Final Analysis of the Phase 2 ELM-2 Study: Odronextamab in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

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Background Odronextamab is a novel, off-the-shelf, CD20×CD3 bispecific antibody that has demonstrated consistent anti-lymphoma activity and a generally manageable safety profile in heavily pretreated patients (pts) with both R/R follicular lymphoma and R/R DLBCL. Encouraging results have been reported in pts who have relapsed following chimeric antigen receptor (CAR) T-cell therapy in the Phase 1 ELM-1 study, and in pts with R/R DLBCL in the Phase 2 ELM-2 study (Kim WS, et al. ASH. 2022). Here, we present the final analysis of the R/R DLBCL cohort from ELM-2 (NCT03888105), reporting long-term efficacy and safety outcomes. Methods Intravenous odronextamab was administered weekly in 21-day cycles during Cycles (C) 1-4. Optimization of the step-up regimen to further mitigate cytokine release syndrome (CRS) was reported previously (Kim WS, et al. ASH 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1, followed by 160 mg on Days 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg every 2 weeks until disease progression or unacceptable toxicity. Pts who achieved a complete response (CR) that was durable for ≥9 months transitioned to dosing every 4 weeks. The final analysis was performed when all pts had the opportunity for ≥36 weeks of follow-up. The primary endpoint was objective response rate (ORR), assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included CR rate, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and changes in scores of patient-reported outcomes. Minimal residual disease (MRD) was included as an exploratory endpoint. Results At the time of data cut-off (Jan 31, 2023) the DLBCL cohort was fully enrolled; 141 pts were evaluable for safety and 127 were evaluable for efficacy, with a median duration of follow-up of 26.2 months. In the safety-evaluable DLBCL population, median age was 66 years (range 24-88), 60% male, 80% Ann Arbor stage III-IV, 56% IPI score ≥3, and median prior lines of therapy was 2 (range 2-8). 17% of pts had transformed disease from indolent lymphoma and 5% had Richter's transformation; 12% were double-hit and 6% triple-hit. In total, 57% of pts were primary refractory and 66% were double refractory to an anti-CD20 antibody and an alkylator in any line of therapy. ORR and CR rate confirmed by ICR were 52% (66/127) and 31% (39/127), respectively, and were consistent across high-risk subgroups. Median DoR was 10.2 months (95% CI: 5.0-not estimable [NE]) and median duration of CR was 17.9 months (95% CI: 9.2-NE); the probability of maintaining CR for 24 months was 48%. Patient-reported outcomes were maintained or improved; of special note, patient-reported pain and emotional functioning scores improved from baseline during the course of treatment. MRD status at 12 weeks was highly predictive of PFS. Safety was generally consistent with previous reports. Treatment-related AEs led to odronextamab interruption/delay in 75 (53%) pts and discontinuation in 14 (10%) pts. The most common treatment-emergent AEs (>30% all grades) were CRS (55%), anemia (43%), and pyrexia (42%). With the optimized 0.7/4/20 mg step-up regimen (n=74), 98% of CRS events were Grade (Gr) 1/2, and only one Gr 3 CRS (confounded by pancreatitis) was reported. CRS events resolved with supportive measures; 26% of pts received tocilizumab for CRS management with the optimized regimen. No ICANS events were reported with the optimized step-up regimen. Gr ≥3 infections occurred in 52 (37%) pts (Gr 5, n=16 [11%]); COVID-19 infections were reported in 23 (16%) pts, which were Gr 5 in 6 (4%) pts. Conclusions Results of the final analysis of the ELM-2 study R/R DLBCL pt cohort confirm the highly encouraging clinical activity of odronextamab in a hard-to-treat pt population, including in pts with high-risk features. Responses were deep and durable with a 48% probability of maintaining CR for 2 years. The safety profile was generally consistent with earlier reports and CRS events were predominantly low grade and manageable. Importantly, continued treatment with odronextamab showed no detrimental effects on patient-reported outcomes. Odronextamab may be an important potential option in future management of R/R DLBCL, and these results support the continued investigation of odronextamab in Phase 3 trials. Updated data will be presented.