events, with two-sided P = .0232 as the efficacy boundary.

Results: Patients (N = 230) were randomly assigned to receive BV + Len + R (n = 112) or placebo + Len + R (n = 118). Two patients in the placebo arm did not receive treatment. With a median follow-up of 16.4 months, the median OS was 13.8 months with BV + Len + R versus 8.5 months with placebo + Len + R (hazard ratio, 0.63 [95% CI, 0.45 to 0.89]; two-sided P = .009). The median PFS was 4.2 months with BV + Len + R versus 2.6 months with placebo + Len + R (hazard ratio, 0.53 [95% CI, 0.38 to 0.73]; two-sided P < .001). The ORR was 64% ([95% CI, 55 to 73]; two-sided P < .001) with BV + Len + R and 42% (95% CI, 33 to 51) with placebo + Len + R; complete response rates were 40% and 19%, respectively. Treatment-emergent adverse events (AEs) occurred in 97% of patients in both arms. In both arms, the most common treatment-emergent AEs were neutropenia, thrombocytopenia, diarrhea, and anemia.

Conclusion: BV + Len + R demonstrated a statistically significant survival benefit with a manageable safety profile in heavily pretreated patients with R/R DLBCL.

Trial registration: ClinicalTrials.gov NCT04404283.

FIG 1.

Enrollment, random assignment, and follow-up. A total of 339 patients were assessed for eligibility, and 230 patients were randomly assigned to receive BV + Len + R or placebo + Len + R. The intention-to-treat population included all randomly assigned patients, and the safety population included patients who received ≥1 dose of the study treatment. BV, brentuximab vedotin; Len, lenalidomide; R, rituximab.

FIG 2.

OS in the intention-to-treat population. (A) Shows the Kaplan-Meier estimates of OS in the intention-to-treat population. The median OS was significantly longer with BV + Len + R. Tick marks on the curves indicate censoring of data. (B) Shows a subgroup analysis of OS. ^aSubgroup with hazard ratio for death of <1. BV, brentuximab vedotin; CAR, chimeric antigen receptor; ECOG PS, Eastern Cooperative Oncology Group performance status; GCB, germinal center B cell; IPI, International Prognostic Index; Len, lenalidomide; NA, not available; OS, overall survival; R, rituximab; R/R, relapsed or refractory.

FIG 3.

PFS in the intention-to-treat population. (A) Shows the Kaplan-Meier estimates of investigator-assessed PFS in the intention-to-treat population. The median PFS was significantly longer with BV + Len + R. Tick marks on the curves indicate censoring of data. (B) Shows subgroup analysis of PFS. ^aSubgroup with hazard ratio for disease progression or death of <1. BV, brentuximab vedotin; CAR, chimeric antigen receptor; ECOG PS, Eastern Cooperative Oncology Group performance status; GCB, germinal center B cell; IPI, International Prognostic Index; Len, lenalidomide; PFS, progression-free survival; R, rituximab.

FIG A1.

PFS in patients with complete or partial response. Kaplan-Meier estimates of investigator-assessed PFS (A) in patients who achieved complete response, and (B) in patients who achieved a partial response. Tick marks on the curves indicate censoring of data. BV, brentuximab vedotin; Len, lenalidomide; NE, not evaluable; PFS, progression-free survival; R, rituximab.

FIG A2.

DOR in the intent-to-treat population. Kaplan-Meier estimates of DOR in evaluable patients per Lugano classification, as determined by the investigator. (A) DOR (complete or partial) in the intent-to-treat population. (B) Duration of complete response in evaluable patients. (C) Duration of partial response in evaluable patients. Tick marks on the curves indicate censoring of data. BV, brentuximab vedotin; DOR, duration of response; Len, lenalidomide; NE, not evaluable; R, rituximab.