Outcomes By Refractory Status and Prior Therapies Received in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL) from the ECHELON-3 Study

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<.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<.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.

Bartlett:Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Celegne: 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; ADC Therapeutics: Research Funding; Autolus: Research Funding; Washington University School of Medicine: Current Employment; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Kite Pharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Kim:Ministry of Science and Technology of Korea: Research Funding; St. Vincent's Hospital, The Catholic University of Korea, Suwon, South Korea: Current Employment. Forward:BeiGene, AstraZeneca, Roche, SeaGen: Honoraria; ADC Therapeutics, AstraZenecam Astellas, BeiGene, IMV, MorphoSys, Roche, SeaGen: Research Funding; AbbVie, AstraZeneca, BeiGene, Celgene/BMS, Janssen, Kite/Gilead, Pfizer, Roche, SeaGen, Servier: Consultancy. Derenzini:Takeda, ADC-Therapeutics, Incyte, Roche, Abbvie, Astra Zeneca, Lilly, Gilead, Sobi, Beigene, Regeneron: Consultancy; Incyte, Roche, Abbvie: Speakers Bureau; Takeda, ADC-Therapeutics, Incyte: Research Funding. Ghesquieres:Gilead, Roche, BMS, Abbvie, Takeda: Honoraria; Roche, BMS, Takeda: Consultancy. Nowakowski:MorphoSys AG: Consultancy, Research Funding; Ryvu Therapeutics: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy; Blueprint Medicines Corporation: Consultancy; TG Therapeutics Inc: Consultancy; Segen: Consultancy; Constellation Pharmaceuticals: Consultancy; Debiopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Selvita Inc: Consultancy; Fate Therapeutics: Consultancy; AbbVie Inc.: Consultancy; Incyte Corporation: Consultancy; F. Hoffmann-La Roche Limited: Consultancy; Bantam Pharmaceutical, LLC: Consultancy; Daiichi Sankyo: Consultancy; Zai Laboratory: Consultancy; MEI Pharma: Consultancy; Karyopharm Therapeutics: Consultancy; Kymera Therapeutics: Consultancy; Celgene Corporation: Consultancy, Research Funding; Curis: Consultancy, Research Funding. 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:Seagen Inc: Divested equity in a private or publicly-traded company in the past 24 months; Pfizer Inc, Gilead Inc: Current equity holder in publicly-traded company; 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:Seagen: Ended employment in the past 24 months; Pfizer: Current Employment. Portell:Merck, Prelude, BeiGene, AstraZeneca, SeaGen/Pfizer, Infinity, Genentech/Roche, Kite: Research Funding; Merck, BeiGene, Jansen, AstraZeneca, AbbVie: Consultancy.

Brentuximab vedotin is not approved for use in DLBCL. The ECHELON-3 clinical trial is exploring brentuximab vedotin in combination with lenalidomide and rituximab.