作者: Alonso, Aranzazu ; Tessoulin, Benoît ; Shariff, Saleem ; Song, Yuqin ; Cho, Seok-Goo ; Brouwer-Visser, Jurriaan ; Poon, Michelle ; Chong, Geoffrey ; Guidez, Stephanie ; Bachy, Emmanuel ; Tani, Monica ; Novelli, Silvana ; Chaudhry, Aafia ; Kim, Tae Min ; Tucker, David ; Jagadeesh, Deepa ; Ubieto, Ana Jiménez ; Luminari, Stefano ; Villasboas, Jose C. ; Taszner, Michal ; Cai, Jingxian ; Ambati, Srikanth ; Walewski, Jan ; Mayer, Laura Magnano ; Mohamed, Hesham ; Uppala, Amulya ; Iskierka-Jażdżewska, Elżbieta

AbstractBackground: 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.

2023-11-02·Blood

Results of a Second, Prespecified Analysis of the Phase 2 Study ELM-2 Confirm High Rates of Durable Complete Response with Odronextamab in Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) with Extended Follow-up

作者: Cho, Seok-Goo ; Shariff, Saleem ; Novelli, Silvana ; Chaudhry, Aafia ; Cai, Jessica ; Walewski, Jan ; Tani, Monica ; Mohamed, Hesham ; Merli, Michele ; Tessoulin, Benoit ; Jagadeesh, Deepa ; Luminari, Stefano ; Zhang, Wei ; Iskierka-Jażdżewska, Elżbieta ; Taszner, Michal ; Bachy, Emmanuel ; Ambati, Srikanth ; Kim, Tae Min ; Jimenez Ubieto, Ana ; Guidez, Stephanie ; Villasboas, Jose. C. ; Uppala, Amulya ; Chi, Lei ; Song, Yuqin ; Tucker, David ; Alonso, Aranzazu ; Chong, Geoffrey ; Magnano, Laura ; Poon, Michelle ; Yi, Shuhua

BackgroundThe 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.MethodsIntravenous 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.ResultsAt 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%]).ConclusionsThe 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.

2023-11-02·Blood

Trial in Progress: A Phase 2 Study of Linvoseltamab for the Treatment of High-Risk Smoldering Multiple Myeloma (LINKER-SMM1)

作者: Aina, Oluwaseun ; Hazra, Anasuya ; Rodriguez Otero, Paula ; Rodriguez Lorenc, Karen ; Kroog, Glenn S. ; Sinha, Arijit ; Mateos, Maria-Victoria ; San Miguel, Jesus ; Steele, Andrew J ; Sarkaria, Shawn M

Background and SignificanceSmoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder that precedes the development of multiple myeloma (MM). Traditionally, patients with SMM have undergone observation until progression to MM, but this paradigm can result in poor outcomes for some patients. Phase 3 clinical trials have demonstrated that early treatment with lenalidomide with or without dexamethasone can delay the development of end-organ damage and improve overall survival among SMM patients with high-risk features. Linvoseltamab (REGN5458) is a fully human B-cell maturation antigen (BCMA)×CD3 bispecific antibody that targets BCMA on plasma cells and CD3 on T cells, resulting in targeted T-cell-mediated cytotoxicity. In the Phase 1/2 LINKER-MM1 study, linvoseltamab alone induced deep and durable responses with a generally manageable safety profile in patients with relapsed/refractory MM (Lee et al. EHA. 2023). These data highlight the potential of novel immunotherapies with promising single-agent activity to be attractive therapeutics for early intervention to prevent progression to MM.Study Design and MethodsLINKER-SMM1 is an open-label, Phase 2 study (NCT05955508) designed to evaluate the safety and efficacy of linvoseltamab monotherapy in adult participants with SMM who are at a high risk of progression to MM. High-risk criteria include having both ≥95% clonal plasma cells in the bone marrow (BM) and immunoparesis and/or ≥2 of the following: serum M-protein >2 g/dL, free light chain ratio >20, and BM plasma cells >20%. Participants must have a confirmed diagnosis of SMM within 5 years of enrollment, Eastern Cooperative Oncology Group performance status ≤1, and adequate organ function to be eligible. Participants will be excluded from enrollment if they have myeloma-defining events, uncontrolled infection, history of allogeneic stem cell transplantation, or received prior treatment for SMM.The study will take place at approximately 15 sites in Spain and will include two parts: Part 1 (safety run-in) to evaluate the preliminary safety and tolerability of linvoseltamab and Part 2 (expansion) to evaluate the clinical activity of the selected dosing regimen. In Part 1, at least 6 participants will receive linvoseltamab starting with a step-up schedule before reaching the full dose. All subsequent treatment with full-dose linvoseltamab will be given over 28-day cycles until completion of 24 cycles or occurrence of a protocol-defined reason for discontinuation. Assuming that initial safety is shown to be acceptable, an additional 34 participants will be enrolled in Part 2 according to the dosing regimen established in Part 1.Post-treatment safety monitoring will continue for up to 90 days after the last dose of linvoseltamab, and participants with an ongoing response will continue routine efficacy assessments until confirmed biochemical progression, start of non-protocol cancer therapy, or death. Long-term follow-up will continue for up to 5 years after the last dose of linvoseltamab.The primary endpoints in Part 1 are frequency of adverse events (AEs) of special interest, including grade ≥2 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and frequency and severity of treatment-emergent AEs. In Part 2, the primary endpoints are complete response (assessed by International Myeloma Working Group criteria) and minimal residual disease (MRD) negativity (10 -5 sensitivity) after 12 and 24 months of treatment. Secondary endpoints include cumulative safety, overall response rate, duration of response, sustained MRD negativity, biochemical and clinical progression-free survival (PFS), time to myeloma-defining event, time to initiation of first-line treatment for MM, and overall survival as well as immunogenicity and serum concentration of linvoseltamab over time. Exploratory endpoints include PFS after the start of first-line treatment for MM, adequacy of stem cell collection, patient-reported outcomes, and various biomarker changes. As this is a proof-of-concept study, results will be analyzed using descriptive statistics and no formal hypothesis testing is planned.Study accrual is planned to begin in Q4 2023.

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