Long-Term Efficacy and Safety of Odronextamab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Pooled Analysis from the ELM-1 and ELM-2 Studies

Introduction Odronextamab, a novel, investigational, CD20×CD3 bispecific antibody, has demonstrated compelling efficacy and a generally manageable safety profile in heavily pretreated patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the CAR-T-naïve and post-CAR-T therapy settings (Ayyappan S et al. ASH 2023; Crombie J et al. ASH 2023). Here, we report long-term efficacy and safety data for odronextamab from a pooled analysis of the DLBCL post-CAR-T cohort in the ELM-1 study (NCT02290951), which was the only pivotal study of a bispecific antibody with a prespecified cohort dedicated to this population, and the CAR-T-naïve DLBCL cohort in the ELM-2 study (NCT03888105). Methods Odronextamab was administered intravenously in 21-day cycles. A step-up dosing regimen with steroid prophylaxis was employed during Cycle 1, followed by 160 mg on Days 1, 8, and 15 of Cycles 2-4. Maintenance therapy consisted of 320 mg every 2 weeks until disease progression or unacceptable toxicity. Patients with durable complete response (CR) for ≥9 months transitioned to dosing every 4 weeks. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using the Lugano classification. Key secondary endpoints included CR rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results The analysis set consisted of a pooled population of 187 patients with R/R DLBCL from ELM-1 (n=60; data cutoff date of January 22, 2024) and ELM-2 (n=127; data cutoff date October 20, 2023). Median duration of follow-up was 23.0 months. Median age was 65.0 years (range 24-88), 61.5% of patients were male, 78.6% had Ann Arbor stage III-IV, 56.7% had an IPI score ≥3, and the median number of prior lines of therapy was 3 (range 2-9). The 60 patients included from ELM-1 had all received prior CAR-T therapy, representing 32.1% of the total pooled population (60/187), and of these, 48.3% (29/60) had relapsed within ≤90 days of initiating CAR-T therapy, and 71.7% (43/60) had CAR-T-refractory disease. Overall, 83.4% of the pooled population had disease that was refractory to the last line of therapy. Median duration of odronextamab exposure was 14.7 weeks; 91.4% (171/187) of the population completed ≥1 cycle, and 59.4% (111/187) completed ≥4 cycles. ORR and CR rate confirmed by ICR were 50.8% (95/187) and 31.6% (59/187), respectively, and were generally consistent across multiple high-risk subgroups, including the post-CAR-T therapy subgroup. Median DOR was 10.5 months (95% CI 5.4-24.8) and median duration of CR was 36.3 months (95% CI 12.4-not evaluable); the probability of maintaining CR for 36 months was 51.0%. The probability of PFS and OS at 36 months was 17.5% and 27.0%, respectively. Safety was generally consistent with previous reports. The most common treatment-emergent adverse events (>30% all grades) were cytokine release syndrome (CRS; 52.9%), anemia (35.8%), pyrexia (39.6%), and neutropenia (31.6%). Adverse events led to treatment discontinuation in 25 patients (13.4%). With the optimized 0.7/4/20 mg step-up regimen (n=100), 48.0% of patients (48/100) had CRS events that were Grade (Gr) 1/2, and one Gr 3 CRS event (confounded by pancreatitis) was reported. All CRS events resolved with supportive measures. No immune effector cell-associated neurotoxicity syndrome events were reported with the 0.7/4/20 mg step-up regimen. Gr ≥3 infections occurred in 46 patients (24.6%; Gr 5, n=16 [8.6%]). COVID-19 infections were reported in 30 patients (16.0%), of which Gr 5 was reported in 6 patients (3.2%). Conclusions This pooled analysis of patients with R/R DLBCL from the ELM-1 and ELM-2 studies, which represents the largest dataset reported for a bispecific antibody in the third-line or later setting, confirms that with longer follow-up the recommended odronextamab dose retains highly encouraging efficacy. Responses were durable, with a 51% probability of maintaining CR for 3 years. The safety profile was generally consistent with earlier reports and CRS events with the 0.7/4/20 mg step-up dosing regimen were predominantly low grade and generally manageable. Importantly, continued treatment with odronextamab demonstrated no detrimental effects on survival outcomes over a longer follow-up period. Odronextamab may be an important potential option in future management of R/R DLBCL, and Phase 3 trials are ongoing. Updated data will be presented.