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 <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.
Bartlett:Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Foresight Diagnostics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Kite Pharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Celegne: Research Funding; BMS: Research Funding; Autolus: Research Funding; ADC Therapeutics: Research Funding; Washington University School of Medicine: Current Employment. Kim:St. Vincent's Hospital, The Catholic University of Korea, Suwon, South Korea: Current Employment; Ministry of Science and Technology of Korea: Research Funding. Fleury:Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Laribi:Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria; BeiGene: Honoraria; Takeda: Honoraria; Jansen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria. Portell:Merck, Prelude, BeiGene, AstraZeneca, SeaGen/Pfizer, Infinity, Genentech/Roche, Kite: Research Funding; Merck, BeiGene, Jansen, AstraZeneca, AbbVie: Consultancy. Boutin:CISSS Montérégie-Centre: Current Employment; BMS, Merck, Roche, Amgen, Beigene, Abbvie, Incyte: Consultancy; BMS, Merck, Roche, Amgen, Beigene, Abbvie, Incyte, Pfizer, Amgen, Taiho, Ipsen, AAA: Honoraria; Roche, Pfizer, Incyte: Research Funding. Lam:AbbVie, Amgen, AstraZeneca, Beigene, Bristol-Myers Squibb, Forus, Gilead, Hoffman-Roche, Incyte, Janssen, Novartis, Pfizer, Johnson & Johnson, Sanofi: Honoraria. Joergensen:Sobi: Consultancy; Novo Nordisk: Current holder of stock options in a privately-held company; Abbvie: Consultancy; Roche: Consultancy; Caribou: Consultancy; Incyte: Consultancy; Kite/Gilead: Consultancy. Ghesquieres:Gilead, Roche, BMS, Abbvie, Takeda: Honoraria; Roche, BMS, Takeda: Consultancy. Nowakowski:Blueprint Medicines Corporation: Consultancy; Ryvu Therapeutics: Consultancy; Incyte Corporation: Consultancy; F. Hoffmann-La Roche Limited: Consultancy; MorphoSys AG: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Fate Therapeutics: Consultancy; Genentech: Consultancy; Selvita Inc: Consultancy; Karyopharm Therapeutics: Consultancy; AbbVie Inc.: Consultancy; Debiopharm: Consultancy; Zai Laboratory: Consultancy; MEI Pharma: Consultancy; Curis: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Constellation Pharmaceuticals: Consultancy; Segen: Consultancy; Bantam Pharmaceutical, LLC: Consultancy; TG Therapeutics Inc: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Kymera Therapeutics: Consultancy. Yasenchak:Pfizer: Consultancy; Beigene: Speakers Bureau. Patterson:Scorpion Therapeutics, Inc.: Ended employment in the past 24 months; Pfizer: Current Employment. Ho:Pfizer Inc.: Current Employment. Rustia:Pfizer Inc, Gilead Inc: Current equity holder in publicly-traded company; Seagen Inc: Divested equity in a private or publicly-traded company in the past 24 months; Gilead Inc: Ended employment in the past 24 months; Pfizer Inc (former Seagen Inc employee acquired by Pfizer): Current Employment. Fanale:Seagen: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; Pfizer: Current Employment, Current holder of stock options in a privately-held company. Fenton:Pfizer: Current Employment; Seagen: Ended employment in the past 24 months. Ribrag:Employment: Ended employment in the past 24 months; AstraZeneca: Honoraria; AstraZeneca, Lilly: Membership on an entity's Board of Directors or advisory committees; Astex, GSK: Research Funding; Abbvie, Ipsen: Speakers Bureau; Belgene: Speakers Bureau; Pegascy: Current Employment.
Brentuximab vedotin is not approved for use in DLBCL. The ECHELON-3 clinical trial is exploring brentuximab vedotin in combination with lenalidomide and rituximab
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