Kim, Jeong‐Ah

Abstract Introduction Diffuse large B-cell lymphoma (DLBCL) is a heterogenous disease with varied expressions of CD30. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate approved for treatment of patients with relapsed or refractory DLBCL in combination with lenalidomide (Len) and rituximab (R). In the phase 3 ECHELON-3 study (NCT04404283), BV + Len + R showed significant overall survival (OS) benefit compared with placebo + Len + R in patients with relapsed or refractory DLBCL. Subgroup analysis from this study showed that BV + Len + R provided clinical benefit regardless of CD30 expression level. We hypothesized that even sub-threshold levels of CD30 expression, below the detection limits of immunohistochemistry (IHC), may be sufficient to elicit the antitumor activity of BV. Here, we further investigated whether trace amounts of CD30 staining are required for patients to benefit from BV + Len + R. Methods In the ECHELON-3 study, patients with relapsed or refractory DLBCL were randomized 1:1 to receive BV + Len + R or placebo + Len + R. The primary endpoint was OS, with progression-free survival (PFS) and objective response rate (ORR), per Lugano 2014, as key secondary endpoints. CD30 expression was assessed by IHC by central and/or local testing. CD30 positivity was scored as the percentage of CD30 positive cells out of neoplastic cells or out of total lymphocytes, when neoplastic cells could not be distinguished. In this updated analysis, patients with CD30 <1% staining by central laboratory IHC were further grouped into CD30 <1% with trace staining and CD30 <1% with no staining. Results Overall, 60 patients in the BV + Len + R group had CD30 <1% expression; of these, 34 had CD30 <1% with trace staining and 26 had CD30 <1% with no staining. In the placebo + Len + R group, 63 patients had CD30 <1% expression; of these, 36 had CD30 <1% with trace staining and 27 had CD30 <1% with no staining. In the overall CD30 <1% groups, numerically greater OS and PFS benefits were observed with BV + Len + R vs placebo + Len + R (HR for OS, 0.57; 95% CI, 0.36-0.89 and HR for PFS, 0.53; 95% CI, 0.34-0.82). In patients with CD30 <1% with trace staining, BV + Len + R showed a numerically higher OS compared with placebo + Len + R, with HR of 0.48 (95% CI, 0.26-0.90); median OS was 15.6 vs 5.2 months. In patients with CD30 <1% with no staining, there was a trend toward higher OS with BV + Len + R vs placebo + Len + R, with HR of 0.66 (95% CI, 0.34-1.28); median OS was 14.8 vs 11.8 months. Similarly, in patients with CD30 <1% with trace staining, BV + Len + R showed a trend toward longer PFS compared with placebo + Len + R, with HR of 0.60 (95% CI, 0.33-1.11); median PFS was 2.8 vs 1.5 months. In patients with CD30 <1% with no staining, a numerically longer PFS benefit was observed with BV + Len + R vs placebo + Len + R, with HR of 0.41 (95% CI, 0.21-0.79); median PFS was 4.2 vs 2.7 months. In the overall groups, ORR was 60.0% with BV + Len + R and 34.9% with placebo + Len + R. Higher ORR was observed with BV + Len + R compared with placebo + Len + R in both CD30 <1% with trace staining (55.9% vs 25.0%) and CD30 <1% with no staining (65.4% vs 48.1%) groups. Conclusions Results from this updated analysis indicate that visible CD30 detection by IHC is not required for response to BV + Len + R in patients with relapsed or refractory DLBCL. Treatment with BV + Len + R showed efficacy benefit compared with placebo + Len + R regardless of CD30 expression level, including in patients with no visible CD30 IHC staining. These results are consistent with those from the overall ECHELON-3 study population, in which significant improvement in OS was demonstrated with BV + Len + R compared with placebo + Len + R.

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 Age correlates with survival in patients (pts) with DLBCL, which has a median age at diagnosis of 67 y. Recent therapeutic advances, including bispecifics and cell therapy, have promising efficacy, but safety and accessibility continue to be limited for older pts. The randomized, global, phase 3 ECHELON-3 study (NCT04404283) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) with brentuximab vedotin (BV) + lenalidomide (Len) + rituximab (R; BV+Len+R) vs placebo+Len+R in pts with R/R DLBCL after ≥ 2 prior systemic therapies who were ineligible for hematopoietic stem cell transplant and/or chimeric antigen receptor (CAR) T-cell therapy. Here, we present safety and efficacy in pts aged ≥65 y. Methods In ECHELON-3, pts were randomized 1:1 to receive BV (1.2 mg/kg) or placebo every 3 weeks (q3w), in combination with R (375 mg/m2) q3w and Len (20 mg) once daily. Granulocyte colony-stimulating factor was required in all cycles. Efficacy was assessed by investigators per Lugano 2014 classification. The primary endpoint was OS, with key secondary endpoints of PFS and ORR. Other secondary endpoints included detailed safety and tolerability. This subgroup analysis comprises pts aged ≥65 y. P values are descriptive. Results A total of 155 pts aged ≥65 y were enrolled from April 2021 to November 2023 and randomized to BV+Len+R (n=79) or placebo+Len+R (n=76). The median age was 75 y (range, 65-89 y); 54% of pts were male, 59% were White, and 19% were Asian. Twenty-three percent and 54% had Ann Arbor stage III and IV disease, respectively, and 64% had high-intermediate or high International Prognostic Index scores (3-5) at enrollment. The most common DLBCL subtype was DLBCL not otherwise specified (58%). Twenty-nine percent of pts had transformed DLBCL. Approximately half (49%) of pts had primary refractory disease, and 81% had disease refractory to their most recent prior line of therapy. Seventy percent of pts had &lt;1% CD30 expression via IHC; 48% of cases had germinal center B-cell origin. Prior CAR-T was reported in 21.9% of pts. At a median follow-up of 16.8 mo (95% CI, 14.3-19.5 mo), median OS was 15.9 mo (95% CI, 11.7 mo-not estimable [NE]) with BV+Len+R vs 8.5 mo (95% CI, 5.5-11.5 mo) with placebo+Len+R (hazard ratio [HR], 0.540; 95% CI, 0.351-0.830; P=.0043). Median PFS was 5.7 mo (95% CI, 4.1-12.7 mo) with BV+Len+R vs 2.8 mo (95% CI, 1.9-4.1 mo) with placebo+Len+R (HR, 0.478; 95% CI, 0.318-0.718; P=.0003). ORR was 70.9% (95% CI, 59.6%-80.6%) with BV+Len+R vs 46.1% (95% CI, 34.5%-57.9%) with placebo+Len+R (P=.0020); complete response (CR) rate was 45.6% vs 19.7%, respectively. Median time to CR was 1.61 mo with both BV+Len+R and placebo+Len+R (range, 1.2-7.3 vs 0.7-4.6 mo, respectively). Median duration of CR was 18.9 mo (95% CI, 12.4 mo-NE) with BV+Len+R vs 5.4 mo (95% CI, 2.8 mo-NE) with placebo+Len+R (HR, 0.416; 95% CI, 0.139-1.250). In total, 154 pts were evaluable for safety analysis (75 pts in placebo+Len+R group). The median number of cycles was 5 (range, 1-34) vs 3 (range, 1-31) in the BV+Len+R and placebo+Len+R groups, respectively. The percentage of pts with any treatment-emergent adverse event (TEAE) was similar between groups (97% with BV+Len+R and 99% with placebo+Len+R); grade ≥3 TEAEs occurred in 89% of pts in the BV+Len+R group and 76% in the placebo+Len+R group. Serious TEAEs and TEAEs leading to death were reported more frequently in the BV+Len+R group (62% and 13%, respectively) than the placebo+Len+R group (47% and 8%, respectively). More pts discontinued study treatment due to TEAEs in the BV+Len+R group than the placebo+Len+R group (20% vs 8%). In total, 39% of pts on BV+Len+R had a peripheral neuropathy event vs 27% of pts on placebo+Len+R; however, the majority of cases were grade 1 (22% and 17%, respectively). Additional information on older pts will be presented. Conclusions BV+Len+R demonstrated a clinically meaningful improvement in all key efficacy outcomes in pts aged ≥65 y, which is consistent with the overall ECHELON-3 population (median age 74 y; 70.5% of pts aged ≥65 y in BV+Len+R group). Differences in some safety endpoints are likely attributable to longer duration of treatment in the BV+Len+R group. No clinically meaningful safety trends in pts aged ≥65 y were identified. These results suggest that BV+Len+R may be an effective treatment option in older pts 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.

Introduction Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is very aggressive, with a historically low complete response (CR) rate (Blood. 2017; 130[16]:1800-1808). Recent research has focused on achieving complete and durable responses in this population, which translate to improvements in overall survival (OS) and progression-free survival (PFS). Results from the randomized, global, phase 3 ECHELON-3 study (NCT04404283) demonstrated a statistically significant and clinically meaningful improvement in OS, PFS, and objective response rate with brentuximab vedotin (BV) combined with lenalidomide (Len) and rituximab (R; BV+Len+R) vs placebo+Len+R in patients (pts) with R/R DLBCL after ≥2 prior systemic therapies. Here, we present subgroup analyses in pts with a best overall response (BOR) of CR (n=67). Methods Pts in the study were randomized (1:1) to receive BV (1.2 mg/kg) or placebo every 3 weeks, in combination with R (375 mg/m2) and Len (20 mg) once daily. In these subgroup analyses, eligible pts had a BOR of CR and some ended study treatment and received any subsequent anticancer therapy. BOR was assessed by investigators according to the Lugano 2014 classification. Duration of response was defined as the time from the start of the first documented CR to the first documented tumor progression per Lugano 2014 or death. Pts who initiated a subsequent nonpalliative anticancer therapy were censored at the most recent prior response assessment. Subsequent nonpalliative anticancer therapies were defined as any systemic therapy received after the end of study treatment. P values are descriptive. Results Of the 112 pts in the BV+Len+R group, 45 (40.2%) had a BOR of CR. Of the 118 pts in the placebo+Len+R group, 22 (18.6%) had a BOR of CR. The median duration of CR was 18.9 months (95% CI, 11.1 months-not estimable [NE]) with BV+Len+R vs not reached (NR) with placebo+Len+R (hazard ratio [HR], 0.527; 95% CI, 0.200-1.389; P=.1891). The median time to CR was 1.58 months (range, 1.2-7.3 months) with BV+Len+R and 1.61 months (range, 0.7-4.6 months) with placebo+Len+R. With a median follow-up of 14.3 months, the median OS in pts with a BOR of CR was 31.5 months (95% CI, 20.3 months-NE) in the BV+Len+R group vs NR in the placebo+Len+R group (HR, 1.044; 95% CI, 0.331-3.298; P=.9407). Median PFS in pts with a BOR of CR was 21.5 months (95% CI, 12.6 months-NE) in the BV+Len+R group vs NR (95% CI, 5.4 months-NE) in the placebo+Len+R group (HR, 0.6333; 95% CI, 0.256-1.567; P=.3198). Results of NR in the placebo+Len+R group are likely attributable to limited follow-up and small sample size. Additional data on baseline characteristics of pts who had CR will be presented. Of the 45 pts with CR in the BV+Len+R group, 42 (93.3%) received no subsequent anticancer therapy. Of the 22 pts with CR in the placebo+Len+R group, 17 (77.3%) received no subsequent anticancer therapy. Conclusions BV doubled the CR rate in pts with R/R DLBCL compared with placebo, and outcomes in pts with CR were durable, with only 6.7% of pts treated with BV+Len+R receiving subsequent systemic anticancer therapy, compared with 22.7% of pts treated with placebo+Len+R receiving subsequent therapy. Overall, BV+Len+R demonstrated a survival benefit in the ECHELON-3 study and is a promising option to achieve complete and durable responses in third- or later-line therapy for pts with R/R DLBCL.

LBA7005 Background: Despite recent advances, there remains a need for novel therapies for pts with R/R DLBCL. BV, an anti-CD30 antibody-drug conjugate, has shown efficacy and safety when combined with lenalidomide (len) and with rituximab (R) in heavily pretreated populations (Bartlett 2022; Ward 2022). The double-blind, global phase 3 ECHELON-3 study (NCT04404283) compared BV with R+len (R2) vs R2 in pts with R/R DLBCL who are ineligible for HSCT or CAR T-cell therapy. Here, we present results from the interim analysis (IA) for overall survival (OS). Methods: Pts with R/R DLBCL received BV+R2 or placebo+R2 (randomized 1:1). Pts received BV (1.2 mg/kg) or placebo q3w, R (375 mg/m2) q3w, and len (20 mg) qd. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints were investigator-assessed progression-free survival (PFS), objective response rate (ORR), and complete response (CR) rate. The preplanned IA was performed at 134 OS events with a prespecified efficacy boundary of 2-sided P=0.0232. Results: 230 pts were randomized: 112 to BV+R2 and 118 to R2; all but 2 pts (both in R2 arm) received ≥1 dose of study drug. Median age was 71 yrs (range, 21-89), 56.5% were male, and 10.9% had an ECOG of 2. Median prior lines of therapy was 3 (range, 2-8); 29% had prior CAR T-cell therapy and 68% were CD30- (<1% CD30 tumor expression). At median follow-up of 16.4 months (mos) (range, 0.1-31.5) (cut-off: January 22, 2024), median OS was 13.8 mos (95% CI: 10.3-18.8) with BV+R2 vs 8.5 mos (95% CI: 5.4-11.7) with R2 (HR 0.629; 95% CI: 0.445-0.891; P=0.0085); OS benefit was consistent across key subgroups. Median PFS was 4.2 mos (95% CI: 2.9-7.1) with BV+R2 vs 2.6 mos (95% CI: 1.4-3.1) with R2 (HR 0.527; 95% CI: 0.380-0.729; P<0.0001). ORR was 64.3% (95% CI: 54.7-73.1) with BV+R2 vs 41.5% with R2 (95% CI: 32.5-51.0; P=0.0006); CR rate was 40.2% vs 18.6%, respectively. In CD30+ vs CD30- subgroups, ORR/CR was 72.2%/38.9% vs 60.5%/40.8% with BV+R2, respectively, and 50.0%/26.3% vs 37.5%/15.0% with R2, respectively. Efficacy analysis including cell of origin will be presented. The safety profile of BV+R2 was tolerable vs R2: Grade (Gr) ≥3 treatment-emergent adverse events (TEAEs) were 88% vs 77%, serious TEAEs were 60% vs 50%, and Gr 5 TEAEs were 12% vs 8%, respectively. Most common TEAEs were neutropenia (46% vs 32%), anemia (29% vs 27%), and diarrhea (31% vs 23%). Rates of peripheral neuropathy for BV+R2 vs R2 were 31% vs 24% (all Gr) and 6% vs 2% (Gr 3). Median treatment duration was 3.6 mos with BV+R2 vs 2.0 mos with R2. Conclusions: Treatment with BV+R2 triplet, compared to R2, demonstrated statistically significant and clinically meaningful improvements in all key efficacy outcomes including OS in high-risk subgroups, with manageable safety. This triplet regimen represents a novel treatment option for pts with heavily pretreated R/R DLBCL. Clinical trial information: NCT04404283 .