Step-up Regimen Research Articles

Phase 3 trial of odronextamab plus lenalidomide versus rituximab plus lenalidomide in relapsed/refractory (R/R) follicular lymphoma (FL) and marginal zone lymphoma (MZL; OLYMPIA-5).

TPS7094 Background: FL and MZL are indolent B-cell non-Hodgkin lymphomas (B-NHLs) that are treated in a similar way in the R/R setting. Despite the efficacy of rituximab–lenalidomide (R2) in patients (pts) with R/R FL, and MZL to a lesser extent, a notable proportion fail to achieve an optimal, durable response. Odronextamab is an off-the-shelf, CD20×CD3 bispecific antibody. In the Phase (Ph) 1 ELM-1 study, odronextamab monotherapy showed antitumor activity and a generally manageable safety profile across R/R B-NHL subtypes, including FL and MZL (Bannerji, et al. Lancet Haematol 2022). In the Ph 2 ELM-2 study, odronextamab elicited an objective response rate of 80% and complete response (CR) rate of 73% in pts with heavily pretreated R/R FL (Villasboas, et al. ASH 2023). The rate of treatment-related adverse events leading to treatment discontinuation was 7.8%. These positive data support the evaluation of odronextamab in R/R FL and MZL in earlier lines of therapy. Combining odronextamab with lenalidomide has the potential to improve efficacy in the R/R setting compared with R2. Methods: OLYMPIA-5 (NCT06149286) is a Ph 3, open-label, randomized study of odronextamab plus lenalidomide versus R2 in pts with R/R FL and MZL. The study consists of Part 1 (safety run-in) followed by Part 2 (randomization). In Part 1, odronextamab and lenalidomide will be administered for 12×28-day cycles or until relapse, progressive disease, withdrawal of consent, or unacceptable toxicity. Odronextamab IV infusion will be administered in a step-up regimen during Cycle (C) 1 to mitigate the risk of cytokine release syndrome, followed by full dose starting from C1 Day 22. In Part 2, pts will be randomized 1:1 to receive 12 cycles of odronextamab plus lenalidomide, or R2 for the first 5 cycles followed by lenalidomide monotherapy for C6–12 per standard schedule (Leonard, et al. J Clin Oncol 2019). Key inclusion criteria: aged ≥18 years; histologically confirmed FL Grade 1–3a or MZL (nodal, splenic, or extra nodal) that is refractory or relapsed after ≥2 cycles of prior systemic therapy that included ≥1 anti-CD20 antibody; measurable disease; ECOG PS 0–2; and adequate organ function. Pts with central nervous system (CNS) lymphoma, history of or current relevant CNS pathology, histological evidence of transformation to high-grade or diffuse large B-cell lymphoma, and prior use of lenalidomide or any CD20×CD3 bispecific antibody within the past 6 months are excluded. The Part 2 primary endpoint is progression-free survival as assessed by independent central review. Key secondary endpoints are CR, best overall response, and overall survival. Minimal residual disease (by ctDNA) analysis is an exploratory endpoint. The trial is currently recruiting and is expected to enroll approximately 24–48 pts in Part 1 and 422 pts in Part 2 (352 R/R FL; 70 R/R MZL) at ~200 global sites. Clinical trial information: NCT06149286 .

Phase 3 trial evaluating the efficacy and safety of odronextamab versus investigator’s choice in previously untreated follicular lymphoma (OLYMPIA-1).

TPS7096 Background: Follicular lymphoma (FL) is an incurable disease in which patients will relapse despite the effectiveness of first-line (1L) rituximab-based chemoimmunotherapy (CIT), indicating the need for alternative 1L treatments that can deepen and prolong response. Odronextamab, an off-the-shelf, CD20×CD3 bispecific antibody, showed compelling efficacy and generally manageable safety as a monotherapy at 3L+ for patients with relapsed/refractory (R/R) FL in the Phase 2 ELM-2 study (Villasboas, et al. ASH 2023). Objective and complete response (CR) rates were 80% and 73%, respectively, median duration of response was 22.6 months, median progression-free survival (PFS) was 20.7 months, and median overall survival was not reached. The rate of treatment-related adverse events leading to treatment discontinuation was 7.8%. The activity of odronextamab monotherapy in this heavily pretreated R/R FL population, including among patients with rituximab-refractory disease, provides a strong rationale for developing odronextamab as a chemotherapy-free option that can improve long-term outcomes in 1L. Methods: OLYMPIA-1 (NCT06091254) is a Phase 3, randomized, open-label, multicenter study of odronextamab versus investigator’s choice of CIT (R-CHOP, R-CVP, or R-bendamustine) in patients with previously untreated FL. The study consists of Part 1 (safety run-in), followed by Part 2 (randomization). In Part 1, patients will receive six 21-day cycles (induction) of intravenous odronextamab, administered in a step-up regimen during Cycle (C) 1 to mitigate the risk of cytokine release syndrome, followed by full dose starting from C2. Patients with CR or partial response at the end of induction will receive 12 doses of odronextamab maintenance given Q8W. In Part 2, patients will be randomized 1:1 to receive induction of six cycles of odronextamab followed by odronextamab maintenance, or CIT followed by rituximab maintenance. Key inclusion criteria: aged ≥18 years; CD20+ FL Grade 1–3a, stage II bulky or stage III/IV; measurable disease; and ECOG performance status 0–2. Patients with central nervous system lymphoma or histological Grade 3b are excluded. The Part 2 primary endpoint is CR at 30 months (CR30) as assessed by independent central review. Key secondary endpoints include PFS, event-free survival, investigator-assessed CR30, and patient-reported outcomes. Biomarkers (including minimal residual disease by ctDNA) will be evaluated as exploratory endpoints. This trial is currently recruiting and is expected to enroll ~12–32 patients in Part 1 and ~446 patients in Part 2 at ~200 global sites. Clinical trial information: NCT06091254 .

Phase 3 trial evaluating the efficacy and safety of odronextamab plus chemotherapy versus rituximab plus chemotherapy in previously untreated follicular lymphoma (OLYMPIA-2).

TPS7099 Background: Odronextamab, an off-the-shelf, CD20×CD3 bispecific antibody, has shown compelling efficacy and generally manageable safety as monotherapy in patients with heavily pretreated relapsed/refractory (R/R) follicular lymphoma (FL), including those with rituximab-refractory disease (Villasboas et al. ASH 2023). In the Phase 2 ELM-2 study, odronextamab demonstrated objective and complete response (CR) rates of 80% and 73%, respectively, and median duration of response of 22.6 months; median overall survival was not reached. Treatment-related adverse events led to treatment discontinuation in 7.8% of patients. These encouraging results support an investigation into whether odronextamab plus chemotherapy is superior to the current FL first-line standard of care of rituximab plus chemotherapy. This study will also evaluate whether odronextamab maintenance is required to achieve progression-free survival (PFS), given the risks associated with sustained B-cell depletion. Methods: OLYMPIA-2 (NCT06097364) is a Phase 3, randomized, open-label, multicenter study of odronextamab plus chemotherapy (Odro-CHOP/Odro-CVP) versus R-CHOP/R-CVP in patients with previously untreated FL. The study consists of Part 1A (dose escalation), Part 1B (dose optimization), and Part 2 (randomization). In Part 1, patients will receive six 21-day cycles (induction) of Odro-CHOP, in which intravenous odronextamab will be administered in a step-up regimen starting on Cycle (C) 1 Day (D) 8 to mitigate the risk of cytokine release syndrome, followed by full dose starting from C2D8. Patients with CR or partial response at the end of induction will receive 12 doses of odronextamab maintenance given Q8W. In Part 2, patients will be randomized 1:1:1 to receive induction of 6 cycles of Odro-CHOP/Odro-CVP with no maintenance (Arm A), Odro-CHOP/Odro-CVP followed by odronextamab maintenance (Arm B), or R-CHOP/R-CVP followed by rituximab maintenance (Arm C). Key inclusion criteria: aged ≥18 years; CD20+ FL Grade 1–3a, stage II bulky or stage III/IV; measurable disease; and ECOG performance status 0–2. Part 1: patients with FL that is R/R (Part 1A only) or previously untreated with Follicular Lymphoma International Prognostic Index-1 (FLIPI-1) score 3–5. Part 2: previously untreated patients with FLIPI-1 score 0–5. Patients with central nervous system lymphoma or histological Grade 3b are excluded. The Part 2 primary endpoint is CR rate at 30 months (CR30) by independent central review. Key secondary endpoints include PFS, event-free survival, investigator-assessed CR30, and patient-reported outcomes. Biomarkers (including minimal residual disease by ctDNA) will be evaluated as exploratory endpoints. This trial is currently recruiting and is expected to enroll up to 64 patients in Part 1 and ~669 patients in Part 2 at ~200 global sites. Clinical trial information: NCT06097364 .

Final Analysis of the Phase 2 ELM-2 Study: Odronextamab in Patients with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Background Odronextamab is a novel, off-the-shelf, CD20×CD3 bispecific antibody that has demonstrated consistent anti-lymphoma activity and a generally manageable safety profile in heavily pretreated patients (pts) with both R/R follicular lymphoma and R/R DLBCL. Encouraging results have been reported in pts who have relapsed following chimeric antigen receptor (CAR) T-cell therapy in the Phase 1 ELM-1 study, and in pts with R/R DLBCL in the Phase 2 ELM-2 study (Kim WS, et al. ASH. 2022). Here, we present the final analysis of the R/R DLBCL cohort from ELM-2 (NCT03888105), reporting long-term efficacy and safety outcomes. 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 WS, et al. ASH 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1, followed by 160 mg on Days 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg every 2 weeks until disease progression or unacceptable toxicity. Pts who achieved a complete response (CR) that was durable for ≥9 months transitioned to dosing every 4 weeks. The final analysis was performed when all pts had the opportunity for ≥36 weeks of 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 the time of data cut-off (Jan 31, 2023) the DLBCL cohort was fully enrolled; 141 pts were evaluable for safety and 127 were evaluable for efficacy, with a median duration of follow-up of 26.2 months. In the safety-evaluable DLBCL population, median age was 66 years (range 24-88), 60% male, 80% Ann Arbor stage III-IV, 56% IPI score ≥3, and median prior lines of therapy was 2 (range 2-8). 17% of pts had transformed disease from indolent lymphoma and 5% had Richter's transformation; 12% were double-hit and 6% triple-hit. In total, 57% of pts were primary refractory and 66% were double refractory to an anti-CD20 antibody and an alkylator in any line of therapy. ORR and CR rate confirmed by ICR were 52% (66/127) and 31% (39/127), respectively, and were consistent across high-risk subgroups. Median DoR was 10.2 months (95% CI: 5.0-not estimable [NE]) and median duration of CR was 17.9 months (95% CI: 9.2-NE); the probability of maintaining CR for 24 months was 48%. Patient-reported outcomes were maintained or improved; of special note, patient-reported pain and emotional functioning scores improved from baseline during the course of treatment. MRD status at 12 weeks was highly predictive of PFS. Safety was generally consistent with previous reports. Treatment-related AEs led to odronextamab interruption/delay in 75 (53%) pts and discontinuation in 14 (10%) pts. The most common treatment-emergent AEs (>30% all grades) were CRS (55%), anemia (43%), and pyrexia (42%). With the optimized 0.7/4/20 mg step-up regimen (n=74), 98% of CRS events were Grade (Gr) 1/2, and only one Gr 3 CRS (confounded by pancreatitis) was reported. CRS events resolved with supportive measures; 26% of pts received tocilizumab for CRS management with the optimized regimen. No ICANS events were reported with the optimized step-up regimen. Gr ≥3 infections occurred in 52 (37%) pts (Gr 5, n=16 [11%]); COVID-19 infections were reported in 23 (16%) pts, which were Gr 5 in 6 (4%) pts. Conclusions Results of the final analysis of the ELM-2 study R/R DLBCL pt cohort confirm the highly encouraging clinical activity of odronextamab in a hard-to-treat pt population, including in pts with high-risk features. Responses were deep and durable with a 48% probability of maintaining CR for 2 years. The safety profile was generally consistent with earlier reports and CRS events were predominantly low grade and manageable. Importantly, continued treatment with odronextamab showed no detrimental effects on patient-reported outcomes. Odronextamab may be an important potential option in future management of R/R DLBCL, and these results support the continued investigation of odronextamab in Phase 3 trials. Updated data will be presented.

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

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.

Odronextamab Demonstrates Durable Complete Responses in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Progressing after CAR-T Therapy: Outcomes from the ELM-1 Study

Background Chimeric antigen receptor (CAR) T-cell therapies have recently been established as an important option for the management of relapsed/refractory (R/R) DLBCL. However, real-world studies suggest that approximately half of all patients (pts) receiving commercial CAR-T therapies will relapse within 6 months. These pts have a poor prognosis, with estimated overall survival (OS) of only 5 months, indicating a significant unmet need. Odronextamab is a novel, off-the-shelf, CD20×CD3 bispecific antibody that has demonstrated activity in both R/R follicular lymphoma and R/R DLBCL. We have previously reported encouraging results with odronextamab from the Phase 1 ELM-1 study (NCT02290951) in pts with R/R DLBCL post CAR-T therapy (Bannerji R, et al. Lancet Haematol. 2022). These results were consistent with the antitumor activity seen in pts with R/R DLBCL from the Phase 2 ELM-2 study (Kim WS, et al. ASH 2022). Here, we present an updated analysis of outcomes in a prespecified cohort of post CAR-T patients from ELM-1. Methods Intravenous odronextamab was administered weekly in 21-day cycles during Cycles (C) 1-4. Revisions to the step-up regimen were reported previously (Bannerji R, et al. Lancet Haematol. 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 160 mg on Days (D) 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg every 2 weeks until disease progression or unacceptable toxicity. Those pts who achieved a complete response (CR) that was durable for ≥9 months transitioned to dosing with 320 mg every 4 weeks. The primary endpoint was objective response rate (ORR), 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. Immune biomarker assessment was an exploratory endpoint. Results As of Dec 20, 2022, 46 pts were treated (safety-evaluable), with 44 pts evaluable for efficacy. For safety-evaluable pts, median age was 63 years (range 27-82), 67% male, 74% Ann Arbor stage III-IV, and 72% were refractory to CAR-T therapy administered in any prior line. 44 pts were evaluable for efficacy after 4.9 months median duration of follow-up. The ORR and CR rate by ICR were 48% (21/44) and 30% (13/44), respectively. Responses were durable, and both median DoR and median duration of CR were not reached. The probability of maintaining a response for 12 months was 62% and the probability of maintaining a CR for 9 months was 86%.A responder analysis of the subgroup of pts who achieved a CR will be presented. The CAR-T treated pts with DLBCL who were evaluable for biomarker analysis (n=10) had lower T-cell counts at baseline compared with CAR-T naive DLBCL pts (n=41 comparable pts who received odronextamab in ELM-2), yet the fold-change of T-cell expansion at C4D15 was greater in CAR-T treated pts versus CAR-T naive pts. T-cell dynamics, such as changes in activation, exhaustion, and memory subsets, will be presented. Safety was generally consistent with that previously reported. Six (13%) pts permanently discontinued odronextamab due to a treatment-emergent AE (device-related infection, pneumonia, dysphagia, gait disturbance, leukemia, and encephalopathy [n=1 each]). The most common treatment-emergent AE was CRS (any grade, 52%). The highest grade of CRS reported was Grade 2, and low-grade CRS events occurred in 46% of pts with the 0.7/4/20 mg step-up regimen. No cases of ICANS were reported in pts with the 0.7/4/20 mg regimen. Grade ≥3 infections occurred in 10 (22%) pts, with no Grade 5 events. No cases of tumor flare were reported. Conclusions Odronextamab monotherapy demonstrates encouraging antitumor activity in heavily pretreated pts who have progressed after CAR-T therapy, with a generally manageable safety profile. Durable CRs were achieved in this difficult-to-treat setting. These data support the potential role of odronextamab in the treatment paradigm for R/R DLBCL. Further studies to evaluate the optimal sequencing and combinations of odronextamab with CAR-T therapy are warranted.

Maintenance of Moderate to High Levels of Functioning and Quality of Life with Odronextamab Monotherapy in Patients with Relapsed or Refractory Follicular Lymphoma

Background: Goals of patient-centered care for management of relapsed or refractory follicular lymphoma (R/R FL) are to improve clinical outcomes while maintaining or improving health-related quality of life (HRQoL). In ELM-2 (NCT03888105), a Phase 2, open-label, multicohort, multicenter study, odronextamab monotherapy demonstrated high and durable complete response rates and generally manageable safety in patients with R/R FL. We report here, for the first time, patient-reported outcome (PRO) results from ELM-2 in patients with R/R FL. Methods: Patients with R/R FL Grade 1-3a received odronextamab IV at 80 mg weekly in 21-day cycles in Cycles (C) 1-4. Optimization of the step-up regimen to mitigate cytokine release syndrome (CRS) was reported previously. Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg in C1, then 80 mg on Days 1, 8, and 15 of C2-4. After C4, odronextamab maintenance continued at 160 mg every 2 weeks until disease progression or unacceptable toxicity. Patients with durable complete response (≥9 months) switched to dosing every 4 weeks. Patients completed EORTC QLQ-C30, FACT-Lym, and EQ-5D-3L questionnaires at Weeks 1 (baseline), 2, 3, 4, and 10, then every 8 weeks for the remainder of the first year and every 12 weeks in the second year. Results here focus on six key PRO scales: EORTC QLQ-C30 Global Health Status/Quality of Life (GHS/QOL), physical functioning (PF), role functioning (RF), and fatigue; FACT-Lym lymphoma subscale (LymS); and EQ-5D-3L visual analog score (VAS). Longitudinal analyses using mixed models for repeated measures (MMRM) were conducted through Week 50 (the last visit with ≥10 patients with PRO data). Changes from baseline were considered statistically significant if the 95% confidence interval did not contain zero. No adjustment for multiplicity was performed, hence all statistical significance is nominal. Published ranges for minimum important difference (MID) to define clinically meaningful changes are: EORTC QLQ-C30 scales, 10 points; FACT-Lym LymS, 2.9-5.4 points; and EQ-5D-3L VAS, 7-12 points. For responder and time to definitive deterioration (TTDD) analyses, the upper end of these published MID ranges was used to define deterioration or improvement. Results: At the ELM-2 interim data cutoff on 31-Jan-2023, 140 patients with R/R FL Grade 1-3a had received at least 1 dose of odronextamab. Median age was 60.5 years (range: 22-84), with 38.6% ≥65 years, 52.9% male, 57.1% White, 32.1% Asian, 52.2% ECOG=0, and 47.1% ECOG=1. Median duration of follow-up was 26.6 months (range: 6.2-37.5). PRO completion rates for EORTC-QLQ-C30, FACT-Lym, and EQ-5D-3L were high at baseline and remained high for all assessments through Week 50. At baseline, moderate levels of general health (GHS/QoL) and high levels of functioning (PF and RF) were observed that were higher (better) than reference values for general cancer or non-Hodgkin's Lymphoma (NHL). Fatigue scores at baseline were lower (less symptoms) than reference values for general cancer or NHL. EORTC QLQ-C30 GHS/QOL, PF, RF, and fatigue scores were maintained from baseline through Week 50 (Table). For EQ-5D-3L VAS, the overall estimated mean changes from baseline improved statistically significantly but did not reach MID thresholds (Table). For FACT-Lym LymS, overall estimated mean change from baseline statistically significantly improved, and scores improved statistically significantly from Weeks 10 to 42 (except Week 34), with clinically meaningful improvements at Weeks 26 and 42 (Figure). The proportion of patients reporting meaningful improvement or stability across the six scales was higher than the proportion reporting meaningful worsening through Week 50 (Table). The median TTDD for EORTC-QLQ-C30 GHS/QoL was 22.41 (95% CI: 14.59 to not yet reached) months, corresponding to the median PFS. Median TTDD was not reached for EORTC QLQ-C30 PF, FACT-Lym LymS, and EQ-5D-3L VAS scales. Conclusions: For patients with R/R FL, patient-reported HRQoL results were favorable during odronextamab treatment until disease progression, with no detriments on patient-reported symptoms, functioning, and overall quality of life. These results complement encouraging clinical efficacy, durability of responses, and tolerability observed in this highly refractory patient population and support the future role of odronextamab in the management of patients with R/R FL.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: MZL is a heterogeneous disease comprising 3 subtypes, extra-nodal MZL of mucosa-associated lymphoid tissue, nodal MZL, and splenic MZL. Treatment of R/R MZL is similar to other indolent B-cell non-Hodgkin lymphoma (B-NHL) subtypes (e.g., follicular lymphoma [FL]), comprising rituximab-based immunochemotherapy regimens that achieve an objective response rate (ORR) of ∼45%–80%. Options after progression on rituximab-based regimens include the BTK inhibitor ibrutinib, which demonstrated an ORR of 46%, but a compete response (CR) rate of only 3%, in its pivotal trial in R/R MZL. Overall, limited options are available after progression on current therapies, and a need remains for more effective treatments for R/R MZL. Odronextamab is a bispecific antibody that binds CD20-expressing B-NHL cells and CD3 on T cells. In the Phase 1 ELM-1 study, odronextamab monotherapy showed antitumor activity and a manageable safety profile in a range of R/R B-NHL subtypes, including MZL (n = 6; ORR 67%) (Bannerji et al. Lancet Haematol, 2022). In the Phase 2 ELM-2 study, odronextamab elicited an ORR of 82% and CR rate of 75% in patients with heavily pretreated R/R FL (Kim, et al. ASH, 2022). These positive data in an indolent B-NHL subtype support evaluation of odronextamab in R/R MZL. Methods: ELM-2 (NCT03888105) is an open-label study of odronextamab in patients with R/R B-NHL comprising 5 disease-specific cohorts: FL, diffuse large B-cell lymphoma, mantle cell lymphoma, MZL, and other B-NHLs. Each cohort will be evaluated separately, and patients recruited from sites across North America, Europe, and Asia-Pacific regions. The MZL cohort is planned to include 78 patients, who will receive IV odronextamab monotherapy until disease progression or other protocol-defined reason for treatment discontinuation. Odronextamab is administered according to a step-up regimen during the first 21-day cycle (C), consisting of 0.7 mg split over C1 Day (D) 1 (0.2 mg) and C1D2 (0.5 mg), 4 mg split over C1D8 and C1D9, and 20 mg split over C1D15 and C1D16. The full 80 mg dose is given QW during C2 to C4, then 160 mg Q2W from C5 onwards. If a patient achieves a CR and has a durable response for ≥9 months after initial determination of the CR, then dosing interval will be decreased from Q2W to Q4W. Patients eligible for the MZL cohort will be ≥18 years of age; relapsed/refractory to ≥2 prior lines of systemic therapy; ECOG performance status ≤1; and have adequate bone marrow and hepatic functions. Patients with prior allogeneic stem cell transplant or CAR T treatment will be excluded. Primary endpoint is ORR (Lugano classification; assessed by independent central review). Key secondary endpoints include ORR (investigator evaluation); CR rate; progression-free survival; overall survival; duration of response; safety; pharmacokinetics; and patient-reported quality of life outcomes. As of January 2023, 19 patients with MZL had enrolled. Encore Abstract—previously submitted to ASCO 2023 and EHA 2023 The research was funded by: Regeneron Pharmaceuticals, Inc. Keywords: indolent non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract. T. M. Kim Consultant or advisory role Boryung, AstraZeneca/MedImmune, Takeda, Novartis, Janssen, Hanmi, and Regeneron Pharmaceuticals, Inc Honoraria: Takeda, Janssen, Regeneron Pharmaceuticals, Inc, Samsung Bioepis, and AstraZeneca Research funding: Celgene, Boryung, Boehringer-Ingelheim, BMS, Bayer, AstraZeneca/MedImmune, Takeda, Roche/Genentech, Novartis, Janssen, Hanmi, Genmab, Merck Serono, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc, and Sanofi M. Taszner Consultant or advisory role Roche and Takeda Honoraria: Roche, Takeda, Novartis, and Servier Educational grants: Roche A. Chaudhry Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc M. Ufkin Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc A. Uppala Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc A. Sabir Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc H. Mohamed Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc S. Ambati Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc E. Bachy Consultant or advisory role Roche, Gilead, ADC Therapeutics, Takeda, Novartis, and Incyte Honoraria: Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, and Sanofi Research funding: Amgen and BMS

Odronextamab in Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) Grade 1-3a: 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 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), pts with FL Grade 1-3a receiving ≥2 prior lines of therapy and treated with odronextamab doses of ≥5 mg, had an ORR of 91% and CR rate of 72%. Responses were durable with a 4-y PFS rate of 54% (Bannerji R, et al. Lancet Haematol. 2022). The RP2D dose in R/R FL pts was determined as 80 mg weekly. Here, we present for the first time, results from a prespecified analysis of the FL Grade 1-3a 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 FL Grade 1-3a who had relapsed or were refractory to ≥2 prior lines of therapy including an anti-CD20 antibody and 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 consisted of 1 mg split over C1 Day (D) 1 and C1D2, and 20 mg split over C1D8 and C1D9, followed by the 80 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 80 mg full dose on C2D1 (0.7/4/20 regimen). 80 mg weekly continued until the end of C4. After C4, maintenance treatment with 160 mg odronextamab occurred every 2 wks 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, 96 pts were evaluable for safety; 85 for efficacy. Median age 59 y (range 22-84), 52% male, 58% FLIPI 3-5, 15.6% had bulky disease, and median prior lines of therapy were 3 (range 2-13). 74% were refractory to their last therapy, 79% refractory to prior anti-CD20 therapy, and 48% had progression of disease within 2 y (POD24). Median duration of study follow-up was 17.3 mos. ORR and CR rate by ICR were 81% (69/85) and 75% (64/85), respectively. ORR and CR rate were consistent across high-risk subgroups, including pts aged ≥65 y, POD24, FLIPI 3-5, and pts refractory to their last line of therapy; ORR and CR rate were also consistent for the subgroup of pts treated with the 0.7/4/20 step-up regimen. Responses were durable with both a median duration of response and a median duration of CR of 18.2 mos. Median PFS was 20.2 mos (95% CI 14.8-not estimable [NE]) and median OS was not reached (95% CI 23.0 mos-NE). TEAEs occurred in 95 (99%) pts, considered treatment related in 86 (90%). In the overall safety evaluable population, the most common TEAEs (>30% all grades) were CRS (51%), pyrexia (32%), anemia (31%), and infusion-related reaction (31%). Following implementation of the 0.7/4/20 step-up regimen in C1, no Grade ≥2 CRS was observed; only Grade 1 CRS was reported in 39% of pts. All CRS events resolved and only 1 pt received tocilizumab for CRS management. No ICANS was reported in the 0.7/4/20 regimen compared with 3% in the 1/20 regimen. COVID-19 was reported (n=13,14%), including Grade ≥3 (n=5, 5%). Treatment-related Grade 5 AEs were reported for 2 pts; treatment-related AEs led to discontinuation in 6 pts. Conclusions Consistent with the ELM-1 Ph1 study, the ELM-2 pivotal Ph2 study of odronextamab demonstrated compelling efficacy in pts with FL Grade 1-3a receiving ≥2 prior lines of therapy, with 75% of pts achieving CR by ICR and an acceptable safety profile. Durability of responses and favorable survival outcomes are clinically important in the context of heavily pretreated, highly R/R FL, where prognosis is typically poor. The 0.7/4/20 step-up regimen compares favorably to other CD20×CD3 bispecifics, with no Grade 2 or higher CRS reported. Odronextamab may represent an important treatment option for R/R FL, providing a more accessible option with favorable benefit/risk compared with existing therapies including CAR T cell therapy. Updated safety and efficacy data will be presented.

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.

CD19 4-1BBL (RO7227166) a Novel Costimulatory Bispecific Antibody Can be Safely Combined with the T-Cell-Engaging Bispecific Antibody Glofitamab in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Background RO7227166 is a bispecific monoclonal antibody that simultaneously targets CD19 on B-cells and 4-1BB on T-cells and other immune cells. In the presence of a T-cell receptor signal and strictly dependent on CD19 crosslinking, RO7227166 provides a strong co-stimulation to T-cells via 4-1BB agonism. RO7227166 is therefore not exhibiting single-agent activity. Our preclinical and clinical data demonstrated 4-1BB upregulation on immune cells by glofitamab and in our in vivo humanized lymphoma xenograft mouse models the combination of glofitamab plus RO7227166 showed increased anti-tumor efficacy mediated by increased infiltration of activated CD8 T-cells within the tumor. We therefore hypothesized that RO7227166 would boost the anti-tumor activity of glofitamab in patients (pts) with B-cell non-Hodgkin lymphoma (B-NHL). Methods We report data from the first-in-human study BP41072 (NCT04077723), a multicenter open label Phase 1 trial investigating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary antitumor activity of RO7227166 in combination with glofitamab (part II of the study) in relapsed/refractory (R/R) B-NHL pts. Pts received 1000mg obinutuzumab 7 days prior to first glofitamab administration to mitigate cytokine release syndrome (CRS). Glofitamab was then dosed following a step-up regimen in cycle 1 (C1), from cycle 2 day 1 (C2D1) on, every 3 weeks (Q3W) for up to 12 cycles. First RO7227166 dose was given on C2D8 and from C3 onwards on the same day as glofitamab. RO7227166 dose escalation was guided by an mCRM EWOC model with overdose control. Response rates were reported based on the Lugano criteria. Results As of June 7, 2022, a total of 46 pts with R/R aggressive B-NHL (diffuse-large B-cell lymphoma [DLBCL]) and 24 pts with R/R indolent B-NHL (23 follicular lymphoma [FL], 1 marginal zone lymphoma [MZL]) received RO7227166 doses ranging from 360µg up to 33mg. So far the dose level with the expected maximum efficacy is not yet reached. Pts had a median age of 66 years, 44.3% were female, with ECOG of 0 (62.9%) or 1 (37.1%). Approximately half of pts had Stage IV disease (44.3%), 18.6% pts had bulky disease (at least one lesion > 6cm), 27.1% had prior CAR-T therapy. Median prior lines of therapy was 3 (range 1-7), with 40% refractory to last prior therapy, 21.4% primary refractory and 12.9% refractory to CAR-T. Across 70 safety evaluable pts, 67 (95.7%) had adverse events (84.3% pts grade 1, 64.3% pts grade 2, 44.3% pts grade 3, 8.6% pts grade 4 and 4.3% pts grade 5). Grade 5 events were pneumocystis jirovecii pneumonia which qualified as dose-limiting toxicity (n=1) and septic shock (n=1) and COVID-19 infection (n=1) which were both assessed as not related to study medications. The most frequent adverse event was CRS with 63 events occurring in 38 (54.3%) pts (maximum grade 1 in 37,1% pts, and maximum grade 2 in 17,1% pts, according to ASTCT score). Of all 63 events (including multiple events for some pts), 55 were related to glofitamab alone (87,3%), 5 events to glofitamab and RO7227166 (8%, all grade 1) and 3 events related to RO7227166 alone (4.8%, all grade 1). Overall the safety profile was mainly driven by glofitamab (Hutchings, et al. 2021) and we are yet to detect an additive safety signal from RO7227166 when combined with glofitamab. RO7227166 exposure increased dose-dependently across the investigated doses. Furthermore, preliminary pharmacodynamic analysis showed further expansion of primed and activated CD8, and effector memory T-cells in the periphery, which supports the expected mode of action of RO7227166 in combination with glofitamab. Of the 56 response-evaluated subjects, pts with DLBCL achieved a best overall response rate (BORR) of 67% and a complete response rate (CRR) of 39%, while the BORR and CRR for patients with FL was 91% and 73%. Summary This is the first study demonstrating that glofitamab can be safely combined with a costimulatory bispecific antibody (RO7227166) in R/R B-NHL. No new safety signals or signs of increased immune-related AEs were detected and the overall safety profile was consistent with that reported from single-agent glofitamab. At doses explored, combination therapy maintains efficacy similar to glofitamab single-agent, and dose escalation continues with additive benefit of the combination expected at higher doses.

Evaluate Dynamics of IL-6 Release during Step-up Dosing of Subcutaneous Administration of Odronextamab Via a Quantitative Systems Pharmacology Modeling Approach

Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, eliciting T-cell-mediated cytotoxicity independent of T-cell receptor-mediated recognition. T-cell activation following odronextamab administration can result in a transient but clinically significant increase in circulating cytokine concentrations. This may lead to cytokine release syndrome (CRS), one of the most important safety concerns with T-cell engaging therapies. As most cytokine release occurs during the early weeks of treatment, a step-up dosing strategy prior to administration of a full treatment dose appears to be a successful strategy to mitigate the level of cytokine release and attenuate the occurrence of CRS. This study was performed to evaluate interleukin (IL)-6 profiles following odronextamab subcutaneous (SC) injection during Cycle 1 step-up dosing (Weeks 1-3) in patients with B-cell non-Hodgkin lymphoma (B-NHL). A quantitative systems pharmacology (QSP) model, which is an emerging mathematical modeling approach that can help improve our understanding of drug-disease interactions and can be used to evaluate hypothetical scenarios in preclinical and clinical settings, was developed and applied to identify SC step-up doses of odronextamab suitable for investigating in clinical studies. Methods A QSP model that can describe IL-6 profiles (a surrogate cytokine associated with CRS) following intravenous (IV) odronextamab was previously developed and calibrated using pharmacodynamic data from the Phase I ELM-1 study (NCT02290951; Toroghi MK. ACoP11 2020. Poster TUE-054). The IV QSP model was updated by adding relevant components (e.g. drug absorption compartment, lymph node compartment) to enable the description of IL-6 profiles following SC administration of odronextamab. Model parameters were calibrated using IL-6 concentration data of other CD20×CD3 bispecific antibodies under SC administration reported in the literature (Matasar M. ASH 2020. Poster 2096). Odronextamab SC step-up doses of interest were proposed and IL-6 profiles of these regimens were simulated with the SC QSP model. In each dosing scenario, IL-6 profiles were simulated in 300 virtual patients. The cytokine release criterion for regimen selection was that the peak IL-6 concentrations of a SC step-up regimen should be lower than peak IL-6 concentrations observed with the previously tested IV regimens. Results Simulation results indicated that the predicted IL-6 profiles were similar with or without split dosing; the former was effectively used in the IV regimen for management of CRS. The predicted highest peak IL-6 value in Week 1 with SC dose of 2 mg was considerably lower than that of IV dosing of 0.7 mg (split 0.2 mg and 0.5 mg over 2 days in Week 1). The predicted highest IL-6 concentration with 2 mg SC was 150 pg/mL and that for 0.7 mg IV was 2,100 pg/mL, indicating a reduction of more than 90%. The predicted IL-6 profiles in Week 4 were similar with 160 mg IV or 400 mg SC doses. Based on the comparison of IL-6 profiles of multiple SC dosing scenarios, SC step-up doses of 2 mg in Week 1, 26 mg in Week 2, and 100 mg in Week 3 were selected, followed by a full dose of 400 mg. The proposed SC regimen is being tested in the clinical study ELM-1 for safety and efficacy evaluations. Conclusion The QSP modeling supported the selection of the odronextamab SC step-up dosing regimen to be evaluated in a clinical study in patients with B-NHL. The selected step-up regimen for SC odronextamab allows adequate step-up to effective therapeutic doses while simplifying and improving overall convenience. The simulations suggest that no split dosing is necessary for SC administration, which may further reduce overall hospital resource burden and requirements for in-patient monitoring.

Optimization of Intravenous Odronextamab Step-up Regimen for Reducing the Risk of High-Grade Cytokine Release Syndrome

Optimization of Intravenous Odronextamab Step-up Regimen for Reducing the Risk of High-Grade Cytokine Release Syndrome

Abstract CT503: A phase I/Ib study of the safety and preliminary efficacy of NZV930 alone and in combination with spartalizumab and/or taminadenant in patients (pts) with advanced malignancies

Abstract Background: The over-expression of CD73 has been linked to many cancers. NZV930, an investigational, CD73-targeting monoclonal antibody (mAb), forms bidentate structures with the CD73 dimer, shutting down the catalytic activity of cell surface and soluble CD73. Taminadenant is an investigational A2AR antagonist and spartalizumab is an anti-PD-1 mAb. Preclinical studies provide compelling antitumor activity when combining CD73, A2AR, and PD-1 blockade. Methods: This first-in-human study (NCT03549000) comprised dose-escalation and dose-expansion parts. Here, we present the dose-escalation results of the four treatment (tx) arms: NZV930 single agent (SA; 60-1000 mg Q2W), NZV930 (200-600 mg Q2W) + spartalizumab (400 mg Q4W) or taminadenant (80-240 mg Q2W), or in combination with spartalizumab (400 mg Q4W) + taminadenant (80-240 mg BID). Eligible pts had selected malignancies, and disease progression following standard therapy. Primary objectives included assessing safety and tolerability and determining the recommended dose for expansion (RDE) of NZV930 SA and its combinations. Secondary objectives were to determine efficacy, characterize the pharmacokinetics (PKs) of NZV930 SA and its combinations, and assess the immunogenicity of spartalizumab and NZV930. Biomarker tumor samples were obtained at screening, C2D1, and C4D1. Results: As of June 10, 2021, 105 pts were enrolled for dose escalation, including pts with CRC (n=63), ovarian cancer (n=15), pancreatic cancer (n=11), NSCLC (n=8), TNBC (n=5), RCC (n=2), and prostate cancer (n=1). Most pts (81%) had been treated with ≥3 lines of prior therapy. In total, 98 pts discontinued, mainly due to disease progression (72%); six were ongoing. At least one tx-related adverse event (TRAE) was reported by 89 pts (85%); these were mostly grade 1-2. A triad of headache, fever, and nausea/emesis was observed after the first infusion of NZV930. Most common TRAEs (≥30%) were headache (67%), nausea and vomiting (32% each), and pyrexia (30%). At least one grade ≥3 TRAE was reported in 15 pts (14%); headache (4%) was most common, accounting for 4/7 DLTs (all grade ≥3). There were no tx-related deaths. Overall, no responses were reported; 12 pts (11%) had stable disease and 69 pts (66%) had progressive disease. NZV930 has good PK properties, with target-mediated drug disposition at lower doses, which normalize to typical IgG-like PKs at higher doses. Biomarker data confirm CD73 target engagement in plasma. Adenosine pathway modulation in tumors and plasma was seen post-NZV930 tx. Conclusions: NZV930 reduced adenosine levels in plasma and tumors. The RDE of NZV930 SA or in combination with spartalizumab and/or taminadenant is 600 mg Q2W with a step-up dosing regimen. NZV930 SA and its combinations exhibited a tolerable safety profile in multiple advanced solid tumors and showed good PK properties. Citation Format: Siqing Fu, Udai Banerji, Philippe L. Bedard, Aitana Calvo Ferrándiz, Alberto Chiappori, Jayesh Desai, Rahima Jamal, Desamparados Roda Perez, Noboru Yamamoto, Erica Vieira, Gabrielle Wong, Kulandayan K. Subramanian, Shunguang Wang, Britta Mueller, Javier A. Otero, Si-Lin Koo. A phase I/Ib study of the safety and preliminary efficacy of NZV930 alone and in combination with spartalizumab and/or taminadenant in patients (pts) with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT503.

MagnetisMM-9: An open-label, multicenter, non-randomized phase 1/2 study of elranatamab in patients with relapsed/refractory multiple myeloma.

TPS8068 Background: Elranatamab (PF-06863135) is a humanized bispecific antibody that targets both B cell maturation antigen (BCMA) on multiple myeloma (MM) cells and CD3 on T cells resulting in T cell- mediated cytotoxicity. In preclinical studies, elranatamab has demonstrated anti-myeloma activity and delayed disease progression. In the ongoing phase 1 MagnetisMM-1 study, elranatamab has demonstrated clinical efficacy and a manageable safety profile in patients with relapsed/refractory MM (Bahlis et al, J Clin Oncol 2021). Elranatamab maximum tolerated dose has not yet been reached. Subcutaneous (SC) elranatamab at the recommended dose of 76 mg QW on a 28-d cycle with a 2 step-up priming dose regimen administered during the first week is currently being evaluated in a phase 2 study, MagnetisMM-3 (Lesokhin et al, Blood, 2021). Methods: MagnetisMM-9 (start date: Oct 2021; estimated completion date: Apr 2025) is an open-label, multicenter, non-randomized phase 1/2 study evaluating an alternative priming regimen to further mitigate cytokine release syndrome (CRS) incidence and severity and to evaluate SC elranatamab Q2W and Q4W dosing regimens in patients with relapsed/refractory MM. In part 1 of the study, patients will receive premedications and 2 step-up priming doses on cycle 1 D1 (4 mg) and D4 (20 mg), followed by elranatamab 76 mg QW for 6 cycles, and a dose Q2W thereafter if partial response or better is achieved and maintained. In part 2, higher doses of elranatamab ( > 76 mg) at increased intervals between doses will be evaluated. The primary endpoint is grade ≥2 CRS rate during cycle 1. Secondary endpoints include dose-limiting toxicities (part 2 only), objective response rate, duration of response, progression-free survival, overall survival, minimal residual disease negativity rate, safety, and pharmacokinetics. Eligible patients should be ≥18 years of age with a MM diagnosis and measurable disease according to IMWG criteria, refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody, relapsed/refractory to their last treatment regimen, and have an ECOG performance status ≤1. Key exclusion criteria are smoldering MM, active plasma cell leukemia, amyloidosis, POEMS syndrome, stem cell transplant within 12 weeks of enrollment, active, uncontrolled bacterial, fungal, or viral infections, or any other active malignancy within 3 years prior to enrollment (except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ), or previous treatment with an anti-BCMA bispecific antibody. The study is open at centers in the USA, UK, Japan, and Taiwan. Clinical trial information: NCT05014412.

Effects of ruminally-protected lysine and Megasphaera elsdenii on performance and carcass characteristics of finishing cattle

Ractopamine hydrochloride is a β-adrenergic agonist (BAA) commonly added to cattle finishing diets that redirects nutrients from fat deposition to protein synthesis and muscle growth. Physiological conditions established by BAA suggests that cattle fed diets containing BAA would have greater requirements for dietary protein to sustain BAA-induced accretion of lean tissue. Three hundred and eighty-four crossbred steers (413 ± 29.2 kg initial body weight) were used in a finishing trial to evaluate effects of ruminally-protected lysine (RPL) supplementation on performance and carcass characteristics of beef steers. Treatments were (2 × 4 factorial) 0, 20, 40, or 60 g/animal daily of SafeGain (i.e., approximately 0, 0.6, 1.2, or 1.8 g of lysine/kg diet dry matter based on an assumed daily feed intake of 10 kg per animal) in conjunction with a BAA (33 mg/kg diet dry matter basis) during the last 42 days on feed (112 days finishing period); and two step-up regimens: traditional 21-day step-up or an accelerated 12-day step-up with an oral dose of Megasphaera elsdenii probiotic (M.e.). Steers were blocked by weight; randomly assigned to treatments; implanted with 200 mg trenbolone acetate, 20 mg estradiol USP, and 29 mg tylosin; and allocated within blocks to 64 concrete-surfaced pens containing 6 steers per pen. A basal diet (dry matter basis) of 688.7 g/kg steam-flaked corn, 200 g/kg corn gluten feed, 70 g/kg alfalfa hay, and 19.1 g/kg vitamin and mineral supplement was fed ad libitum once daily. Ruminally-protected lysine was supplemented only during the BAA administration period, which comprised the last 42 days on feed. At the end of the finishing period, pens of cattle were weighed and then transported to a commercial abattoir. Harvest order, hot carcass weight, and liver abscess incidence and severity were evaluated the day of harvest. Longissimus muscle area, back fat, marbling score, USDA Yield Grade and USDA Quality Grade data were collected following a 36-hour refrigeration period. There were no effects of RPL supplementation or M.e. on average daily gain (P > 0.63), dry matter intake (P > 0.45), or feed efficiency (P > 0.81) of finishing steers; but liver abscess incidence was increased with RPL supplementation (P < 0.05; 28.3, 39.0, 46.9 and 39.4 % for cattle fed 0, 20, 40 and 60 g/animal daily of RPL, respectively). An interaction between RPL and M.e. was observed for hot carcass weight (P = 0.01). Dosing cattle with M.e. with an accelerated transition period decreased marbling score (P = 0.03) and yielded a lower percentage of carcasses grading Choice (P = 0.03) than those traditionally adapted. No other effects of M.e. or RPL were observed for carcass characteristics (P> 0.10). Thus, supplementation of RPL in conjunction with ractopamine hydrochloride yielded no benefits during feedlot finishing; however, an accelerated step-up program with M.e. yielded finishing performance comparable to that of traditionally-adapted cattle.

Early combination therapy with etanercept and methotrexate in JIA patients shortens the time to reach an inactive disease state and remission: results of a double-blind placebo-controlled trial

BackgroundRemission is the primary objective of treating juvenile idiopathic arthritis (JIA). It is still debatable whether early intensive treatment is superior in terms of earlier achievement of remission. The aim of this study was to evaluate the effectiveness of early etanercept+methotrexate (ETA+MTX) combination therapy versus step-up MTX monotherapy with ETA added in refractory disease.MethodsA multi-centre, double-blind, randomized study in active polyarticular JIA patients treated with either ETA+MTX (n = 35) or placebo+MTX (n = 33) for up to 24 weeks, followed by a 24-week open-label phase. The efficacy endpoints included pedACR30 criteria improvement at week 12, inactive disease at week 24, and remission at week 48. Patients who failed to achieve the endpoints at week 12 or at week 24 escaped to open-label ETA+MTX. Safety was assessed at each visit.ResultsBy intention-to-treat analysis, more patients in the ETA+MTX group reached the pedACR30 response at week 12 (33 (94.3%)) than in the placebo+MTX group (20 (60.6%); p = 0.001). At week 24, comparable percentages of patients reached inactive disease (11 (31.4%) vs 11 (33.3%)). At week 48, 11 (31.4%) and eight (24.2%) patients achieved remission. The median (+/−IQR) times to achieve an inactive disease state in the ETA+MTX and placebo+MTX groups were 24 (14–32) and 32 (24–40) weeks, respectively. Forty-four (74/100 patient-years) adverse events (AEs) were reported, leading to treatment discontinuation in 6 patients.ConclusionsEarly combination therapy with ETA+MTX proved to be highly effective compared to the standard step-up regimen. Compared to those treated with the standard regimen, more patients treated with a combination of ETA+MTX reached the pedACR30 response and achieved inactive disease and remission more rapidly.

Identification of novel step-up regimen of intralesional triamcinolone acetonide in scalp alopecia areata based on a double-blind randomized controlled trial.

Although intralesional triamcinolone acetonide (TA) is the most commonly prescribed treatment for localized alopecia areata (AA), the literature regarding the optimal concentration for attaining better efficacy with the most acceptable side effects is scarce. To compare hair regrowth and local side effects of various concentrations of intralesional TA in scalp AA using clinical and dermoscopic parameters. A double-blind randomized control trial with four treatment groups (10, 5, 2.5 mg/ml TA and normal saline [NS]) was conducted between March 2018 and August 2019. After recruitment, each AA patch was divided into quadrants and randomized before first injection. Injections were given and outcome parameters were analyzed every 4-weekly till 12-weeks. Statistical analysis was done by the R software employing generalized estimation equation. P-value <.05 was considered significant. Out of 105-patients (168-AA patches), 75-patients (121-patches) completed the study. Hair regrowth scale of all TA concentrations was better than NS group (P < .001). Other parameters such as quadrants with poor clinical response and dermoscopic disease activity signs were also favorable in TA groups in comparison to NS. However the evidence of atrophy and telangiectasia was maximum in 10 mg/mL group. 10 mg/mL TA showed a comparatively better response at the cost of increased adverse effects. Based on the clinical benefit and adverse risk assessment from our study, it may be better to start with 2.5 mg/mL intralesional TA in limited scalp AA patients. It can be implied that the concentration of TA can be increased as a step-up regimen based on the serial clinical and dermoscopic response.

333 Effects of ruminally-protected lysine and Megasphaera elsdenii on performance and carcass characteristics of finishing cattle

Abstract Crossbred steers (n = 448; 352 ± 25 kginitial body weight) were used to evaluate impact of Megasphaera elsdenii (ME; Lactipro advance, MS Biotec, Wamego, KS), alone or in combination with ruminally-protected lysine (RPL; USA Lysine, Kemin Industries, Inc., USA), on performance and carcass traits of finishing steers in a randomized complete block design. Steers were blocked by initial body weight and randomly assigned within block to one of 64 pens (7 steers/pen) in a 2 x 2 factorial treatment arrangement. Factors consisted of RPL (0 or 40 g/steer daily) and two step-up regimens (21-d without ME or 10-d with ME). Four step-up diets were used to transition cattle to finishing diets containing (dry basis) 60% steam flaked corn, 7% wheat straw, 30% sweet bran, and supplement. Diets were fed once daily ad libitum. Freeze-dried ME was re-hydrated and dosed orally (1x1010 CFU/steer) on d 1, and top-dressed (1x107 CFU/steer daily) onto diets daily thereafter. Data were analyzed using a mixed model with ME, RPL and the interaction as fixed effects, and block as the random effect. There were no interactions between ME and RPL (P &gt; 0.05). Steers given ME consumed 16% less roughage compared to their counterparts without (P &lt; 0.05), but gain, dry matter intake, and gain:feed were similar (P &gt; 0.10). Administering ME tended to increase percentage of USDA Prime carcasses (0.5 vs 2.7%; P &lt; 0.06). Feeding RPL did not affect feedlot performance, carcass weight, longissimus muscle area, marbling score, 12th-rib fat thickness, or liver abscess incidence (P &gt; 0.10), but tended to increase yield grade (P &lt; 0.07). In conclusion, use of Megasphaera elsdenii with an accelerated step-up program yielded feedlot performance and carcass traits comparable to those of cattle adapted with a conventional, 21-d step-up program, but supplemental lysine was without effect.

Abstract 2378: Differential exhaustion on cytokine release (DECREASE) by ERY974, a novel T-cell-redirecting antibody targeting glypican-3: A new type of T-cell exhaustion

Abstract Background: T cell-redirecting antibody (TRAB), which bispecifically binds to CD3 and tumor antigen, is a key player in next-generation cancer immunotherapy (CIT). Because TRAB can redirect T cells regardless of their TCR specificity, it is expected to be efficacious in immune checkpoint inhibitor-resistant tumors. The CD19-targeting bispecific T cell engager, blinatumomab, has been used for the treatment of blood cancers, and CEA-TCB and IMCgp100 have shown promising clinical efficacy in solid tumors as well. ERY974 is another promising TRAB targeting glypican-3 (GPC3) and a phase 1 study is in progress (Ishiguro et al., Sci Transl Med 2017). On the other hand, cytokine release syndrome (CRS) has been recognized as a common side effect of TRAB. Thus, mitigation of CRS is an urgent issue. Intra-patient step-up dosing regimens have been incorporated in clinical trials to reduce cytokine release, but the mechanism behind this phenomenon remains elusive. In this study, we pre-clinically explored the phenomenon and its mechanism by using ERY974. Method &amp; Results: GPC3-expressing human cancer cells were incubated with human PBMCs and ERY974. The incubated PBMCs were harvested and mixed with newly prepared GPC3-expressing cancer cells and higher doses of ERY974. The pre-treated PBMCs showed reduced cytokine production compared to that without pre-treatment, while maintaining the same level of T cell-dependent cellular cytotoxicity (TDCC). Comprehensive gene expression analysis of the pre-treated PBMCs was also conducted. A murine cancer cell line expressing human GPC3 was established and implanted into immune competent mice. A mouse surrogate version of ERY974 (mERY974) was first administered at a low dose expected to elicit weak anti-tumor activity, and mice were then treated with a higher dose of mERY974. Anti-tumor activity was similar regardless of the pre-treatment, but plasma cytokine levels were shown to be reduced in the pre-treated mice upon administration of the higher dose of mERY974. Conclusion: Cytokine production following the high-dose ERY974 treatment was mitigated by the low-dose pre-treatment in vitro and in vivo. Cytotoxic activity did not decrease in this setting, thus demonstrating that the pre-treatment selectively suppressed only cytokine production. It is well known that repeated stimulation of TCR leads to T-cell exhaustion. The phenomenon we observed here can also be characterized as a sort of exhaustion, but is quite unconventional. Thus, we propose a new type of exhaustion and suggest calling it ‘Differential exhaustion on cytokine release (DECREASE)’. Management of CRS is critical for the clinical use of TRAB. A detailed analysis of the mechanism of DECREASE currently in progress, is expected to contribute to the development of desired dosing regimens for this new type of CIT agent. Citation Format: Mayumi Hoshino, Yuji Sano, Yasuko Kinoshita, Yumiko Azuma, Toshiaki Tsunenari, Yoko Kayukawa, Mizuho Noguchi, Takahiro Ishiguro, Shohei Kishishita, Noriaki Sawada, Mika Endo, Junichi Nezu. Differential exhaustion on cytokine release (DECREASE) by ERY974, a novel T-cell-redirecting antibody targeting glypican-3: A new type of T-cell exhaustion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2378.