Forward, Nicholas

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.

Introduction Patients (pts) with progressive disease after ≥2 prior lines of systemic therapy are unlikely to derive additional benefit from current salvage immunochemotherapies, and survival declines significantly with each subsequent treatment. Pts with refractory disease following second-line therapy have worse outcomes, with reported overall response rates (ORRs) of 1% to 14% and overall survival (OS) of 5 months (Blood. 2017;130[16]:1800-1808). While chimeric antigen receptor (CAR) T-cell therapy has become a preferred strategy in the second- and third-line settings, pts with R/R disease following CAR-T experience dismal survival, with progression-free survival (PFS) and OS as low as 3 and 5 months, respectively, and no agreed standard of care post CAR-T (Blood. 2022;140[24]:2527-2529). The randomized, global, phase 3 ECHELON-3 study (NCT04404283) was conducted in pts with R/R DLBCL after ≥2 prior therapies who were ineligible for hematopoietic stem cell transplant and/or CAR-T. Here, we present subgroup analyses in pts with 2 prior lines of therapy, refractory disease, or prior CAR-T. Methods In these subgroup analyses of ECHELON-3, eligible pts had 2 prior lines of systemic therapy, disease refractory to the last prior therapy, or prior exposure to CAR-T. Pts could qualify for ≥1 subgroup and were analyzed separately. Refractory disease was defined as stable or progressive disease as best overall response to last line of treatment or relapse ≤6 months from the end of treatment. Pts were randomized 1:1 to receive brentuximab vedotin (BV; 1.2 mg/kg) or placebo every 3 weeks (q3w), in combination with rituximab (R; 375 mg/m2) q3w and lenalidomide (Len; 20 mg) once daily. Efficacy was assessed by investigators per Lugano 2014 classification. The primary endpoint was OS, with key secondary endpoints of PFS and ORR. P values are descriptive. Results In total, 230 pts were enrolled in ECHELON-3 from April 2021 to November 2023, with a median follow-up of 16.4 months (range, 0.1-31.5 months). Overall, 94 pts with 2 prior lines of systemic therapy were enrolled and randomized to BV+Len+R (n=48) or placebo+Len+R (n=46). Median OS was 16.3 months (95% CI, 12.6 months-not estimable) with BV+Len+R vs 8.5 months (95% CI, 4.1-15.8 months) with placebo+Len+R (hazard ratio [HR], 0.557; 95% CI, 0.317-0.977; P=.0388). Median PFS was 7.1 months (95% CI, 3.6-12.6 months) with BV+Len+R vs 2.7 months (95% CI, 1.4-4.0 months) with placebo+Len+R (HR, 0.462; 95% CI, 0.279-0.764; P=.0020). ORR was 68.8% (95% CI, 53.7%-81.3%) with BV+Len+R vs 43.5% with placebo+Len+R (95% CI, 28.9%-58.9%; P=.0216); complete response (CR) rate was 52.1% vs 13.0%, respectively. Additional data for pts by lines of therapy received will be presented. In total, 194 pts with disease refractory to the most recent systemic therapy were enrolled and randomized to BV+Len+R (n=98) and placebo+Len+R (n=96). Median OS was 11.7 months (95% CI, 8.8-16.3 months) with BV+Len+R vs 5.5 months (95% CI, 3.7-8.5 months) with placebo+Len+R (HR, 0.566; 95% CI, 0.396-0.808; P=.0015). Median PFS was 4.1 months (95% CI, 2.8-5.4 months) with BV+Len+R vs 1.5 months (95% CI, 1.4-2.6 months) with placebo+Len+R (HR, 0.508; 95% CI, 0.363-0.712; P&lt;.0001). ORR was 59.2% (95% CI, 48.8%-69.0%) with BV+Len+R vs 29.2% (95% CI, 20.3%-39.3%) with placebo+Len+R (P&lt;.0001); CR rate was 34.7% vs 11.5%, respectively. Overall, 67 pts who received prior CAR-T were enrolled and randomized to BV+Len+R (n=32) and placebo+Len+R (n=35). Median OS was 15.6 months with BV+Len+R vs 4.4 months with placebo+Len+R (HR, 0.38; 95% CI, 0.2-0.75). Median PFS was 3.0 months with BV+Len+R vs 1.4 months with placebo+Len+R (HR, 0.41; 95% CI, 0.22-0.76). ORR was 65.6% (95% CI, 46.8%-81.4%) with BV+Len+R vs 25.7% (95% CI, 12.5%-43.3%) with placebo+Len+R (P=.0014); CR rate was 37.5% vs 11.4%, respectively. Conclusions BV+Len+R demonstrated a clinically meaningful improvement in all key efficacy outcomes, including CR and OS, in pts with 2 prior lines of therapy, disease refractory to prior treatment, or prior CAR-T. This treatment benefit was generally consistent with that observed in the overall ECHELON-3 study population. Therefore, BV+Len+R has the potential to address an unmet need for effective and tolerable therapy in heavily pretreated pts, as described above.