Brentuximab Vedotin Triplet Supplies Stronger Survival Sign vs R2 in R/R DLBCL
Brentuximab vedotin (Adcetris; BV) plus lenalidomide (Revlimid) and rituximab (Rituxan; R2) considerably improved key efficacy outcomes, together with general survival (OS), in contrast with R2 and placebo in relapsed/refractory diffuse giant B-cell lymphoma (DLBCL), in response to interim knowledge from the part 3 ECHELON-3 examine (NCT04404283) introduced through the 2024 ASCO Annual Assembly.1
Findings from the first evaluation confirmed that the BV mixture lowered the chance of demise by 37% vs the placebo/R2 routine (HR, 0.629; 95% CI, 0.445-0.891; P = .0085), assembly the trial’s main finish level. 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 eight.5 months (95% CI, 5.4-11.7), respectively.
Therapy with the BV triplet additionally led to a major enchancment in progression-free survival (PFS) vs R2, translating to a 47% discount within the threat of illness development or demise (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 elevated from 2.6 months (95% CI, 1.4-3.1) within the R2 arm to 4.2 months (95% CI, 2.9-7.1) within the BV arm.
Notably, the OS and PFS advantages with the BV triplet had been noticed no matter CD30 expression, cell origin, or prior CAR T-cell remedy, and survival outcomes had been superior to R2 throughout all analyzed subgroups.
“ECHELON-3 [is] the primary randomized, placebo-controlled part 3 examine to show an OS profit in sufferers with relapsed/refractory DLBCL who’ve acquired greater than 2 prior traces of systemic remedy,” lead examine writer Jeong A Kim, MD, of St. Vincent’s Hospital, the Catholic College of Korea College of Medication in Suwon, acknowledged in an oral presentation of the info. “This triplet mixture has the potential to deal with a excessive unmet want in sufferers with relapsed/refractory DLBCL, significantly those that should not in a position to obtain CAR T-cell remedy or a bispecific antibody or who’ve a relapsed/refractory illness following this remedy.”
Amongst sufferers with relapsed/refractory DLBCL, prior analysis has proven that this CD30-targeted antibody-drug conjugate (ADC) elicited responses no matter CD30 standing. In a previous part 2 examine (NCT01421667), efficacy-evaluable sufferers (n = 48) achieved an ORR of 44% (95% CI, 29.5%-58.8%) and CR price of 17% with BV monotherapy. Furthermore, the ORR was 46% for efficacy-evaluable sufferers (n = 13) handled with BV together with rituximab, at a median follow-up of two.8 months.2 When added to lenalidomide in a part 1 trial (NCT02086604), BV elicited an ORR of 57% (95% CI, 39.6-72.5), with a CR price of 35% (95% CI, 20.7-52.6) within the general inhabitants (n = 37) at a median follow-up of 14.3 months (vary, 0.5-66.6).3
“This superior remedy included T-cell–directed remedy, however there stays a excessive unmet want for a available and tolerable routine,” Kim defined through the presentation,1 including that, “…at present reported real-world OS charges for the third line or past are lower than a 12 months.”
ECHELON-3 enrolled sufferers 18 years of age or older with eligible subtypes of relapsed/refractory DLBCL who had acquired not less than 2 prior traces of remedy and had been ineligible for, or had skilled illness relapse following, hematopoietic stem cell transplantation (HSCT) or CAR-T cell remedy. Sufferers had been additionally required to have an ECOG efficiency standing (PS) of 0 to 2 and FDG-avid, measurable illness. Those that had beforehand acquired BV or lenalidomide, had lively cerebral/meningeal illness, or had grade 2 or increased peripheral neuropathy had been excluded from the examine. Notably, granulocyte colony–stimulating issue prophylaxis was required per protocol.
Upon enrollment, sufferers had been stratified in response to CD30 standing (1% or higher vs lower than 1%), cell of origin (germinal B-cell [GCB] vs non-GCB], and prior publicity to CAR T-cell remedy or HSCT (acquired vs not). They had been then randomly assigned 1:1 to obtain 20 mg of oral lenalidomide every day and 375 mg/m2 of intravenous rituximab each 3 weeks with both 1.2 mg/kg of BV or placebo administered intravenously each 3 weeks.
The first finish level was OS within the intention-to-treat inhabitants. Key secondary finish factors included investigator-assessed PFS, ORR, CR price, and period of response (DOR) utilizing Lugano 2014 standards; OS within the CD30-positive inhabitants; in addition to security and tolerability.
Of the 339 sufferers screened, 112 and 118 had been randomly assigned to the BV triplet vs R2, respectively. Two sufferers within the placebo arm withdrew consent with out receiving examine remedy, leaving 116 sufferers within the security inhabitants; all 112 sufferers had been included within the security inhabitants within the experimental arm. A complete of twenty-two and 14 sufferers within the experimental and placebo arms, respectively, are at present on examine remedy.
Sufferers discontinued remedy as a result of progressive illness (53% in BV arm; 70% in R2 arm), toxicity (16%; 8%), investigator resolution (1%; 1%), affected person’s resolution not as a result of toxicity (11%; 6%), different causes not as a result of toxicity (0%; 1%), withdrawal of consent (5%; 8%), demise (48%; 58%), or long-term follow-up (27%; 19%). The median remedy period was 3.6 months (vary, 0.5-26.4) with the BV triplet and a couple of.0 months (vary, 0.1-26.6) with the R2 routine.
Kim reported “The affected person demographics and historical past of prior remedy was usually nicely balanced between the teams.” The median age of sufferers was 74.0 years (vary, 29-87) within the BV triplet arm and 70.0 years (vary, 21-89) within the R2 arm. Nearly all of sufferers throughout each arms had been 65 years of age or older (71%; 64%), male (54%; 59%), and White (58%; 47%). Eleven p.c of sufferers in each arms had an ECOG PS of two.
Sufferers acquired a median of three prior remedy traces within the BV triplet arm (vary, 2-8) and R2 arm (vary, 2-7). Amongst prior systemic therapies acquired, the most typical had been anthracycline (98%; 97%) and former anti-CD20 remedy (98%; 97%), adopted by CAR T-cell remedy (29%; 30%), bispecific antibodies (13%; 17%), and HSCT (9%; 15%).
Over half of sufferers throughout each arms had DLBCL not in any other case specified (56%; 54%), with 29% and 23% of sufferers, respectively, displaying remodeled DLBCL within the BV and placebo arms. The cell of origin for 54% of sufferers in each arms. Furthermore, 68% of these in each arms had a CD30 expression stage of lower than 1%. Different illness traits embody Ann Arbor stage III/IV illness on the time of examine entry (74%; 83%), a global prognostic index rating of not less than 3 on the time of enrollment (60%; 60%), main refractory illness (57%; 54%), and had been refractory to their final prior DLBCL remedy (88%; 81%).
Additional efficacy evaluation demonstrated that response charges had been considerably increased with the BV triplet vs placebo routine (P = .0006), and constant profit was noticed no matter CD30 expression. Inside the general inhabitants, the BV mixture produced an ORR of 64.3% (95% CI, 54.7%-73.1%), together with a CR price of 40.2% (95% CI, 31.0%-49.9%); the ORR was 41.5% (95% CI, 32.5%-51.0%) within the R2 arm, with a CR price of 18.6% (95 %CI, 12.1%-26.9%).
The median DOR within the general inhabitants elevated from 3.0 months (95% CI, 2.8-5.4) with the R2 routine to eight.3 months (95% CI, 4.2-15.3) with the addition of BV. Amongst those that achieved a CR, the median DOR was 18.9 months (95% CI, 11.1 months-not reached [NR]) within the BV triplet arm and NR (95 % CI, 2.8-NR) within the R2 arm. The median time to CR onset was 1.58 months (vary, 1.2-7.3) and 1.61 months (vary, 0.7-4.6) in these respective teams.
Relating to security, Kim famous, “The BV mixture was nicely tolerated, AEs had been manageable with a dose modification, and [data were] according to the recognized security profile of every drug.”
Therapy-emergent antagonistic results (TEAEs) occurred in 97% of sufferers in each arms; grade 3 or increased TEAEs had been reported in 88% of these within the BV arm and 77% of these within the R2 arm. Notably, 9% of sufferers in every arm skilled grade 3 or increased febrile neutropenia. Grade 5 TEAEs had been reported in 12% and eight% of sufferers within the BV and R2 arms, respectively. Any-grade peripheral neuropathy TEAEs occurred in 31% and 24% of sufferers in these respective teams.
“Total, BV given together with lenalidomide and rituximab was tolerable, demonstrated by excessive relative dose depth for BV of practically 95%,” Kim acknowledged.
Neutropenia and thrombocytopenia had been the most typical TEAEs reported within the BV group; neutropenia and anemia had been essentially the most regularly noticed TEAEs within the R2 group.
On the conclusion of remedy, 34% of sufferers within the BV arm and 47% within the R2 arm acquired any subsequent remedy. Causes for continued remedy included progressive illness (27%; 38%), relapsed illness (5%; 4%), a secondary malignancy (0%; 2%) or different causes (4%; 7%). Subsequent therapies included anti-CD20 brokers (8%; 9%), an ADC (6%; 5%), bispecific antibodies (4%; 9%), CAR T-cell remedy (4%; 4%), tafasitamab (Monjuvi; 4%; 1%), and different non-specified remedies (11%; 23%).
Disclosures: Dr Kim had no relationships to reveal.
References
- Kim J, Hahn U, Kim WS, et al. Brentuximab vedotin together with lenalidomide and rituximab in sufferers with relapsed/refractory diffuse giant B-cell lymphoma: Outcomes from the part 3 ECHELON-3 examine. J Clin Oncol. 2024, 42(suppl 16):LBA7005.doi:10.1200/JCO.2024.42.16_suppl.LBA7005
- Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates goal responses in a part 2 examine of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015;125(suppl 9):1394-1402. doi:10.1182/blood-2014-09-598763
- Ward JP, Berrien-Elliott MM, Gomez F, et al. Section 1/dose enlargement trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse giant B-cell lymphoma. Blood. 2022;139(suppl 13):1999-2010. doi:10.1182/blood.2021011894
