CD3 Bispecific Antibody Research Articles

Real-World Patient Profile and Step-up Dosing Process of Early Initiators of Teclistamab for Multiple Myeloma in US Hospitals - an Updated Analysis Using Premier Healthcare Database

Introduction: Teclistamab, a first-in-class B-cell maturation antigen (BCMA) x CD3 bispecific antibody with a personalized, weight-based dosing schedule, gained US regulatory approval in October 2022 for the treatment of triple-class exposed relapsed/refractory multiple myeloma (MM). Teclistamab administration is initiated with a step-up dosing (SUD) period, which includes two step-up doses followed by the first treatment dose. In a prior analysis of 40 patients, we found that early initiators of teclistamab were elderly, diverse, and had significant comorbidities, yet most of the patients completed SUD without delay (Tan SOHO 2023). To continue describing the real-world profile of patients initiating this novel therapy, we updated the prior analysis with a larger sample size and more data. This updated analysis revisited outcomes reported previously, including patient characteristics and SUD process, and evaluated the incidence and management of cytokine release syndrome (CRS) observed in the real-world United States (US) hospital setting. Methods: This was a real-world, retrospective, observational study using the Premier Healthcare Database, a hospital chargemaster database covering approximately 20% of US hospitals. We identified hospital encounters with ≥1 teclistamab administration between November 1, 2022 and April 1, 2023, with the earliest encounter as index. To be included, patients were required to have ≥1 diagnosis of MM (International Classification of Diseases, 10 th Revision, Clinical Modification [ICD-10-CM]: C90.0x) on or prior to index, ≥18 years of age on index, and no evidence of clinical trial engagement on or after index. We descriptively analyzed characteristics across all patients in the study, and SUD patterns and CRS in those who completed SUD. CRS was identified in two ways: ICD-10-CM codes and a published algorithm of CRS-related symptom and treatment codes (Keating algorithm). Results: A total of 113 patients with ≥1 teclistamab administration were included. Median (interquartile range) age was 65.0 (58-74) years; 21.2% were age ≥75 years; 61.1% had Medicare insurance. Most were male (61.1%), White (65.5%), and non-Hispanic (82.3%), with 21.2% Black. Most patients were treated at urban (97.4%) teaching hospitals (84.1%) with ≥300 beds (89.4%). During hospital encounter for SUD, 62.0% of patients had documented hypertension, 57.5% had anemia, 38.9% had renal impairment/failure, and 36.3% had peripheral neuropathy. Of 88 patients with available dose strength data, 58 (65.9%) completed SUD by data cut-off, with all SUD doses administered in one inpatient admission. Similar to the prior report, the mean (standard deviation) length of stay was 8.6 (1.7) days after omitting extreme outliers. Most patients had a 3-day (39.7%) or 2-day (20.7%) interval between SUD doses. Among the 58 patients who completed SUD, 25.9% of patients had an ICD-10-CM diagnosis code for CRS, with 19.0% with grade 1 and 6.9% with grade 2 as the highest grade. Per the Keating algorithm, 46.6% of patients experienced CRS-related symptoms, and a majority (41.4%) were classified as mild CRS. The most common symptoms indicative of CRS were fever (24.1%) and hypotension (17.2%) (Table 1). At any time during SUD, 10.3% patients received tocilizumab, 100% received corticosteroids, and 87.9% received acetaminophen (Table 2). Conclusion: This updated analysis of the first national real-world study of teclistamab confirmed that these initial patients were diverse, elderly, and had significant comorbidities, and most completed SUD without delay. Additionally, fewer than half of patients in this real-world cohort experienced CRS, as identified using ICD-10-CM codes. Limitations of our analysis include the small sample size, reliance on chargemaster data with inherent limitations (e.g., misclassification and coding errors), and the estimation of CRS incidence and management using diagnosis codes. However, this is the largest, real-world hospital-data analysis of patients initiating teclistamab within the first 5 months of market availability. Further updates are needed to augment the data with more patients and longer follow-up time.

Optimizing Siglec-8-Directed Immunotherapy for Eosinophilic and Mast Cell Disorders

Current treatments for diseases in which eosinophils and/or mast cells play an important pathogenic role are often insufficiently effective. One promising target for these disorders is sialic acid immunoglobulin (Ig)-like lectin 8 (Siglec-8), but there are only few monoclonal antibodies (mAbs) against Siglec-8 available, and, so far, Siglec-8-directed therapies have largely focused on unconjugated mAbs, which may lack efficacy. To raise new human mAbs as basis for novel therapeutics, we immunized transgenic (“humanized”) mice with 3T3 cells expressing human full-length Siglec-8 (Siglec-8 FL) or a chimeric mouse/human protein consisting of the V-set domain of mouse CD33 fused with the membrane-proximal C2-set domain of human Siglec-8 or the V-set domain of mouse Siglec-F fused to the membrane-proximal C2-set domain of human Siglec-8. Among 9 unique mAbs we identified and recombinantly produced, 6 (1B6, 1H4, 1B4, 1E1, 1E4, 1E2) recognized Siglec-8 via binding of the V-set domain, 1 (2A3) via binding of the membrane-distal C2-set domain, and 2 (2A7, 2F10) via binding to the membrane-proximal C2-set domain. All mAbs tested were efficiently internalized into Siglec-8+ cells (up to 75% within 4 hours), suggesting their potential to deliver cytotoxic payloads. To assess the value of Siglec-8-directed immunotherapies engaging T or NK cells, we generated tool T cell-engaging Siglec-8/CD3 bispecific antibodies (BiAbs) in the scFv-scFv format as well as Siglec-8 CAR NK cells, using binding sequences from Siglec-8 V-set mAbs. Very low concentrations (10-25 pM) of a Siglec-8/CD3 BiAb built on 1B6 elicited dose-dependent cytolytic activity against EOL-1, HL-60 as well as LUVA cells transduced with Siglec-8 FL. This BiAb also exerted Siglec-8-specific cytotoxicity against HMC 1.2 cells that were enriched for Siglec-8 expression as well as parental LUVA cells, which both display very few Siglec-8 molecules. Similarly, KHYG-1 cells transduced with a Siglec-8 V-set-directed 41BB co-stimulatory domain-containing CAR generated from scFv sequences from 1B6 or 1H4 induced significant cytotoxicity against EOL-1 and RS4;11 cells transduced with Siglec-8 FL. To examine the relationship between the efficacy of T cell and NK cell-engaging therapies and the distance from the target epitope on Siglec-8 to the cell membrane, we engineered human AML and ALL cell line pairs expressing comparable levels of either Siglec-8 FL or an artificial variant of Siglec-8 containing only the V-set domain on the extracellular portion of the protein (Siglec-8 V-set) to bring the V-set domain closer to the cell membrane, and used these cell line pairs as targets for Siglec-8 V-set-directed BiAbs and CAR-modified immune effector cells. Siglec-8 V-set/CD3 BiAbs exerted greater cytotoxicity against AML and ALL cells expressing Siglec-8 V-set than cells expressing Siglec-8 FL. Likewise, Siglec-8 V-set-directed CAR NK cells exerted greater cytotoxicity against AML and ALL cells expressing Siglec-8 V-set than cells expressing Siglec-8 FL, demonstrating that altering the position of the Siglec-8 mAb binding epitope changes the effector functions of Siglec-8 mAb-derived therapies and suggesting membrane-proximal targeting via one of the C2-set domains could enhance Siglec-8-targeted therapies that engage T or NK cells as immune effector cells. To test whether mAbs recognizing one of the C2-set domains could indeed serve as basis for potent therapeutics, we generated a Siglec-8 C2-set/CD3 BiAb in the scFv-scFv format using binding sequences from 2A3 and found it effectively killed EOL-1, ML-1, RS4;11, and LUVA cells transduced with human Siglec-8 FL at very low concentrations. This BiAb also exerted Siglec-8-specific cytotoxicity against Siglec-8-enriched HMC 1.2 cells and parental LUVA cells, which both display Siglec-8 at very low copy number. Likewise, KHYG-1 cells transduced with a Siglec-8 C2-set CAR generated from 2A3 or 2F10 induced significant cytotoxicity against EOL-1 and RS4;11 cells transduced with Siglec-8 FL as well as against Siglec-8-enriched HMC 1.2 cells, albeit to a very modest extent. Together, our data demonstrate Siglec-8-directed immunotherapies can be highly potent, even against target cells expressing very limited copy numbers of Siglec-8 molecules, supporting their further development for use in patients with difficult-to-treat eosinophilic and mast cell disorders.

Teclistamab Improves Patient-Reported Symptoms and Health-Related Quality of Life in Relapsed or Refractory Multiple Myeloma: Results From the Phase II MajesTEC-1 Study

IntroductionPatients with relapsed or refractory multiple myeloma (RRMM) report significantly lower HRQoL compared with patients with newly diagnosed MM and experience further deterioration in HRQoL with each relapse and subsequent treatment. Therefore, consideration of the impact of treatment on HRQoL in addition to clinical outcomes is vital. Patients and MethodsIn the phase I/II MajesTEC-1 (NCT03145181, NCT04557098) study, patients with RRMM who received teclistamab, an off-the-shelf, T-cell redirecting BCMA × CD3 bispecific antibody, had deep and durable responses with manageable safety. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30-item and the EuroQol 5 Dimension 5 Level descriptive questionnaire. Changes over time from baseline were measured with a repeated measures mixed-effects model. Proportions of patients with clinically meaningful improvement after starting treatment and time to clinically meaningful worsening were assessed. ResultsCompliance was maintained throughout the study. Compared with baseline, positive changes were observed for pain, global health status, and emotional functioning with treatment; other assessments were largely unchanged from baseline. Post hoc analysis showed patients with deeper clinical response generally reported improved HRQoL outcomes. Following an initial decline in HRQoL in some scales, the proportion of patients reporting clinically meaningful improvements increased, while the proportion reporting clinically meaningful worsening decreased over time. Clinically meaningful improvements in pain were reported in ≥40% of patients at most assessment time points. ConclusionsThese results complement previously reported clinical benefits and support teclistamab as a promising therapeutic option for patients with RRMM.

A Phase 1 First-in-Human Monotherapy Study of F182112, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed or Refractory Multiple Myeloma

Introduction: Outcomes of relapsed or refractory Multiple Myeloma（RRMM） are generally poor after receiving current arsenal of therapies. Several novel kinds of drugs targeting BCMA are being developed to overcome resistance in this heavily treated patient population. F182112 is a BCMA x CD3 bispecific antibody that redirects CD3 + T cells to mediate T-cell activation and subsequently caused lysis of BCMA-expressing myeloma cells. A phase 1 clinical trial, NTP-F182112-001, has been launched to evaluate the safety and efficacy of F182112 in patients with RRMM. Shan Dong New Time Pharmaceutical Co. Ltd provides the funding support for the research. Clinical trial information: NCT04984434. Methods: This is a first-in-human, open-label, multicenter, phase 1 study. It has enrolled patients with RRMM who aged ≥ 18 years and previously received at least 2 prior lines of therapy including at least a proteasome inhibitor and an immunomodulatory agent. F182112 was administered intravenously once a week. First four dose cohorts of F182112 (0.01, 0.1, 0.3 and 1μg/kg) were planned for accelerated titration phase and the following four dose cohorts (3, 10, 20, and 30 μg/kg) were planned for i3+3 dose escalation phase . Primary objectives were to access safety and tolerability by monitoring adverse events (AEs) per CTCAE v5.0, with exception of CRS grading per ASTCT 2018. The target rate of dose-limiting toxicity (DLT) was 25% (equivalence interval± 5%). In addition, soluble BCMA, cytokines and immunophenotyping were analysed in peripheral blood. The pharmacokinetics and immunogenicity of F182112 were also explored. Results : As of July 24, 2023, 22 patients have been treated with F182112 (0.01-30 μg/kg) at eight escalating dose levels. Median age was 64.5 years (range 52-74). All of patients were followed up at least five weeks and the median follow-up was 3 months (range 1-18). Fifteen (68.1%) patients received ≥4 prior lines of therapy and 15 (68.1%) patients were refractory to last lines of therapy. Treatment-related AEs (TRAEs) were reported in 18 (82%) pts, with grade ≥3 and serious AEs occurring in 14 (64%) and 4 (18.2%) pts, respectively. The most common TRAEs(≥20%) were CRS (72.7%), lymphopenia (68.2%), neutropenia (54.6%), leukopenia (50%) and anemia (31.8%). All CRS was grade 1 or 2 and the median duration time was 2 days (1-5). One dose-limiting toxicities (ALT elevation, grade 3) occurred at 10 μg/kg dose level. No patients required F182112 dose reduction due to AEs. As of this date cut-off, 20 of the 22 patients were evaluated for response（Figure 1）. The overall response rate (ORR) was 45% (9/20), 30% (6/20) patients had stable disease (SD) and 25% (5/20) patients experienced disease progression (PD). At dose cohorts of 10ug/kg and 20ug/kg （n=9），ORR was 77.8%（7/9）with very good partial remission or better (≥VGPR) rate of 44% (4/9) and stringent complete remission (sCR) rate of 33% (3/9). At the dose cohort of 30ug/kg (n=4), ORR was 25% (1/4), one patient of this dose cohort with extramedullary mass larger than 5cm in diameter at baseline experienced disease progression due to the mass enlargement, though his serum M protein decreased by 60.27%. F182112 exhibited a favorable PK profile in its target patient population of RR MM, with F182112 exposures increasing in a dose-related manner. Conclusions: F182112 in patients with RRMM is well tolerated with preliminary antitumor activity and a favorable PK profile in patients，supporting further evaluation.

Longitudinal Correlative Profiles of Responders, Nonresponders, and Those with Relapse on Treatment with Teclistamab in the Phase 1/2 MajesTEC-1 Study of Patients with Relapsed/Refractory Multiple Myeloma

Introduction: Teclistamab (tec) is the only approved B-cell maturation antigen (BCMA) × CD3 bispecific antibody with a personalized, weight-based dosing schedule for the treatment of triple-class exposed relapsed/refractory multiple myeloma (RRMM). In the phase 1/2 MajesTEC-1 study (NCT03145181/NCT04557098), tec demonstrated deep and durable responses. To better understand mechanisms of resistance and relapse in MajesTEC-1, we assessed longitudinal BCMA expression and immune profiles. Methods: Patients (N=165) with RRMM received subcutaneous tec 1.5 mg/kg weekly after step-up doses of 0.06 and 0.3 mg/kg, with the option to switch to every-other-week dosing if they achieved at least a partial response after ≥4 cycles of therapy in phase 1 or a complete response or better for ≥6 months in phase 2. Bone marrow and peripheral blood samples at baseline, on treatment, and at disease progression (PD) were analyzed by flow cytometry for BCMA expression and immune cell populations. Bone marrow aspirates were analyzed by cytometry by time of flight (CyTOF) for immune cell populations. Soluble BCMA (sBCMA) was analyzed in serum samples by electrochemiluminescence ligand binding. Results: Patients who responded to tec had a greater recovery of CD3+ T cells in the periphery and bone marrow during the first treatment cycles, which was sustained over time compared with nonresponders. Greater activation during the first cycle was observed in responders, indicated by a transient increase in CD38 on CD8+ T cells. In contrast, an exhausted T-cell phenotype in the blood and bone marrow was observed longitudinally in nonresponders vs responders, indicated by increasing and sustained levels of activation and exhaustion markers including persistence of CD38+ T cells and expression of LAG-3, PD-1 (Figure 1A), PD-1/LAG-3, and PD-1/TIM-3 on CD4+ or CD8+ T cells. Higher levels of immunosuppressive regulatory T cells (Tregs), including CD38+ Tregs, were also sustained in the periphery in nonresponders compared with responders. BCMA expression and sBCMA levels were assessed in a subset of patients who initially responded then relapsed on tec, who had matched baseline and end-of-treatment/PD samples. There were no significant changes in the frequency of BCMA+ plasma cells, BCMA receptor density, or sBCMA levels at PD relative to baseline, suggesting BCMA loss was not a mechanism of relapse in these patients. In contrast, higher proportions of peripheral CD4+ and/or CD8+ T cells expressing CD38, TIM-3, PD-1, and PD-1/TIM-3 were observed at relapse vs baseline. Analysis of bone marrow progression samples using CyTOF in patients who relapsed showed significantly lower CD28 expression on CD8+ T cells, significantly higher expression of exhaustion markers (CD38, PD-1, TIM-3, EOMES, and TOX) and perforin on CD4+ and/or CD8+ T cells, a higher frequency of CD4+ and CD8+ T cells expressing TIM-3 and co-expressing CD38/TOX, PD-1/TIM-3, and TOX/TIM-3 (Figure 1B), and significantly higher CD38 expression on T-cell receptor gamma delta T cells, at PD than at baseline. PD-1 and TIGIT expression was also significantly higher at PD than at baseline across CD25hiCD127dim and/or CD25hiCD127dimFoxP3+ Tregs in patients who relapsed. Conclusions: Patients responding to tec exhibited a differential immune profile in early cycles compared with nonresponders, with greater transient T-cell activation. In contrast, an exhausted T-cell phenotype was sustained in nonresponders during the first 2 treatment cycles. While mutations in BCMA cannot be excluded, we did not detect BCMA loss as a mechanism of relapse, but observed a dysfunctional immune phenotype at PD, with increased T-cell exhaustion and higher frequency of gamma delta T cells and immunosuppressive Tregs. These results suggest the importance of immune fitness and T-cell function in achieving and maintaining a response to tec. Ongoing studies will evaluate these correlatives in earlier treatment lines, where patients may have more favorable immune profiles.

Updated Safety and Efficacy Results of Abbv-383, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in a First-in-Human Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma

Updated Safety and Efficacy Results of Abbv-383, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in a First-in-Human Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma

Efficacy and Safety of Elranatamab in Black Patients with Relapsed/Refractory Multiple Myeloma (RRMM): A Subgroup Analysis of the Magnetismm Studies

INTRODUCTION Multiple myeloma disproportionately impacts ethnic and racial minority groups, affecting both incidence and outcome. There is limited evidence-based data for clinical decision making for minority populations, including Black patients (Habr and Corsaro, Hematol Oncol 2022). Elranatamab is a B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the phase 2 registrational trial MagnetisMM-3, elranatamab demonstrated clinical efficacy in BCMA-naïve and BCMA-exposed patient populations. Here, we report the efficacy and safety of elranatamab in a pooled analysis of Black or African American patients with RRMM across 3 studies in the MagnetisMM program, including MagnetisMM-1 (MM-1; NCT03269136), MagnetisMM-3 (MM-3; NCT04649359), and MagnetisMM-9 (MM-9; NCT05014412). METHODS Eligible patients included in this pooled analysis had previously received at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody, and were either naïve or exposed to prior BCMA-directed therapy (antibody-drug conjugate [ADC] and/or CAR T-cells). All patients received subcutaneous elranatamab at the effective doses of 215-1000 µg/kg or fixed dose equivalent of 76 mg (MM-1) or 76 mg once-weekly (MM-3 and MM-9). Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. Evaluation of overall response rate (ORR) was assessed per IMWG criteria. Adverse events (AEs) and laboratory abnormalities were graded by National Cancer Institute Common Terminology Criteria for AEs v4.03 (MM-1) or v5.0 (MM-3 and MM-9). American Society for Transplantation and Cellular Therapy criteria (Lee DW, et al. Biol Blood Marrow Transplant 2019) were used for grading cytokine release syndrome (CRS) and immune effect cell-associated neurotoxicity syndrome (ICANS). RESULTS Of 24 Black or African American patients in the pooled analysis who received elranatamab, the median age was 61.5 years (36-76), 75.0% had R-ISS Stage I or II disease, 79.2% had prior stem cell transplant, and 91.7% patients had an Eastern Cooperative Oncology performance status of 0 or 1. Patients had a median of 6 prior lines of therapy (range, 2-14), with 91.7% and 45.8% having triple-class and penta-drug refractory disease, respectively. Seven patients (29.2%) received prior BCMA-directed therapy as either an antibody-drug conjugate (ADC; n=5), CAR-T (n=4), or both (n=2). After a median follow-up of 13.3 months, the median duration of treatment was 9.0 months; 6 (25%) patients were still on treatment. The most common reasons for treatment discontinuation were progressive disease (41.7%), AEs (12.5%), and death (12.5%). The ORR was 58.3%, with 41.7% of patients achieving complete responses (CR) or better (Table). The median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were 18.4, 14.4, and 21.2 months, respectively. Common treatment-emergent AEs (TEAEs) included CRS, anemia, and neutropenia (Table). Infections were reported in 15 patients (any grade, 62.5%; grade 3/4, 20.8%). Two cases of ICANS (both grade 2) were reported. One patient died due to disease progression (metastases to meninges), and four patients died due to a TEAE other than disease progression: 1 patient each due to COVID-19, septic shock, sudden death, and pulmonary embolism. CONCLUSIONS Elranatamab demonstrated clinical activity and a manageable safety profile in Black or African American patients with RRMM, supporting the use of elranatamab in this subgroup of patients. Efficacy and safety results are comparable to those observed for the overall population of patients treated with elranatamab in the phase 2 MagnestisMM-3 trial. No new safety signals were observed.

Circulating Tumor DNA Analysis Associates with Progression-Free Survival (PFS) with Odronextamab Monotherapy in Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL): Identification of Minimal Residual Disease Status and High-Risk Subgroups from the Phase 2 ELM-2 Study

Background Molecular characterization of B-cell non-Hodgkin lymphoma (B-NHL), through circulating tumor DNA (ctDNA) assessment of minimal residual disease (MRD) has been proposed as a tool to predict clinical outcome. Odronextamab, a CD20×CD3 bispecific antibody, demonstrated deep and durable responses and a generally manageable safety profile in patients (pts) with R/R FL or DLBCL in the Phase 2 ELM-2 study (NCT03888105; Kim TM et al. and Kim WS et al. ASH. 2022). In the overall populations, 12-month PFS rates were 64% and 29%, respectively. Using ctDNA from ELM-2, we show that these assessments associate with clinical outcomes following odronextamab treatment. Methods In ELM-2, pts received IV odronextamab in 21-day cycles, with step-up dosing in Cycle (C) 1, 80 mg (FL)/160 mg (DLBCL) QW in C2-4, then 160 mg (FL)/320 mg (DLBCL) Q2W until disease progression or unacceptable toxicity. Baseline (BL) ctDNA and tumor biopsies were used for molecular profiling. BL and on-treatment ctDNA were used for MRD determination in the biomarker population (BP; pts required ≥1 available plasma biomarker sample to be included in the BP). The first post-BL ctDNA sample was collected on C5 Day (D) 1, at the time of positron emission tomography-computed tomography (PET-CT). A modified AVENIO ctDNA analysis workflow (Roche; research only) was used for next-generation sequencing, based on the cancer personalized profiling by deep sequencing technique (Kurtz et al. J Clin Oncol. 2018). Whole blood cell pellets were used to filter out germline allele variants. MRD negativity was reported when the P value for variant allele frequency was >0.005. Results The BP comprised 53 FL pts and 63 DLBCL pts; at BL, all FL pts and all but one DLBCL pt were MRD(+). Pts remaining on study until C5D1 had similar PFS regardless of whether they were in the BP or overall population (FL, n=111; DLBCL, n=83). Pts who were MRD(-) at C5D1 had significantly longer PFS vs. those who remained MRD(+) (FL: HR 0.27 [95% CI 0.09-0.84], P=0.024 [Fig. 1a]; DLBCL: HR 0.29 [95% CI 0.12-0.71], P=0.007). In pts with FL achieving complete response (CR) by PET-CT at C5D1, a trend for prolonged PFS was observed in those who were MRD(-) (n=26) at this timepoint vs. those who were MRD(+) (n=17; HR 0.29 [95% CI 0.07-1.1], P=0.072). Pts with DLBCL who were MRD(-) at C5D1 (n=20) had similar PFS benefit regardless of PET-CT CR status (HR 0.56 [95% CI 0.10-3.11], P=0.511). Four DLBCL pts who were MRD(-) and did not achieve CR by PET-CT at C5D1 (partial response, n=3; stable disease, n=1) went on to achieve PET-CT CR at a later timepoint. Mutational analyses of BL ctDNA identified TP53 as the most frequent mutation (FL, n=34/53 [64%] mutation-evaluable pts; DLBCL, n=44/58 [76%]). In FL pts, TP53 mutations were associated with MRD(+) status at C5D1 (Fisher's exact test, P=0.002) and predicted significantly shorter PFS (HR 3.57 [95% CI 1.01-12.69]; P=0.049); this association was not observed in DLBCL. LymphGen classification (Wright et al. Cancer Cell. 2020) of BL ctDNA in pts with DLBCL identified mostly MCD and EZB subtypes (MCD, n=15; EZB, n=14; ST2, n=1; BN2, n=1; other, n=26). EZB-subtype pts treated with odronextamab had significantly longer PFS compared with MCD-subtype pts (HR 0.23 [95% CI 0.07-0.83]; P=0.025 [Fig. 1b]). Using BL ctDNA, cell of origin was determined in 43/58 pts with DLBCL; odronextamab treatment led to similar PFS in higher-risk non-germinal-center B-cell-like (non-GCB, n=18 [42%]) pts vs. GCB pts (n=25 [58%]; HR 1.62 [95% CI 0.72-3.62]; P=0.244). Further molecular assessment focused on gene fusions in DLBCL pts in the BP (39 with local laboratory gene fusion and ctDNA analyses, 24 with only ctDNA analyses). Odronextamab led to similar PFS in pts with double-hit (n=15) or triple-hit (n=5) fusions compared to those without (n=43; P=0.343 and P=0.140, respectively). Conclusions This study is among the first to analyze ctDNA in pts with R/R FL and DLBCL in a pivotal trial. This non-invasive method allows molecular characterization of pts with no available tissue, enabling identification of high-risk subgroups. CtDNA MRD status at C5D1 of odronextamab treatment was highly associated with PFS in pts with FL and DLBCL and in the future could form the basis of response-directed treatment paradigms. Molecular characterization in tumor biopsies, including CD20, will be presented. Ongoing monitoring of ctDNA may serve as an important early progression marker in R/R FL and DLBCL.

Model-Based Exploration of the Impact of Prophylactic Tocilizumab on IL-6 Dynamics in Multiple Myeloma Patients Receiving Teclistamab Treatment

Introduction: Teclistamab is the only approved B-cell maturation antigen (BCMA) × CD3 bispecific antibody (BsAb) with personalized, weight-based dosing for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM).In the MajesTEC-1 study (NCT03145181 and NCT04557098), the incidence of all grade (mostly grade 1 or 2) cytokine release syndrome (CRS) was 72.1% (Moreau et al. 2022). The cytokine interleukin-6 (IL-6) is found to be increased in the serum of patients with CRS (Shimabukuro-Vornhagen et al. 2018). Tocilizumab is a humanized IL-6 receptor-inhibiting monoclonal antibody. As a competitive antagonist, tocilizumab inhibits the IL-6 pathway by competing with IL-6 for binding to IL-6 receptor (IL-6R), resulting in lower IL-6R receptor occupancy (RO) by IL-6, thereby blocking IL-6 signaling. By blocking IL-6R, tocilizumab also reduces IL-6R-mediated IL-6 clearance, which leads to an increase in serum IL-6 levels (Uchiyama et al. 2008). It has been published previously that a single dose of prophylactic tocilizumab reduced the overall incidence of CRS to 26% after teclistamab administration, which represents a 64% reduction compared to the CRS incidence observed in MajesTEC-1 (van de Donk et al. 2023). A mechanism-based PK/PD model was used to evaluate the impact of tocilizumab prophylactic treatment on the soluble IL-6R (sIL-6R), IL-6 and the duration of the blockade of IL-6 signaling pathway in the patients following teclistamab treatment. Methods: A mechanism-based PK/PD model was built by using reported tocilizumab PK parameters and sIL-6R target engagement. The time course of IL-6R RO for patients receiving prophylactic tocilizumab following teclistamab treatment was estimated from the PK profiles of tocilizumab and competitive binding kinetics. Among the patients with evaluable serum IL-6 levels, the highest peak serum IL-6 concentration in the patients who didn't have CRS (N=9) from prophylactic tocilizumab cohort of MajesTEC-1 was selected as the worst-case scenario. The IL-6R RO in patients receiving prophylactic tocilizumab in the worst-case scenario was characterized by model simulations and the results were compared to the calculated IL-6R RO in the cohorts following teclistamab treatment without prophylactic tocilizumab (N=40). Results: Time course of serum IL-6 levels following teclistamab treatment showed higher and earlier induction in the cohort with tocilizumab prophylaxis compared to the cohort without tocilizumab prophylaxis. Among the patients who received tocilizumab prophylactic treatment, the median peak serum IL-6 level was 208.6 pg/mL and the highest peak serum IL-6 level was 1701.8 pg/mL in patients who didn't have CRS. The model simulation results showed that a single dose of tocilizumab at 8 mg/kg IV given prophylactically could lower the IL-6R RO by IL-6. In a patient with 1700 pg/mL of serum IL-6 treated with tocilizumab, IL-6R RO was maintained below the level of RO achieved with 10 pg/mL of serum IL-6 in the absence of tocilizumab for approximately 10 days. An IL-6 level of 10 pg/mL was considered as a representative value in the patients who did not have CRS following teclistamab at the approved dosing regimen without prophylactic tocilizumab, as more than half (58%) of these patients showed peak serum IL-6 level below 10 pg/mL. The duration of IL-6R RO reduction covers the two step-up doses (SUD) and the first full treatment dose according to the teclistamab approved dosing schedule. Conclusions: The modeling and simulation results showed that a single dose of tocilizumab given prophylactically at 8 mg/kg could block IL-6R RO for approximately 10 days following the 1 st step up dose of teclistamab. The results further support this approach for lowering overall risk of CRS during the SUD schedule in multiple myeloma patients treated with teclistamab.

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.

Updated Results of Talquetamab, a GPRC5D×CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma with Prior Exposure to T-Cell Redirecting Therapies: Results of the Phase 1/2 MonumenTAL-1 Study

Introduction: Novel T-cell redirecting therapies (TCR), including chimeric antigen receptor T-cell therapy (CAR-T) and bispecific antibodies (BsAbs), are important new treatment options for patients (pts) with relapsed/refractory multiple myeloma (RRMM) but result in a new unmet need for pts who relapse following these therapies. Talquetamab is the most advanced BsAb therapy targeting G protein-coupled receptor family C group 5 member D (GPRC5D), a novel antigen that is overexpressed on malignant plasma cells but is expressed at low levels on B cells and bone marrow progenitors. Previous results from the phase 1/2 MonumenTAL-1 study (NCT03399799/NCT04634552) demonstrated deep and durable responses with talquetamab in pts with RRMM, with an overall response rate (ORR) of >71% in 288 pts naive to TCR and 65% in 51 pts with prior TCR. Here, we present updated results in pts with prior TCR, including an additional 19 pts enrolled since the prior analysis. Methods: Eligible pts for phase 1 of the study had progressed on or could not tolerate established multiple myeloma therapies.In phase 2, eligible pts had been exposed to ≥3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody. The current analysis includes all pts across phase 1 and 2 of the study who received 1 of the 2 recommended phase 2 doses of subcutaneous talquetamab (0.4 mg/kg weekly [QW] or 0.8 mg/kg every other week [Q2W]) and who were exposed to a TCR (prior CAR-T and BsAb), as well as pts exposed to both a TCR and a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate (ADC). Results: As of Jan 17, 2023, 70 pts were enrolled with prior TCR. Overall, 44 (63%) were <65 years old; 65 (93%) received ≥4 prior lines of therapy; 58 (83%) and 29 (41%) were triple-class and penta-drug refractory, respectively; 21 (30%) had extramedullary disease, 24 (34%) had high-risk cytogenetics, and 12 (17%) had International Staging System stage III disease. Fifty of 70 pts received prior CAR-T (48/50 anti-BCMA CAR-T), 25 pts received prior BsAb (23/25 anti-BCMA BsAb), and 5 pts received both. Eight of 70 pts received prior treatment with BCMA ADC. Among BCMA-exposed pts, ORR was comparable between pts receiving prior BCMA CAR-T and prior BCMA ADC, and similar to the overall population; ORR was lower in pts receiving prior BCMA BsAb (Table). Median duration of response (mDOR) was similar between the overall population (12.3 mo; 95% CI, 6.5-not estimable [NE]) and pts with prior BCMA CAR-T (12.3 mo; 95% CI, 4.8-NE), but was shorter in pts with prior BCMA BsAb (6.5 mo; 95% CI, 1.9-NE). In the prior CAR-T group, ORR was comparable in those who received CAR-T as immediate prior line vs at any prior line of therapy before talquetamab (75.9% [22/29] vs 71.4% [15/21], respectively). In the prior BsAb group, ORR was lower in those who received BsAb as immediate prior line vs at any prior line of therapy before talquetamab (28.6% [2/7] vs 61.1% [11/18], respectively). In the prior BsAb group, ORR was 62.5% (5/8) in pts who had ≥9 mo interval between last dose of the prior BsAb and talquetamab, 50% (3/6) in those who had ≥6 to <9 mo interval, and 45.5% (5/11) in those who had <6 mo interval. Conclusions: These updated results from pts with prior TCR in the phase 1/2 MonumenTAL-1 study show continued strong efficacy of GPRC5D-targeting talquetamab across populations exposed to TCR (predominantly anti-BCMA), with notable ORR of 73% and mDOR of >1 year in the post-CAR-T setting. More than 50% of pts exposed to prior BsAb responded, and outcomes data in these pts may offer insight into optimal sequencing. Together with previously published data, these results support talquetamab as a versatile treatment option that provides robust responses in TCR/BCMA-naive and TCR/BCMA-exposed pts with RRMM. Acknowledgments: This study was funded by Janssen Research & Development, LLC. Medical writing support was provided by Michelle Yang, PharmD, of Eloquent Scientific Solutions, and funded by Janssen Global Services, LLC.

Odronextamab Monotherapy for the Treatment of Relapsed/Refractory (R/R) Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL): Focus on Clinical Pharmacology and Pharmacometrics in the ELM-1 and ELM-2 Studies

Background Odronextamab is a CD20×CD3 bispecific antibody that binds CD20 on B-cells and CD3 on T-cells, triggering T-cell-mediated cytotoxicity of malignant B-cells. Odronextamab demonstrated clinically meaningful efficacy and generally manageable safety in patients (pts) with R/R FL and DLBCL in the Ph 1 ELM-1 (NCT02290951; Bannerji R, et al . Lancet Haematol. 2022) and Ph 2 ELM-2 (NCT03888105) studies (Kim TM. ASH. 2022; Kim WS. ASH. 2022). Here, assessments of pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response (E-R) analyses for efficacy and safety are presented, to support posology for the treatment of R/R FL and DLBCL. Methods Pts enrolled in ELM-1 and ELM-2 received IV odronextamab step-up doses of 0.7, 4, and 20 mg in Weeks (Wks) 1-3 of Cycle (C) 1 (21-day/cycle), odronextamab QW (FL: 80 mg; DLBCL: 160 mg) during C2-4, then odronextamab Q2W (FL: 160 mg; DLBCL: 320 mg) until disease progression or unacceptable toxicity. Pts who achieved a durable complete response for ≥9 months transitioned to Q4W dosing. After odronextamab infusion, serum samples were collected over time, odronextamab serum concentrations measured, and data analyzed using descriptive and population PK methods. Blood samples were collected to measure T-cells, T-cell activation and proliferation markers (e.g. HLA-DR, Ki67), peripheral CD19 + B-cells, and cytokines. E-R for efficacy was assessed with trough concentration at time of first efficacy assessment (C trough at Wk 12) and best overall response using logistic regressions. E-R for safety was assessed with odronextamab concentrations at the time of a safety event and safety events including any grade (Gr) and Gr ≥3 treatment-emergent AEs (TEAEs) via multivariate analyses. Results The PK of odronextamab were characterized in 507 pts and were similar between different ethnic populations across B-cell non-Hodgkin lymphoma types. Concentration-time profiles were similar with step-up doses in pts with FL and DLBCL. Exposure in pts with DLBCL was 2-fold higher than in FL during C2-4, in line with the 2× higher dose. PD profiles were similar in pts with FL and DLBCL. Rapid, pronounced, and prolonged B-cell depletion in blood was observed following infusion. Early T-cell activation and proliferation was observed, with T-cell expansion higher in clinical responders vs. nonresponders. Transient cytokine release was mainly observed in C1 and was infrequent in subsequent cycles. In pts with FL, the probability of clinical response increased with odronextamab exposure and the largest response (89%) was achieved at exposures consistent with the median C trough of 80 mg QW at Wk 12, supporting use of 80 mg QW for FL. Exposures associated with 80 mg QW in C2-4 were maintained or exceeded with subsequent 160 mg Q2W maintenance doses. In pts with DLBCL, the probability of clinical response increased with odronextamab exposure, but less steeply than for FL. The largest response (57%) was achieved at exposures consistent with the median C trough of 160 mg QW at Wk 12, supporting use of 160 mg QW for DLBCL. Exposures associated with 160 mg QW were maintained or exceeded with subsequent 320 mg Q2W maintenance doses. Exposure-safety analysis showed consistent results in FL and DLBCL. Among multiple factors evaluated that had potential to be associated with TEAEs, odronextamab exposure was not associated with any Gr or Gr ≥3 TEAEs, including cytokine release syndrome and infections, over time. Conclusions PK analyses showed predictable concentration-time profiles through step-up dosing, at treatment doses, and during maintenance. PD analyses showed durable and complete depletion of B-cells; T-cell activation, proliferation, and expansion; and transient cytokine release, consistent with the mechanism of action of odronextamab. In comparison with DLBCL, clinical response increased with odronextamab exposure faster for FL and can reach a higher response at 80 mg QW. Therefore, a higher odronextamab dose of 160 mg QW is needed to achieve maximal response for DLBCL. The studied regimens showed clinically meaningful activity and acceptable tolerability, and the risk of any Gr or Gr ≥3 TEAEs is not increased from low to high odronextamab exposures. Comprehensive PK, PD, exposure-efficacy, and exposure-safety analyses demonstrated that the selected odronextamab dose regimens have favorable efficacy and generally manageable safety profiles for the treatment of R/R FL and DLBCL.

Mechanisms of Resistance and Relapse with Talquetamab in Patients with Relapsed/Refractory Multiple Myeloma from the Phase 1/2 MonumenTAL-1 Study

Introduction: Talquetamab (tal), a novel GPRC5D×CD3 bispecific antibody (BsAb), has shown deep and durable responses with overall response rates (ORRs) >71%, including in high-risk populations, and a clinically manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (MM) in the MonumenTAL-1 study (NCT03399799/NCT04634552). To better understand mechanisms of resistance and relapse in pts treated with tal, baseline and longitudinal GPRC5D expression and immune profiles were assessed in pts treated with the 0.4 mg/kg weekly (QW) recommended phase 2 dose, including a separate cohort of pts who received prior T-cell redirection therapy (prior TCR; chimeric antigen receptor [CAR]-T cell and BsAb therapies). Methods: MonumenTAL-1 is a first-in-human, phase 1/2, single-arm study of tal monotherapy. Eligible pts had MM and were intolerant to or progressed on established therapies (phase 1) or had ≥3 prior lines of therapy (LOT) including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody (phase 2). Analyses were performed in pts receiving tal 0.4 mg/kg QW who did not receive prior TCR (no prior TCR cohort) and pts receiving tal 0.4 mg/kg QW who received prior TCR (prior TCR cohort). Baseline and on-treatment bone marrow or whole blood were analyzed by flow cytometry for GPRC5D expression and immune cell profiles, respectively. For mechanisms of resistance, samples were analyzed in responders (defined as ≥PR) and nonresponders (defined as stable or progressive disease [PD]); for mechanisms of relapse, samples were analyzed at baseline and at end of treatment (EOT)/PD. Results: Median prior LOT was 6 and 5 in the prior and no prior TCR cohorts, respectively. T-cell counts at baseline were similar between cohorts, whereas pts in the prior TCR cohort had higher expression of single coinhibitory markers (LAG-3, TIM-3, PD-1), dual coinhibitory markers (PD-1/LAG-3 and PD-1/TIM-3), and activation markers (CD38 and CD25) on CD8+ T cells, along with a higher frequency of immunosuppressive regulatory T cells (Tregs) compared with the no prior TCR cohort. GPRC5D was highly expressed on MM cells at baseline; however, expression was variable among pts in both cohorts and was not associated with clinical response. In both cohorts, correlative analyses with response showed that nonresponders vs responders had a more exhausted peripheral immune phenotype at baseline, indicated by lower T-cell counts and higher frequencies of Tregs and expression of coinhibitory markers (LAG-3, TIM-3) on CD8+ T cells. In the first cycle following tal administration, greater and transient activation of T cells was observed in responders vs nonresponders. In addition, greater recovery of CD3+ T cells was observed and sustained in responders within 2 cycles of treatment, whereas persistence of CD38+ expression on CD8+ T cells, higher presence of Tregs, and sustained expression of LAG-3, TIM-3, and PD-1 on CD8+ T cells was observed in nonresponders, consistent with the baseline correlative analysis in the prior and no prior TCR cohorts (Figure). Finally, analysis of progression samples of pts who initially responded and then progressed with tal showed a higher expression of coinhibitory receptors (LAG-3, TIM-3, CD38, PD-1/LAG-3, PD-1/TIM-3) on peripheral CD4+ or CD8+ T cells in both cohorts compared with baseline, indicative of an exhausted T-cell phenotype at relapse. Overall, these correlative data were comparable between prior TCR and no prior TCR cohorts. Conclusions: Baseline immune profiling in heavily pretreated pts from MonumenTAL-1 suggested that compared to pts with prior TCR, pts with no prior TCR had a favorable immune fitness profile (less T-cell dysfunction and immune suppression). In both cohorts, baseline and longitudinal correlative analyses suggest a mechanism of resistance for nonresponders including lower T-cell counts and higher frequency of Tregs and expression of coinhibitory markers on CD8+ T cells, whereas responders show greater T-cell activation and recovery of CD3+ T cells that was sustained longitudinally. Progression data indicated an exhausted T-cell phenotype for pts who relapsed on tal. Approaches to overcome resistance, including combination trials with anti-CD38 monoclonal antibodies (eg, daratumumab) and PD-1 inhibitors as well as alternative dosing regimens, are currently being studied.

Symptoms, Functioning, and Health-Related Quality of Life in Patients with Relapsed/Refractory Multiple Myeloma Treated with Talquetamab: Updated Patient-Reported Outcomes from the Phase 1/2 MonumenTAL-1 Study

Introduction: Patients (pts) with advanced and heavily pretreated relapsed/refractory multiple myeloma (RRMM) have worse health-related quality of life (HRQoL) than those at earlier stages of the disease and have limited treatment options available to enable improvement in HRQoL, particularly those who are triple-class exposed. Talquetamab (tal), a novel GPRC5D×CD3 bispecific antibody, has shown deep and durable responses in the MonumenTAL-1 study (NCT03399799/NCT04634552) in pts with RRMM. Here, we report patient-reported outcomes (PROs) from the MonumenTAL-1 study, focusing on data through cycle 21 from the tal 0.4 mg/kg weekly (QW) dosing cohort (initial results presented at ASH 2022) and new data through cycle 15 from the tal 0.8 mg/kg every other week (Q2W) dosing cohort. Methods: MonumenTAL-1 is a first-in-human, phase 1/2, single-arm study of tal monotherapy. Pts with triple-class exposed RRMM received the recommended phase 2 doses of tal (0.4 mg/kg QW or 0.8 mg/kg Q2W). PRO assessments included the following instruments: the European Organisation for Research and Treatment of Cancer quality of life questionnaire core 30 (EORTC QLQ-C30), a cancer-specific PRO instrument, with scores ranging from 0 to 100 (higher scores indicate better global health status [GHS] and functioning, whereas higher scores for symptoms represent worse severity, and a 10-point change from baseline indicates meaningful change); the EuroQol 5-Dimension 5-Level (EQ-5D-5L) visual analogue scale (VAS), which rates pt health from 0 (worst) to 100 (best); and the Patient Global Impression of Severity (PGIS) instrument, a single item that assesses severity of disease. PRO instruments were administered at screening, day 1 of cycle 1, then day 1 of every other cycle. Results for each instrument are presented for specific cycles that have a larger sample size (n≥30); later cycles presented for the QW cohort are due to longer follow-up duration (median,18.7 months) compared with the Q2W cohort (median, 12.3 months), for which earlier cycles are presented. Results: As of January 17, 2023, phase 2 data were available for 122 and 109 pts who received ≥1 administration of tal QW or Q2W, respectively; compliance for completion of the EORTC QLQ-C30 was >97% at baseline and >80% at most post-treatment visits (in each cohort). Least squares (LS) mean change from baseline demonstrated clinically significant improvements in GHS (16.4 points QW, 8.8 points Q2W) and physical functioning (9.6 points QW, 3.1 points Q2W) at cycle 15 in QW and cycle 11 in Q2W cohorts, respectively, along with reductions in fatigue (-10.1 points QW, -5.9 points Q2W) and pain (-16.8 points QW, -1.9 points Q2W) symptoms at cycle 15 in QW and cycle 11 in Q2W cohorts, respectively (Figure). An increasing ability to engage in social roles and activities (role functioning) was also reported by pts in the QW cohort, with an 8.5-point improvement from baseline at cycle 15. Pts in the QW cohort reported meaningful improvement from baseline at later cycles; these improvements were particularly evident in GHS (57%) and social function (47%) at cycle 15. In the Q2W cohort, meaningful improvements from baseline in fatigue (45%) and emotional function (42%) were larger at cycle 7. Pts' global impression of their MM disease severity (PGIS) also improved from baseline, consistent with the meaningful improvement data: for example, in the QW cohort, ratings were 10.8% (very severe) and 40.8% (severe) at baseline compared with 0% and 6.7%, respectively, at cycle 15; in the Q2W cohort, ratings were 11.1% (very severe) and 34.3% (severe) at baseline compared with 2.8% and 19.4%, respectively, at cycle 11. Pts reported improvements from baseline in their health status (EQ-5D-5L VAS score), with LS mean change of 8.1 (95% CI, 2.6, 13.7) and 2.7 (95% CI -2.3, 7.7) at cycle 9 in the QW and Q2W cohorts, respectively. Median time to improvement from baseline in most EORTC QLQ-C30 subscales and EQ-5D-5L VAS scores was ~2 months in both cohorts; estimates of median time to first worsening ranged from 2 to ~9 months. Conclusions: Meaningful improvements from baseline in MM symptoms, physical function, and overall HRQoL were observed in tal QW and Q2W cohorts, with durable and short-term improvements, respectively. These favorable results in PROs add to the efficacy and safety profile of tal, highlighting tal as a compelling treatment option for pts with triple-class exposed RRMM.

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.

Optec: A Phase 2 Study to Evaluate Outpatient Administration of Teclistamab, a BCMA-Targeting Bispecific Antibody, in Patients with Multiple Myeloma

Background: Teclistamab is the only approved BCMA×CD3 bispecific antibody with a personalized, weight-based dosing schedule for the treatment of triple-class exposed relapsed/refractory multiple myeloma (RRMM). It is FDA approved for patients (pts) of therapy (LOTs), including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. In the pivotal MajesTEC-1 study (Moreau et al NEJM 2022), teclistamab showed deep and durable responses and a manageable safety profile in heavily pretreated pts with RRMM who had limited treatment options. The incidence of all grade cytokine release syndrome (CRS) during the first 2 cycles was 70%. Most pts experienced CRS following step-up doses 1 (42%) or 2 (35%), or the initial treatment dose (24%); 33% of pts experienced recurrent CRS. Most CRS events were grade 1/2 and fully resolved without discontinuation or dose reduction of teclistamab. One (0.6%) case of grade 3 CRS occurred in a pt who pneumonia but resolved in 2 days. No grade 4 or 5 CRS occurred. Tocilizumab is a monoclonal antibody targeting the interleukin-6 receptor (IL-6R) which is used to manage CRS resulting from T-cell redirection therapy. Preclinical data indicate that inhibition of IL-6 signaling prior to teclistamab administration can prevent CRS development without impacting anti-tumor activity (Li et al Ann. Oncol. 2019). In MajesTEC-1, pts who received a single IV dose of tocilizumab before the first teclistamab step-up dose (n=23) showed a reduction in the incidence of all grades of CRS, compared with the overall study population (26% vs 72%). Currently, there are no data on the safety of administering the step-up doses of teclistamab in the outpatient (OP) setting, but OP step-up dosing may make teclistamab more accessible. Therefore, we seek to investigate whether the use of prophylactic tocilizumab can reduce the incidence and severity of CRS associated with teclistamab and allow safe OP administration of the step-up dosing. Methods: This single-arm, non-randomized, multicenter, prospective study (NCT05972135) will evaluate CRS incidence and severity after prophylactic tocilizumab in pts treated with teclistamab in the OP setting. A target of 50 participants will be enrolled with an initial PK/PD safety cohort (n=10). Objectives through end of study include recurrent CRS, grade ≥3 and any grade infections, neurotoxicity including ICANS, neutropenia, febrile neutropenia, and efficacy. Eligible pts are ≥18 years with a documented diagnosis of RRMM who have previously received ≥4 LOTs. Pts with rapidly progressing disease, central nervous system involvement, active infection, or contraindication to tocilizumab will be excluded from the trial. Prior to the treatment phase, pts will participate in a 28-day screening phase to determine study eligibility. During the treatment phase, a single dose of tocilizumab will be administered at 8 mg/kg IV, 2 to 4 hours prior to step-up dose 1 of teclistamab (Cycle 1 Day 1) in an outpatient setting (Figure 1). Teclistamab will then be administered at step-up doses of 0.06 mg/kg subcutaneously (SC) (Cycle 1 Day 1) and 0.3 mg/kg SC (Cycle 1 Days 3-5), followed by 1.5 mg/kg SC (Cycle 1 Day 8), with weekly administration for twelve 28-day cycles or until disease progression or unacceptable toxicity. Teclistamab may be reduced to 1.5 mg/kg SC every two weeks for participants who achieve partial response or better after 6 months of therapy. Safety evaluations will include physical examination, vital sign measurements, neurological examination, assessment of ECOG performance status, and clinical safety laboratory assessments. IVIG is recommended in pts with serum IgG <4 g/L. Follow-up of participants during the study will include monitoring for all adverse events, disease progression, and survival until end of study. By studying the feasibility and safety of administering the step-up dosing schedule in an outpatient setting, teclistamab may become more accessible to pts with RRMM and limited treatment options.

Patterns of Response to 200 Mg Linvoseltamab in Patients with Relapsed/Refractory Multiple Myeloma: Longer Follow-Up of the Linker-MM1 Study

Background Linvoseltamab, a B-cell maturation antigen (BCMA)×CD3 bispecific antibody, demonstrated promising efficacy and generally manageable safety as therapy for relapsed/refractory multiple myeloma (RRMM; Lee et al. ASCO 2023). Here we report additional analysis of efficacy, including response pattern over time, and safety. Methods To enroll into LINKER-MM1 (NCT03761108) patients (pts) had to have multiple myeloma (MM) that either progressed on/after ≥3 lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody; or that was ≥triple-class (PI/IMiD/anti-CD38 antibody) refractory. Pts received intravenous linvoseltamab once a week through week 14, then once every two weeks. In the 200 mg phase 2 expansion cohort, pts achieving very good partial response (VGPR) or better received linvoseltamab once every four weeks after week 24. Primary endpoint was objective response rate (ORR). Key secondary endpoints included progression free survival (PFS) and overall survival. Treatment-emergent adverse events (TEAEs) reported are those that occurred from first dose until 30 days after the end of study treatment. Results As of February 28, 2023, 117 MM pts enrolled into the 200 mg cohort; median age was 70 (range: 37-91) with 26% ≥75, 26% were non-white, 14% had extramedullary (excluding paramedullary) plasmacytomas ≥2 cm, 36% had a high-risk cytogenetics, 22% had bone marrow plasma cells ≥50%, and 74% were ≥triple-class refractory. Median duration of follow-up was 5.6 months (interquartile range [Q1-Q3]: 3.02-8.34) ORR was 71% with ≥complete response (CR) rate of 30%. Responses deepen over time: median time to ≥partial response (PR) was 0.95 months (Q1-Q3: 0.76-1.87); median time to ≥VGPR was 1.87 months (0.79-3.55); and median time to ≥CR was 5.32 months (3.71-7.69). Moreover, high ORR and high rates of ≥CR were observed in many subgroups of difficult-to-treat MM pts. Specifically, ORR and ≥CR rates were: 70% and 29% in pts with ≥triple-class refractory disease; 68% and 26% in pts ≥75 years old; 62% and 26% in pts with high cytogenetic risk; and 47% and 18% in pts with International Staging System stage III. High rates of overall response and ≥CR were also observed in patients with high tumor burden as determined by various measures including bone marrow plasmacytosis ≥50% (50% and 31%) and soluble BCMA at baseline ≥ 0.4mg/L (55% and 25%). Kaplan-Meier (KM) estimated median duration of response was not reached (NR) (95% confidence interval [CI] non-evaluable [NE], NE), and probability of response at 12 months was 79% (95% CI 63, 89). KM estimated median PFS was NR (95% CI NE, NE) and probability of PFS at 12 months was 66% (95% CI 52, 77). TEAEs occurred in all patients with Grade [Gr] ≥3 in 79%. The most common TEAE was cytokine release syndrome (any grade: 45%, Gr3-4: 1%, Gr5: 0; tocilizumab was utilized to treat these symptoms in 16 [13.7%] pts). Other common TEAEs were cough (33%, 0, and 0), neutropenia (32%, 31%, and 0), diarrhea (32%, 2%, and 0), and fatigue (32%, 0, and 0). Rate of infections of any grade was 59.8% with ≥Gr3 in 36.8%. The most common infections were pneumonia (any grade 17.1%, ≥Gr3 13.7%), upper respiratory tract infection (12.0%, and 2.6%), and COVID-19 (12.0%, 5.1%). Opportunistic infections (any grade) were observed in 9 (7.7%) pts including 7 (6.0%) pts ≥Gr3. Twenty-six of 117 (22%) pts were treated with intravenous immunoglobulin. Conclusions Linvoseltamab 200 mg induced deep responses in patients with RRMM including those with high-risk myeloma and high tumor burden, and deepened responses over time while maintaining a generally manageable safety profile. More mature data with longer follow-up will be reported at the meeting.

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

Background and Significance Smoldering 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 Methods LINKER-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.

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.

Trial in Progress: Phase 1 Trial Evaluating the Safety and Tolerability of Odronextamab in Combination with Cemiplimab in Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Background and Significance CD20×CD3 bispecific antibodies (bsAbs) have emerged as an important immunotherapeutic approach for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). These agents have shown compelling efficacy in indolent B-NHL, with the CD20×CD3 bsAb odronextamab demonstrating 75% complete response (CR) rates and encouraging durability of responses (median duration of response [DoR], 20.5 months) in heavily pretreated patients with R/R follicular lymphoma in the ELM-2 study (Kim TM, et al. ASH. 2022). In comparison, patients with R/R diffuse large B-cell lymphoma who were treated with odronextamab in the same study demonstrated a CR rate of 31%, and median DoR was 10.2 months (Kim WS, et al. ASH. 2022). These data indicate an unmet need for treatment strategies that can improve the depth and durability of responses in patients with aggressive R/R B-NHL. Combination therapy with drugs that complement the mechanism of action of CD20×CD3 bsAbs may provide an opportunity to address this unmet need. Cemiplimab is a human immunoglobulin G4 (IgG4) monoclonal antibody directed against programmed cell death protein 1 (PD-1), blocking PD-1- and programmed cell death ligand 1 (PD-L1)-driven inhibitory T-cell signaling. Combining odronextamab and cemiplimab provides an attractive therapeutic opportunity to improve anti-tumor efficacy while restricting T-cell exhaustion, and preliminary results for this combination provided proof of concept, with evidence of clinical activity and manageable tolerability in patients with B-lymphoid malignancies (n=12; Topp MS, et al. ASH. 2017). Here, we investigate whether the addition of cemiplimab to odronextamab can improve the depth and durability of response in patients with previously treated aggressive B-NHL. Study Design and Methods This is a Phase 1, open-label, multicenter, dose-escalation and -expansion study that will take place at up to 28 sites globally (NCT02651662). Intravenous (IV) odronextamab is administered in 21-day cycles, initially as monotherapy and with step-up dosing during Cycle (C) 1 to mitigate the risk of cytokine release syndrome (Figure). Full-dose odronextamab is administered on Day (D) 1, D8 and D15 of C2-C4, and then on D15 of each cycle during maintenance (C5 onwards) until disease progression or treatment discontinuation. IV cemiplimab starts on C2D15 at the specified dose level (DL1-DL7) and is administered on D15 of subsequent cycles. The dose-limiting toxicity (DLT) period is 28 days from the start of cemiplimab administration. At the end of dose escalation, a regimen will be selected for further investigation in dose expansion. Approximately 60 patients will be enrolled. Patients will be aged ≥18 years with aggressive CD20+ B-NHL that is R/R after ≥2 lines of systemic therapy containing an anti-CD20 antibody and an alkylating agent. Patients must have measurable disease, Eastern Cooperative Oncology Group performance score (ECOG PS) ≤1, and adequate bone marrow and organ function. Exclusion criteria include primary central nervous system lymphoma, prior allogeneic stem cell transplantation, autoimmune disease, prior adverse events from anti-PD-1/PD-L1 therapy, and uncontrolled infections. Primary endpoints are safety, tolerability, DLTs, and to determine the recommended Phase 2 dose of the combination regimen of odronextamab and cemiplimab. Secondary endpoints include pharmacokinetics, immunogenicity, and preliminary anti-tumor activity (overall response rate, CR rate, and DoR, according to the Lugano classification). There are no formal hypotheses for this study and analyses will be descriptive in nature.