Cai, Jingxian

Abstract Introduction Odronextamab, a CD20×CD3 bispecific antibody, demonstrated compelling efficacy with a generally manageable safety profile in heavily pretreated patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) in the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. Ann Oncol 2024). Pts in ELM-2 received odronextamab monotherapy until disease progression or unacceptable toxicity, with dosing frequency reduced to every 4 weeks (Q4W) in those with sustained complete response (CR) for at least 9 months. Here, we report longer term outcomes in the global FL population of ELM-2, including efficacy and safety in pts who switched to Q4W dosing. Methods Details of the ELM-2 study for the R/R FL cohort have been reported previously. Odronextamab monotherapy was administered intravenously, with step-up dosing in Cycle (C) 1 to help mitigate the risk of cytokine release syndrome (CRS), followed by 80 mg in C2–4, then 160 mg every 2 weeks (Q2W) maintenance. Pts with a CR for ≥9 months switched from 160 mg Q2W to Q4W. Pts with the opportunity for response assessment at 12 weeks were included in this analysis. Primary endpoint was objective response rate (ORR) per Lugano criteria by independent central review (ICR). Key secondary endpoints included CR rate, duration of response (DOR), and progression-free survival (PFS) by ICR, overall survival (OS), and safety. Results As of May 5, 2025 data cutoff, 128 pts with R/R FL Grade (Gr) 1–3a were evaluable for efficacy and safety analysis (overall global population). Median duration of odronextamab exposure was 42.9 weeks (range 0.4–264.0) and median follow-up was 34.1 months (95% CI 33.8–37.9). Eligible pts (n=48) switched to Q4W dosing, with median duration of follow-up from time of switching to Q4W dosing of 19.7 months (95% CI 16.2–31.9). Baseline characteristics were generally similar between the overall population and the subgroup of pts who switched to Q4W dosing. The ORR by ICR in the overall population was 80.5% and CR rate was 74.2%, with a median DOR of 26.0 months and median duration of CR of 32.2 months. In pts with sustained CR for ≥9 months who transitioned to Q4W maintenance, the median DOR from time of switching was 31.5 months. In the overall population, the median PFS was 24.1 months and median OS was not reached (estimated 24- and 36-month OS rates: 70.1% and 64.3%, respectively). In pts with CR, median PFS was 38.0 months and median OS was not reached (24- and 36-month OS rates: 80.1% and 75.2%). All 128 pts had treatment-emergent adverse events (TEAEs), with Gr ≥3 TEAEs reported in 112 pts (87.5%). Discontinuation due to TEAEs occurred in 29 pts (22.7%), and 5 pts died due to treatment-related TEAEs. With the 0.7/4/20 mg step-up regimen, CRS was reported in 55.0% (33/60; Gr 3 in 1 pt) of pts, with no new CRS events observed after switching to Q4W. Infections occurred in 81.3% (Gr ≥3, 46.1%) of pts, with COVID-19 (any Gr, 39.8%) the most frequent. After switching to Q4W dosing, the rate of any grade infection was 81.3% (Gr ≥3, 39.6%). Opportunistic infections (narrow SMQ defined) were reported in 18% (Gr ≥3, 8.6%) of pts in the overall population, with 22.9% (Gr ≥3, 8.3%) of pts having an opportunistic infection after switching to Q4W. Conclusions In the ELM-2 study with ~3-year follow-up in heavily pretreated pts with R/R FL, odronextamab continued to demonstrate deep and durable responses, as well as encouraging PFS and OS, particularly in the majority of pts who achieved CR. Responses remain durable in those who switched to Q4W dosing, lasting for a median additional 31.5 months from the time of switching, demonstrating the long-term, continued therapeutic benefit of odronextamab in pts with R/R FL. The safety profile remained generally manageable, with no new safety signals observed, and no evidence of increased infection risk in pts who switched to Q4W maintenance. Updated data will be presented.

7049 Background: Odronextamab, an investigational off-the-shelf CD20×CD3 bispecific antibody, demonstrated compelling efficacy and a generally manageable safety profile in heavily pretreated pts with R/R FL in the primary analysis of the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. Ann Oncol 2024). We present updated efficacy and safety data for odronextamab in pts with R/R FL from ELM-2 after >2 yrs follow-up. Methods: Odronextamab was administered intravenously until disease progression/unacceptable toxicity, with Cycle (C) 1 step-up dosing to help mitigate cytokine release syndrome (CRS) risk, as reported previously. Pts with a complete response (CR) for ≥9 months (mo) switched from maintenance dosing Q2W to Q4W. Primary endpoint: objective response rate (ORR) per Lugano criteria by independent central review (ICR); secondary endpoints: CR rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS). Results: At the updated data cutoff (Aug 15, 2024), 157 pts with centrally confirmed R/R FL Grade (Gr) 1–3a were enrolled. Median no. of treatment cycles: 19.0 (range 0.1–117.3); 96.2% (n = 151) and 82.8% (n = 130) of pts completed C1 and C4, respectively. The global cohort comprised 128 pts evaluable for efficacy. At a median efficacy follow-up of 28.3 mo, ORR was 80.5% (n = 103) by ICR and CR rate was 74.2% (n = 95); 92.2% of responders achieved CR. Responses were durable (median DOR, 26.0 mo; median duration of CR, 32.2 mo). ORR was consistent across high-risk subgroups (Follicular Lymphoma International Prognostic Index score 3–5, 78.4%; progression of disease within 2 yrs of frontline therapy, 81.0%). Median PFS was 23.0 mo (estimated 36-mo PFS rate, 37.5%), and median OS was 54.2 mo (estimated 36-mo OS rate, 62.6%). Median PFS was longer in pts who were minimal residual disease (MRD) negative (42.4 mo) versus MRD positive (21.6 mo) at Week 12. Of 47/128 pts who switched to Q4W dosing, 32 remained in CR. The odronextamab long-term safety profile was consistent with the primary analysis. All 157 pts had TEAEs (Gr ≥3, 86.0%), and 15.3% discontinued treatment due to TEAEs (most common: COVID-19 infection, 2.5%). With 0.7/4/20 mg step-up dosing (n = 89), CRS events were mostly low grade (Gr 1, 46.1%; Gr 2, 13.5%; Gr 3, n = 1; Gr ≥4, n = 0), occurred mostly in C1, and resolved in a median of 8.4 hrs. Immune effector cell-associated neurotoxicity syndrome was reported in one pt (Gr 2). Infections were reported in 79.0% of pts (124/157; Gr ≥3, 42.0%). COVID-19-related infections were reported in 38.2% of pts (Gr 5, 5.7%). Conclusions: With longer follow-up, odronextamab demonstrated durable responses in heavily pretreated pts with R/R FL from ELM-2, with robust efficacy in those with high-risk features, and a generally manageable safety profile. Overall, these compelling results support odronextamab as a potential off-the-shelf treatment option for pts with R/R FL. Clinical trial information: NCT03888105 .

Introduction CD19-directed CAR T-cell therapies are an important option for the management of relapsed/refractory (R/R) DLBCL. Studies suggest that ~50% of pts receiving CAR T-cell therapies will relapse within 6 months, with an estimated overall survival (OS) of only 5 months. Additionally, 25-35% of pts do not receive subsequent treatment, indicating a high unmet need. CD19 loss is a potential mechanism of resistance to CAR T-cell therapies; thus, treatments that target alternate B-cell antigens are an attractive option. Here, we report for the first time the primary analysis of the ELM-1 expansion cohort investigating the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in pts with R/R DLBCL progressing after CAR T-cell therapy (NCT02290951). Methods Pts aged ≥18 with DLBCL and disease progression after CAR T-cell therapy received intravenous odronextamab weekly in 21-day (D) cycles during Cycles (C) 1-4, with steroid prophylaxis and step-up dosing in C1 (described previously), followed by 160 mg on D 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg Q2W until disease progression or unacceptable toxicity. Pts with complete response (CR) for ≥9 months transitioned to Q4W dosing. All pts received infection prophylaxis. The primary analysis was conducted when all pts had completed ≥9 months of follow-up. Primary endpoint was objective response rate (ORR), as assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), and OS. Exploratory endpoints included immune biomarker assessment. Results As of January 22, 2024, 60 pts were treated and evaluable for efficacy and safety, with median follow-up of 16.2 months. Prior CAR T-cell therapies were axi-cel (50%), tisa-cel (12%), liso-cel (10%), and not specified (28%). Median time since prior CAR T-cell therapy was 6.5 months (range 1.2-46.2). Median age was 63 years (range 27-82; aged ≥75 years: 10%), and 65% were male. Pts had received a median of 3 prior lines of therapies (range 2-9); 77% of pts were refractory to their last therapy, 77% were double refractory, and 72% were refractory to prior CAR T-cell therapy. 48% of pts relapsed within 90 D of CAR T-cell therapy, and 67% relapsed within 180 D. Of the 20 pts with available tumor biopsies at baseline, 10 were CD19(-) and only 2 were CD20(-). 92% of pts completed C1 and 52% completed ≥4 C of treatment. The median duration of treatment was 12 weeks (range 0.7-154.1). The ORR and CR rate by ICR were 48% and 32%, respectively, and were consistent across pts with high-risk features and across prior CAR T products. ORR in pts relapsing in ≤90 D was 21% (6/29) and in pts relapsing in ≤180 D was 33% (13/40). ORR was observed even in pts with low CD20. Median DOR was 14.8 months (95% CI 2.8-not estimable [NE]) and median duration of CR was not reached (NR) (95% CI 3.3-NE); the probability of maintaining CR for 24 months was 68%. Median PFS was 4.8 months (95% CI 2.6-5.4) and median OS was 10.2 months (95% CI 4.6-15.8). Median PFS and OS in complete responders was NR. T-cell counts increased at Week 14 and demonstrated a functional phenotype (CD69 expression and TEMRA count), which was confirmed by ex vivo stimulation. T-cell expansion was observed regardless of CAR T product or time from CAR T administration. The most common TEAE was CRS (any grade [G]: 48%; G1: 25%; G2: 23%; G≥3: 0%). G≥3 TEAEs occurred in 77% of pts (most common: neutropenia 17%, anemia 13%, and neutrophil and white blood cell count decrease 10% each). Five pts (8%) permanently discontinued odronextamab due to AEs (COVID-19, pneumonia, encephalopathy, epilepsy, and gait disturbance [n=1 each]). There was one treatment-related death (COVID-19 pneumonia). No cases of ICANS were reported. G≥3 infections occurred in 12 pts (20%); 2 were due to COVID-19. No cases of tumor flare or TLS were reported. Conclusions ELM-1 is the only study to prospectively evaluate efficacy and safety of a CD20×CD3 bispecific antibody in pts with R/R DLBCL progressing after CAR T-cell therapy. Odronextamab monotherapy was associated with encouraging efficacy and generally manageable safety in a setting with limited treatment options and historically dismal outcomes. Efficacy was observed even in pts relapsing in ≤90 D, supporting the potential of odronextamab as an accessible, off-the-shelf option in the post-CAR T setting.

Abstract Background: R/R FL is an incurable disease and outcomes worsen with successive relapses. A high unmet need remains for therapies that improve tumor control and extend survival after relapse. Odronextamab, an off-the-shelf CD20×CD3 bispecific antibody, demonstrated compelling efficacy, generally manageable safety, and maintenance of pt-reported overall quality of life scores from baseline in an interim analysis of the ELM-2 study (NCT03888105) in heavily pretreated pts with R/R FL (Villasboas et al. ASH 2023). Here, for the first time, we present the primary analysis of R/R FL in ELM-2. Methods: IV odronextamab was administered in 21-day cycles (C) until disease progression/unacceptable toxicity. Steroid prophylaxis and step-up dosing (0.7/4/20 mg) were used in C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 80 mg on Days (D) 1, 8, and 15 of C2-4. Maintenance dosing continued at 160 mg Q2W, or Q4W if complete response (CR) was durable for 9 months (mo). Primary endpoint was objective response rate (ORR) per Lugano criteria by independent central review (ICR). Secondary endpoints included CR rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Primary analysis was performed when 128 pts had ≥52 weeks’ follow-up. Results: At data cutoff (Oct 20, 2023), 128 pts with FL Grade (Gr) 1-3a were evaluable for efficacy and safety: median age 61 yrs (range 22-84); FLIPI risk score 3-5 57.8%; POD24 49.2%; median 3 prior lines of therapy (2-13); 71.9% refractory to last treatment (Tx); 74.2% refractory to an anti-CD20 antibody. The median no. of Tx cycles was 19.4 (0.1-95.9); 95.3% and 85.2% of pts completed C1 and C4, respectively.Median efficacy follow-up was 20.1 mo; ORR was 80.5% and CR rate was 73.4% confirmed by ICR. Responses were durable (median DOR 22.6 mo; median DOCR 25.1 mo). Median PFS was 20.7 mo and 24-mo PFS was 46.1%. Median OS was not reached and 24-mo OS was 70.1%.The odronextamab safety profile was generally manageable and consistent with previous reports. Tx-emergent adverse events (AEs) occurred in all pts (Gr ≥3 85.9%); 15.6% had AEs leading to Tx discontinuation. With 0.7/4/20 mg step up (n=60), CRS events were mostly low grade (Gr 1 45.0%; Gr 2 10.0%; Gr 3 in 1 pt), occurred mostly in C1, and resolved in a median of 2 days; ICANS was reported in 1 pt (Gr 2). Infection rates were consistent with heavily pretreated, immunosuppressed pts (Leonard et al. JCO 2019; Hayne et al. BBMT 2020), occurring in 79.7% (102/128) of pts (Gr 4/5 14.0%; COVID-19 36.7% [Gr 5 6.3%]).Conclusion: Odronextamab demonstrated deep and durable responses in heavily pretreated pts with R/R FL; 91% of responders achieved CR, correlating with favorable PFS and OS at 24 mo. Odronextamab had a generally manageable safety profile and a low incidence of Gr 3 CRS/ICANS. Odronextamab could offer an important off-the-shelf Tx option for pts with heavily pretreated R/R FL. Citation Format: Geoffrey Chong, Michal Taszner, Silvana Novelli, Seok-Goo Cho, Jose C. Villasboas, Ana Jiménez Ubieto, Benoît Tessoulin, Michelle Poon, David Tucker, Jan Walewski, Yuqin Song, Emmanuel Bachy, Stephanie Guidez, Aranzazu Alonso, Deepa Jagadeesh, Stefano Luminari, Laura Magnano Mayer, Elżbieta Iskierka-Jażdżewska, Monica Tani, Jingxian Cai, Amulya Uppala, Saleem Shariff, Jurriaan Brouwer-Visser, Aafia Chaudhry, Hesham Mohamed, Srikanth Ambati, Tae Min Kim. Primary analysis of the Phase 2 ELM-2 study: Odronextamab in patients (pts) with relapsed/refractory follicular lymphoma (R/R FL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT243.