Uppala, Amulya

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.

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.

Background The class of CD20×CD3 bispecific antibodies (BsAbs) has emerged as an important anti-lymphoma modality for patients (pts) with R/R B-cell non-Hodgkin lymphoma. Odronextamab, a novel, off-the-shelf, CD20×CD3 BsAb, has previously demonstrated compelling efficacy in both R/R diffuse large B-cell lymphoma and R/R FL. In pts with R/R FL, odronextamab monotherapy achieved 75% complete response (CR) rates and encouraging durability of responses, and showed generally manageable safety, in the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. ASH. 2022). Here, we report the results of a second, pre-specified interim analysis of ELM-2. 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 TM, et al. ASH. 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1, followed by 80 mg on Days 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 160 mg every 2 weeks until disease progression or unacceptable toxicity. Pts who achieved a durable CR for ≥9 months transitioned to dosing every 4 weeks. A pre-specified interim analysis was performed when 80 pts had completed ≥12 months 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 data cut off (Jan 31, 2023), the global study was fully enrolled and included 140 safety-evaluable pts with FL; 128 pts were efficacy-evaluable and 85 pts had ≥12 months follow-up. The median duration of study follow-up for efficacy was 26.6 months. In the safety-evaluable FL population, median age was 60.5 years (range 22-84), 53% were male, and pts had received a median of 3 (range 2-13) prior lines of therapy. 73% of pts were refractory to their last therapy, 41% were double refractory, and 74% were refractory to an anti-CD20 antibody. 50% of pts had progression of disease within 2 years (POD24) and 29% had a prior autologous hematopoietic stem cell transplant. ORR and CR rate by ICR were 80% (102/128) and 72% (92/128), respectively, and were consistent across pts with high-risk features. Responses were durable, with both median DoR and duration of CR of 21.7 months; the probability of maintaining CR for 24 months was 48%. Median PFS was 20.7 months (95% CI: 16.7-26.5) and median OS was not reached; the probability of survival at 3 years was 63%. Patient-reported overall quality of life (QoL) scores were maintained during the course of treatment. MRD status at 12 weeks was highly predictive of PFS. Safety was generally consistent with previous reports, and no new treatment-related Grade (Gr) 5 events were recorded since the first interim analysis. The most common treatment-emergent AEs (>30% all grades) were CRS (55%), anemia (34%), neutropenia (34%), and pyrexia (33%). With the optimized 0.7/4/20 mg step-up regimen (n=72), 98% of CRS events were Gr 1/2, and only one pt had Gr 3 CRS. All CRS events resolved with supportive measures; 13 pts received tocilizumab for CRS management with the optimized regimen. Only one low-grade ICANS event was reported with the optimized regimen. Gr ≥3 infections occurred in 50 (36%) pts (Gr 5, n=14 [10%]); COVID-19 infections were reported in 46 (35%) pts (Gr 5, n=8 [6%]). Conclusions The results of this pre-specified analysis of the Phase 2 ELM-2 study continue to demonstrate deep and durable responses with odronextamab in heavily pretreated, refractory pts with R/R FL. 90% of responders were complete responders, with a 48% probability of maintaining CR for 2 years. High CR rates appear to translate to favorable, long-term survival outcomes in the setting of incurable disease. The incidence of AEs was consistent with earlier reports, with no new treatment-related Gr 5 events. Importantly, continued treatment with odronextamab had no detrimental effects on overall QoL. These data underscore the promise of odronextamab as a potentially effective agent for the management of R/R FL. Updated data will be presented.