Odronextamab in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): Results from a Prespecified Analysis of the Pivotal Phase II Study ELM-2

Background Odronextamab is a hinge-stabilized, human IgG4-based CD20×CD3 bispecific antibody (Ab) that binds CD20 on B cells and CD3 on T cells, triggering T-cell-mediated cytotoxicity of malignant B cells. In ELM-1 (Ph1, NCT02290951), odronextamab demonstrated encouraging activity in pts with DLBCL receiving ≥2 prior lines of therapy (LOT). DLBCL pts treated with odronextamab at doses ≥80 mg had an ORR of 53% and a CR rate of 53%. Responses were durable with 88% probability of an ongoing response at 12 mos (Bannerji R. et al. Lancet Haematol. 2022). The R2PD for R/R DLBCL was determined as 160 mg weekly. Here, we present for the first time, results from a prespecified analysis of the 160 mg DLBCL cohort from the pivotal ELM-2 study (Ph2, NCT03888105), which incorporated an optimized step-up regimen designed to maintain efficacy while minimizing acute toxicity including cytokine release syndrome (CRS). Methods ELM-2 is a global, multicenter study enrolling pts at 91 sites in 13 countries. Adult pts with DLBCL who had relapsed or were refractory to ≥2 prior LOT including an anti-CD20 Ab and an alkylator were enrolled. IV odronextamab was administered in 21-day cycles with steroid prophylaxis and weekly step-up dosing during Cycle (C) 1 to mitigate risk of acute toxicity. The initial step-up regimen was 1 mg split over C1 Day (D) 1 and C1D2, and 20 mg split over C1D8 and C1D9, followed by the 160 mg full dose on C1D15 (1/20 regimen). The 1/20 regimen was revised during the study to further mitigate CRS risk by adding an intermediary step-up dose. The modified regimen consisted of 0.7 mg split over C1D1 (0.2 mg) and C1D2 (0.5 mg), 4 mg split over C1D8 and C1D9, and 20 mg split over C1D15 and C1D16, followed by the 160 mg full dose on C2D1 (0.7/4/20 regimen). 160 mg weekly continued until the end of C4. After C4, maintenance treatment was 320 mg odronextamab every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was ORR assessed by independent central review (ICR) according to Lugano 2014 criteria. CRS was assessed using 2019 ASTCT criteria. Results As of April 20, 2022, 121 pts with DLBCL were evaluable for safety; 90 for efficacy. Median age 67 y (range 24-88), 60% male, 80% Ann Arbor stage III-IV, 58% IPI score ≥3, median prior LOT 2 (range 2-8), and 56% were primary refractory. 65% were double refractory to anti-CD20 Ab and alkylator in any LOT. Median duration of study follow-up was 17.1 mos. ORR and CR rate by ICR were 53% (48/90) and 37% (33/90), respectively, and were consistent across high-risk subgroups and in the subgroup treated with the 0.7/4/20 step-up regimen. CRs were durable; median duration of CR was not reached (95% CI: 10.2 mos-not estimable) and the probability of an ongoing CR at 9 mos was 73%. TEAEs occurred in 117 (97%) pts, considered treatment related in 102 (84%). In the overall safety-evaluable population, the most common TEAEs (>30% all grades) were CRS (53%), pyrexia (41%), and anemia (34%). Following implementation of the 0.7/4/20 step-up regimen in C1, no Grade ≥3 CRS events were observed. Only Grades 1 and 2 CRS were observed in 35% and 13% of DLBCL pts, respectively. All CRS events resolved with supportive measures; 20% of pts received tocilizumab and none required vasopressors or mechanical ventilation for CRS management. ICANS was reported in only 2 pts (4%) following revisions to step-up dosing, and both were low grade; ICANS occurred in 6% of pts with the 1/20 regimen. Treatment-related Grade 5 AEs occurred in 2 pts (2%), and treatment-related AEs led to odronextamab discontinuation in 8 pts (7%). Conclusions In the first results from a pivotal Ph 2 trial, odronextamab demonstrated clinically meaningful efficacy, durable CRs, and manageable safety with only low grade ICANS reported with the 0.7/4/20 regimen. The results of this study confirm the preliminary odronextamab activity observed in ELM-1, and collectively show odronextamab efficacy both before and after CAR T therapy in hard-to-treat, highly aggressive R/R DLBCL, while at the same time demonstrating a manageable safety profile. The 0.7/4/20 odronextamab step-up dose regimen for C1 mitigates the risk of high-grade CRS, which has been observed consistently with other bispecifics and CAR T therapies and may present an important future option for the management of pts with R/R DLBCL. Updated safety and efficacy data will be presented.