Brentuximab Vedotin Triplet Improves Survival Over R2 Across Key R/R DLBCL Subgroups

The addition of brentuximab vedotin (Adcetris; BV) to standard lenalidomide (Revlimid) and rituximab (Rituxan; R2) led to statistically significant and clinically meaningful improvements in all key efficacy outcomes, including overall survival (OS), vs R2 and placebo in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to interim data from the phase 3 ECHELON-3 study (NCT04404283) presented during the 2024 ASCO Annual Meeting.¹

Findings from the primary analysis showed that the BV combination reduced the risk of death by 37% vs the placebo/R2 regimen (HR, 0.629; 95% CI, 0.445-0.891; P = .0085), meeting the trial’s primary end point. At a median follow-up of 15.5 months (95% CI, 12.2-18.1) for the triplet (n = 112) and 18.9 months (95% CI, 12.2-23.2) for the doublet (n = 118), the median OS was 13.8 months (95% CI, 10.3-18.8) and 8.5 months (95% CI, 5.4-11.7), respectively.

Treatment with the BV triplet also led to a significant improvement in progression-free survival (PFS) vs R2, translating to a 47% reduction in the risk of disease progression or death (HR, 0.527; 95% CI, 0.380-0.729; P < .0001). At a median follow-up of 8.8 months (95% CI, 6.9-10.9) and 11.1 months (95% CIO, 8.6-14.2), respectively, the median PFS increased from 2.6 months (95% CI, 1.4-3.1) in the R2 arm to 4.2 months (95% CI, 2.9-7.1) in the BV arm.

Notably, the OS and PFS benefits with the BV triplet were observed regardless of CD30 expression, cell origin, or prior CAR T-cell therapy, and survival outcomes were superior to R2 across all analyzed subgroups.

“ECHELON-3 [is] the first randomized, placebo-controlled phase 3 study to demonstrate an OS benefit in patients with relapsed/refractory DLBCL who have received more than 2 prior lines of systemic therapy,” lead study author Jeong A Kim, MD, of St. Vincent’s Hospital, the Catholic University of Korea School of Medicine in Suwon, stated in an oral presentation of the data. “This triplet combination has the potential to address a high unmet need in patients with relapsed/refractory DLBCL, particularly those who are not able to receive CAR T-cell therapy or a bispecific antibody or who have a relapsed/refractory disease following this treatment.”

Among patients with relapsed/refractory DLBCL, prior research has shown that this CD30-targeted antibody-drug conjugate (ADC) elicited responses regardless of CD30 status. In a prior phase 2 study (NCT01421667), efficacy-evaluable patients (n = 48) achieved an ORR of 44% (95% CI, 29.5%-58.8%) and CR rate of 17% with BV monotherapy. Moreover, the ORR was 46% for efficacy-evaluable patients (n = 13) treated with BV in combination with rituximab, at a median follow-up of 2.8 months.² When added to lenalidomide in a phase 1 trial (NCT02086604), BV elicited an ORR of 57% (95% CI, 39.6-72.5), with a CR rate of 35% (95% CI, 20.7-52.6) in the overall population (n = 37) at a median follow-up of 14.3 months (range, 0.5-66.6).³

“This advanced treatment included T-cell–directed therapy, but there remains a high unmet need for a readily available and tolerable regimen,” Kim explained during the presentation,¹ adding that, “...currently reported real-world OS rates for the third line or beyond are less than a year.”

ECHELON-3 enrolled patients 18 years of age or older with eligible subtypes of relapsed/refractory DLBCL who had received at least 2 prior lines of therapy and were ineligible for, or had experienced disease relapse following, hematopoietic stem cell transplantation (HSCT) or CAR-T cell therapy. Patients were also required to have an ECOG performance status (PS) of 0 to 2 and FDG-avid, measurable disease. Those who had previously received BV or lenalidomide, had active cerebral/meningeal disease, or had grade 2 or higher peripheral neuropathy were excluded from the study. Notably, granulocyte colony–stimulating factor prophylaxis was required per protocol.

Upon enrollment, patients were stratified according to CD30 status (1% or greater vs less than 1%), cell of origin (germinal B-cell [GCB] vs non-GCB], and prior exposure to CAR T-cell therapy or HSCT (received vs not). They were then randomly assigned 1:1 to receive 20 mg of oral lenalidomide daily and 375 mg/m2 of intravenous rituximab every 3 weeks with either 1.2 mg/kg of BV or placebo administered intravenously every 3 weeks.

The primary end point was OS in the intention-to-treat population. Key secondary end points included investigator-assessed PFS, ORR, CR rate, and duration of response (DOR) using Lugano 2014 criteria; OS in the CD30-positive population; as well as safety and tolerability.

Of the 339 patients screened, 112 and 118 were randomly assigned to the BV triplet vs R2, respectively. Two patients in the placebo arm withdrew consent without receiving study treatment, leaving 116 patients in the safety population; all 112 patients were included in the safety population in the experimental arm. A total of 22 and 14 patients in the experimental and placebo arms, respectively, are currently on study treatment.

Patients discontinued treatment due to progressive disease (53% in BV arm; 70% in R2 arm), toxicity (16%; 8%), investigator decision (1%; 1%), patient’s decision not due to toxicity (11%; 6%), other reasons not due to toxicity (0%; 1%), withdrawal of consent (5%; 8%), death (48%; 58%), or long-term follow-up (27%; 19%). The median treatment duration was 3.6 months (range, 0.5-26.4) with the BV triplet and 2.0 months (range, 0.1-26.6) with the R2 regimen.

Kim reported “The patient demographics and history of prior treatment was generally well balanced between the groups.” The median age of patients was 74.0 years (range, 29-87) in the BV triplet arm and 70.0 years (range, 21-89) in the R2 arm. The majority of patients across both arms were 65 years of age or older (71%; 64%), male (54%; 59%), and White (58%; 47%). Eleven percent of patients in both arms had an ECOG PS of 2.

Patients received a median of 3 prior treatment lines in the BV triplet arm (range, 2-8) and R2 arm (range, 2-7). Among prior systemic therapies received, the most common were anthracycline (98%; 97%) and previous anti-CD20 therapy (98%; 97%), followed by CAR T-cell therapy (29%; 30%), bispecific antibodies (13%; 17%), and HSCT (9%; 15%).

Over half of patients across both arms had DLBCL not otherwise specified (56%; 54%), with 29% and 23% of patients, respectively, displaying transformed DLBCL in the BV and placebo arms. The cell of origin for 54% of patients in both arms. Moreover, 68% of those in both arms had a CD30 expression level of less than 1%. Other disease characteristics include Ann Arbor stage III/IV disease at the time of study entry (74%; 83%), an international prognostic index score of at least 3 at the time of enrollment (60%; 60%), primary refractory disease (57%; 54%), and were refractory to their last prior DLBCL therapy (88%; 81%).

Further efficacy assessment demonstrated that response rates were significantly higher with the BV triplet vs placebo regimen (P = .0006), and consistent benefit was observed regardless of CD30 expression. Within the overall population, the BV combination produced an ORR of 64.3% (95% CI, 54.7%-73.1%), including a CR rate of 40.2% (95% CI, 31.0%-49.9%); the ORR was 41.5% (95% CI, 32.5%-51.0%) in the R2 arm, with a CR rate of 18.6% (95 %CI, 12.1%-26.9%).

The median DOR in the overall population increased from 3.0 months (95% CI, 2.8-5.4) with the R2 regimen to 8.3 months (95% CI, 4.2-15.3) with the addition of BV. Among those who achieved a CR, the median DOR was 18.9 months (95% CI, 11.1 months-not reached [NR]) in the BV triplet arm and NR (95 % CI, 2.8-NR) in the R2 arm. The median time to CR onset was 1.58 months (range, 1.2-7.3) and 1.61 months (range, 0.7-4.6) in these respective groups.

Regarding safety, Kim noted, "The BV combination was well tolerated, AEs were manageable with a dose modification, and [data were] consistent with the known safety profile of each drug.”

Treatment-emergent adverse effects (TEAEs) occurred in 97% of patients in both arms; grade 3 or higher TEAEs were reported in 88% of those in the BV arm and 77% of those in the R2 arm. Notably, 9% of patients in each arm experienced grade 3 or higher febrile neutropenia. Grade 5 TEAEs were reported in 12% and 8% of patients in the BV and R2 arms, respectively. Any-grade peripheral neuropathy TEAEs occurred in 31% and 24% of patients in these respective groups.

“Overall, BV given in combination with lenalidomide and rituximab was tolerable, demonstrated by high relative dose intensity for BV of nearly 95%,” Kim stated.

Neutropenia and thrombocytopenia were the most common TEAEs reported in the BV group; neutropenia and anemia were the most frequently observed TEAEs in the R2 group.

At the conclusion of treatment, 34% of patients in the BV arm and 47% in the R2 arm received any subsequent treatment. Reasons for continued treatment included progressive disease (27%; 38%), relapsed disease (5%; 4%), a secondary malignancy (0%; 2%) or other causes (4%; 7%). Subsequent therapies included anti-CD20 agents (8%; 9%), an ADC (6%; 5%), bispecific antibodies (4%; 9%), CAR T-cell therapy (4%; 4%), tafasitamab (Monjuvi; 4%; 1%), and other non-specified treatments (11%; 23%).

Disclosures: Dr Kim had no relationships to disclose.

References

1. Kim J, Hahn U, Kim WS, et al. Brentuximab vedotin in combination with lenalidomide and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma: Results from the phase 3 ECHELON-3 study. J Clin Oncol. 2024, 42(suppl 16):LBA7005.doi:10.1200/JCO.2024.42.16_suppl.LBA7005
2. Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015;125(suppl 9):1394-1402. doi:10.1182/blood-2014-09-598763
3. Ward JP, Berrien-Elliott MM, Gomez F, et al. Phase 1/dose expansion trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma. Blood. 2022;139(suppl 13):1999-2010. doi:10.1182/blood.2021011894