Epcoritamab Plus Gemcitabine and Oxaliplatin Versus Rituximab, Gemcitabine, and Oxaliplatin in Transplant-Ineligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients: A Match-Adjusted Comparative Analysis

Introduction: Epcoritamab, a novel subcutaneously administered CD3xCD20 bispecific antibody (bsAb) being developed as a core therapy across several lymphoma subtypes, is currently approved for the treatment of adults with different types of R/R LBCL after ≥2 systemic therapies. The combination of epcoritamab with standard treatments has been shown to be safe and efficacious; epcoritamab in combination with gemcitabine and oxaliplatin (Epcor+GemOx) has provided deep and durable responses with favorable survival benefits in a transplant-ineligible R/R DLBCL study population, of which 99% was from the United States and Europe (EPCORE NHL-2; NCT04663347). The rituximab plus gemcitabine and oxaliplatin (R-GemOx) regimen has been a widely used treatment for patients with R/R DLBCL ineligible for transplant, albeit with suboptimal efficacy outcomes. In the absence of direct comparisons of these regimens, this study assessed the comparative efficacy of Epcor+GemOx vs R-GemOx in patients with R/R DLBCL ineligible for transplant.

Methods: Individual patient-level data (IPD) from EPCORE NHL-2 arm 5 were compared to 2 sources of clinical practice data for patients with R/R DLBCL treated with R-GemOx: published data from Cazalles et al (2021) and IPD from the US-based COTA electronic health record database. The Cazalles study reports the results of a large retrospective analysis of patients with R/R DLBCL treated in 2 academic centers in France. The COTA database includes de-identified IPD with demographic and clinical information from numerous academic and community clinical sites in the US. For the comparison to Cazalles, logistic propensity score models were used to weight the Epcor+GemOx cohort to create match-adjusted distributions of baseline characteristics with the R-GemOx cohort in Cazalles. For the comparison to COTA, inverse probability of treatment weighting was employed to balance covariates between the Epcor+GemOx and R-GemOx cohorts. Analyses were restricted to chimeric antigen receptor T-cell therapy (CAR T)-naive patients from EPCORE NHL-2, as the comparator cohorts did not include patients treated with CAR T. Overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS) were compared for Epcor+GemOx vs R-GemOx.

Results: A total of 74 patients treated with Epcor+GemOx (median follow-up: 13.2 months) were compared to 196 R-GemOx-treated patients from Cazalles et al (median follow-up: 22 months). After match-adjustment, Epcor+GemOx (ORR 86.8%) demonstrated significantly higher ORR, corresponding to a 48.5% advantage over R-GemOx (ORR 38.3%) with an odds ratio (OR) of 2.3 (95% CI 1.8-2.9; P<0.0001). Adjusted CR rate was also significantly higher with Epcor+GemOx vs R-GemOx (71.2% vs 32.7%; 38.6% difference; OR 2.2 [95% CI 1.6-3.0]; P<0.0001). Median PFS was significantly longer with Epcor+GemOx (26.7 months) vs R-GemOx (4.8 months; hazard ratio [HR] 0.38 [95% CI 0.22-0.67]; P<0.001). Median OS was not reached (NR) for Epcor+GemOx vs 10.0 months with R-GemOx (HR 0.54 [95% CI 0.29-1.0]; P=0.05), corresponding overall to a 62% reduction in the risk of a progression event and a 46% reduction in the risk of mortality with Epcor+GemOx vs R-GemOx.

A total of 72 patients were treated with R-GemOx in COTA (median follow-up: 7.5 months) and compared to 74 Epcor+GemOx patients. After adjustment, ORR was significantly higher with Epcor+GemOx vs R-GemOx (88.5% vs 35.6%; OR 2.5 [95% CI 1.8-3.4]; P<0.0001). Adjusted CR rate was also significantly higher with Epcor+GemOx (63.9% vs 10.2%; OR 6.3 [95% CI 3.1-12.7]; P<0.0001). Adjusted median PFS was significantly longer with Epcor+GemOx (11.2 months) vs R-GemOx (2.4 months; HR 0.23 [95% CI 0.15-0.36]; P<0.0001). Adjusted median OS was also significantly longer with Epcor+GemOx (21.6 vs 8.3 months; HR 0.47 [95% CI 0.30-0.74]; P=0.002), corresponding overall to a 77% reduction in the risk of a progression event and a 53% reduction in the risk of mortality with Epcor+GemOx vs R-GemOx.

Conclusions: In this indirect treatment comparison analysis,Epcor+GemOx provided significantly superior efficacy benefits in terms of ORR, CR, PFS, and OS vs standard-of-care R-GemOx. While subject to the limitations of comparisons outside of controlled trials, findings indicate the compelling efficacy of Epcor+GemOx as a novel therapeutic option for transplant-ineligible patients with R/R DLBCL.

Munoz:Curio: Honoraria; Portola: Research Funding; Merck: Research Funding; Genmab: Consultancy; Genzyme: Consultancy; Genentech/Roche: Consultancy, Research Funding; ADC Therapeutics: Consultancy; OncView: Honoraria; Gilead/Kite: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Pfizer: Consultancy; Alexion: Consultancy; Fosunkite: Consultancy; Seattle Genetics: Consultancy, Research Funding; Karyopharm: Consultancy; Aurobindo: Consultancy; Verastem: Consultancy, Research Funding; Epizyme: Consultancy; Novartis: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; MEI: Consultancy; TG Therapeutics: Consultancy; AstraZeneca: Consultancy; Eli Lilly: Consultancy; Bayer: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; Targeted Oncology: Honoraria; Alexion: Consultancy; BeiGene: Consultancy; Pharmacyclics/Abbvie, Bayer, Gilead/Kite, Beigene, Pfizer, Janssen, Celgene/Bristol Myers Squibb, Kyowa, Alexion, Fosunkite, Seattle Genetics, Karyopharm, Aurobindo, Verastem, Genmab, Genzyme, Genentech/Roche, ADC Therapeutics, Epizyme, Beigene, Novartis,: Consultancy; Kyowa: Consultancy; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Pharmacyclics/Abbvie: Consultancy, Honoraria, Research Funding; Bayer, Gilead/Kite, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium, Novartis, Beigene.: Research Funding; Targeted Oncology, OncView, Curio, Genzyme, and Physicians' Education Resource.: Honoraria. Rosenthal:RMEI, Curio Science, Targeted Oncology, OncLiveU: Other: Educational Workshop Speaker Role. Ip:MJH life sciences Graticule: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Speakers Bureau; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria; Seagen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; COTA: Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Darrah:Kite, MorphoSys: Membership on an entity's Board of Directors or advisory committees. Wang:Genmab: Current Employment, Current equity holder in publicly-traded company. Zhang:Genmab: Current Employment, Current equity holder in publicly-traded company. Mutebi:Genmab: Current Employment, Current equity holder in publicly-traded company, Other: stockholder. Jun:Genmab: Current Employment, Current equity holder in publicly-traded company, Other: stockholder. Ding:Genmab: Current Employment, Current equity holder in publicly-traded company. Chhibber:Genmab: Current Employment, Current equity holder in publicly-traded company, Other: stockholder. Rivas Navarro:Genmab: Current Employment, Current equity holder in publicly-traded company. Risum:Genmab: Current Employment, Current equity holder in publicly-traded company. Atiya:Genmab: Current Employment, Current equity holder in publicly-traded company, Other: stockholder of Genmab. Brodkin:Genmab: Current Employment, Current equity holder in publicly-traded company. Wang:AbbVie: Current Employment, Current equity holder in publicly-traded company, Other: stockholder of AbbVie. Alshreef:AbbVie: Current Employment, Current equity holder in publicly-traded company, Other: stockholder. Harb:AbbVie: Current Employment, Current equity holder in publicly-traded company, Other: stockholder of AbbVie. Sacchi:Genmab: Current Employment, Current equity holder in publicly-traded company, Other: owns Genmab stock. Hoehn:Genmab: Current Employment, Current equity holder in publicly-traded company. Karimi:Lilly/Loxo: Research Funding; Merck: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche/Genentech: Other: Travel Expenses, Research Funding; AstraZeneca: Research Funding; ADC Therapeutics: Consultancy, Honoraria; Xencor: Research Funding.