Step-up Dosing Research Articles

Baseline CD4 T Cells Are Associated with Improved Response to CD20-CD3 Bispecifics in Lymphoma

Background: Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. Mosun is approved for the treatment of patients (pts) with relapsed/refractory follicular lymphoma (FL) after two or more systemic therapies and has shown activity in both aggressive non-Hodgkin lymphoma (aNHL) and indolent (iNHL). Previous reports have shown that CD20 loss is a common mechanism of resistance to Mosun (Schuster SJ, ASCO 2022). However, as the mechanism of action of Mosun is T cell mediated killing of tumor cells, we sought to characterize the immune microenvironment of tumor samples from patients with NHL treated with Mosun. Here we report integrated biomarker analysis of pt samples from the phase I/II Mosun monotherapy trial (NCT02500407). Methods: Baseline and at-progression biopsies were collected from 240 relapsed/refractory NHL pts from the fixed dosing (arm A) and Cycle 1 step-up dosing (arm B) cohorts, including 78 DLBCL, 89 FL, 37 transformed FL (trFL), and 36 other aNHL and iNHL histologies (including MCL, MZL, SLL, & RS). A total of 265 biopsies were profiled via RNASeq, including 58 paired baseline and at-progression samples. As a proxy for immune subset prevalence, immune gene signatures were calculated using principal component analysis. Association with best overall response was calculated using limma with histology and archival status included as covariates for the pooled cross-histology analysis, or with archival status for within-histology comparisons. Significance for exploratory analysis was defined as false-discovery rate (FDR)<0.05. Results: Pooled analysis of all baseline biopsies identified expression of 76 genes as significantly associated with response (Figure 1A). A number of immune-related genes, such as ITGAL, IL6R, and TOX2 were expressed at higher levels in responders. Gene signature analysis revealed that most of the top hits were T cell related, with T follicular helper (Tfh) signatures most strongly associated with response. Analysis of individual histologies revealed that the majority of genes identified had indication-specific associations, with significant hits in DLBCL (n=472) or trFL (n=4). No hits were found in FL after FDR correction. DLBCL hits appeared mostly tumor-specific (HLA-E, DOK1, and ITGA2), while trFL hits were more associated with CD4 T cell biology (TIGIT and FOXN3). The Tfh signature was the most strongly associated with response in trFL, and was also nominally significant in FL (Figure 1B). The signature displayed a histology-specific expression profile, with lower expression in aNHL and higher expression in iNHL. A split was observed in trFL, with responders showing signature scores similar to iNHL and non-responders like aNHL. Other CD4-but not CD8-signatures showed a similar profile. At progression, a small number of genes showed sustained changes, with reductions in XCR1 & CLEC9A, and induction of ALOX15B seen in patients up to 2 years after the last Mosun administration, suggesting long-term changes in the immune microenvironment during the development of resistance. Conclusions: Baseline biomarker data reveal an important role for CD4 T cells in Mosun response and suggest that higher prevalence of CD4s may be a factor in the improved response to Mosun in indolent NHL. Our data specifically point to Tfh cells as potential drivers of response, although the mechanisms by which Tfh contributes to response, as well as the implications for other bispecifics, requires more exploration.

Alterations in Immune Cell Composition during First-Line Therapy with Mosunetuzumab for Follicular or Marginal Zone Lymphoma

Background: Bispecific CD20xCD3 antibodies (BiAbs) that engage T-cells to eliminate CD20+ B-cells have emerged as a potent immunotherapy for the treatment of follicular (FL) and marginal zone (MZL) lymphomas. BiAbs have primarily been studied in patients with extensive prior immunosuppressive and lymphodepleting therapies, so their effects on the immune system without such exposures are not well understood. Unlike cellular therapies, BiAbs are administered continuously over time, spanning from 6 months to an indefinite period, and recent studies have raised concerns about T-cell exhaustion due to continuous BiAb exposure in B-lymphoblastic leukemia (Philipp et al, Blood 2022). Mosunetuzumab is a BiAb approved for treatment of relapsed/refractory FL. The ongoing phase 2 BrUOG-401 trial (NCT04792502) is investigating mosunetuzumab as first-line therapy for FL or MZL. Here, we present preliminary results focusing on treatment-induced changes in circulating immune cells. Methods: Patients with previously untreated, high-burden or symptomatic FL or MZL received subcutaneous mosunetuzumab for 8 planned cycles (C) with step-up dosing in C1 (day 1: 5mg, day 8 & 15: 45 mg; then 45mg on day 1 of C4-C8). Patients without a complete response (CR) at interim assessment after C4 also received lenalidomide augmentation (10mg daily) during C5-8. Immune cell subsets were examined using multicolor flow cytometry (BD LSRII Analyzer). Peripheral blood samples were collected longitudinally before C1, on day 1 of C2 and C5, and 4-6 weeks after the end of therapy (EOT). Median cell abundance and marker expression were compared using generalized linear mixed models with patient and sample-level random effects. Analysis was performed in R (v.4.3.1) using the flowCore, flowStats and diffcyt packages; uncorrected P<0.05 was considered statistically significant. Results: As of July 2023, 13 patients (median age 62, 77% women, 77% FL, 23% MZL) were accrued in the trial. At data cutoff, 7 have completed therapy, 11 were evaluable for response, and 8 attained CR ( Fig. A). So far, only 1 patient started lenalidomide; samples collected while on lenalidomide were excluded from analysis. No instances of cytokine release syndrome (CRS) or neurotoxicity were observed. CR's occurred early (by C5). Mosunetuzumab resulted in a rapid, deep, and sustained depletion of circulating CD19+ B-cells. A significant decrease in circulating CD8+ T-cells was noted at cycle 2 (from median 20% to 12%, P<0.001; Fig. B), followed by recovery (19% at C5). Among the CD8+ subsets, the naïve CD8+ T-cells (CD45RA+CCR7+CD27+) decreased relatively at C5 & EOT, while effector memory T-cells (CD45RA-CD45RO+CD27-CD62L-) increased. Notably, we observed a significant early, temporary, increase in the expression of LAG3 at C2 on CD8+ T-cells ( P=0.033), and a more pronounced increase in PD1 expression ( P=0.001), which persisted through the EOT ( Fig. B). No significant changes were observed in total abundance of CD4+ T-cells. However, CD4+CD25+CD127- Tregs notably increased at C2 ( P=0.008). This increase specifically driven by CD45RA+ “naïve” Tregs ( P<0.001 at C2), which remained elevated relative to CD45RO+ Tregs at C5 and EOT. All Tregs showed a significant increase in LAG3 expression at C2 ( P<0.001), which then subsided. In contrast to CD8+ T-cells, there was no significant increase in PD1 expression on CD4+ T-cells ( P=0.20 at C2). Throughout the therapy, there was a progressive increase in NK cells ( P=0.001 at EOT), with no significant shift in the relative proportions of CD16high or CD161high NK cells. Conclusions: In this initial investigation of immune cell changes in patients who received mosunetuzumab without prior chemotherapy exposure, we observed B-cell depletion and a temporary decrease in CD8+ cytotoxic T-cells (implying their migration out of the bloodstream), aligning with mosunetuzumab's mechanism of action. Additional data from this trial will aid in understanding whether the persistent increase in PD1+CD8+ T-cells and expansion of Tregs are linked to a functionally exhausted phenotype and whether lenalidomide could potentially reverse it. Although our observation is limited by sample size, it can still provide insights into optimizing the administration schedules of BiAb therapy in future trials (e.g., intermittent vs. continuous) or determining the most suitable timing for checkpoint inhibitor combinations.

Population Pharmacokinetics and CD20 Binding Dynamics for Mosunetuzumab in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (R/R NHL)

Introduction: Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. Clinical data from GO29781 (NCT02500407), a Phase I/II, open-label, multicenter dose-escalation and expansion study of Mosun in pts with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL), was used to develop a population pharmacokinetic (popPK) model describing Mosun concentration-time data. Prior to initiation of Mosun, many patients had circulating levels of other anti-CD20 drugs (e.g. rituximab (R) or obinutuzumab (G)) from prior treatment. In order to elucidate exposure-response (ER) relationships in the presence of these competitors, CD20 binding and R/G pharmacokinetics were incorporated into the popPK model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. Methods: Mosun PK data were available in 439 pts with indolent or aggressive R/R NHL who received either Mosun fixed dosing (n= 32; 0.05-2.8mg every 3 weeks (q3w)) or Cycle 1 step-up dosing (n=407, 0.4/1.0/2.8 - 1/2/60/30mg). The popPK model was developed using NONMEM® software (v7.4.3), with a clinical cut-off date of December 4, 2020. Clinically relevant covariates were investigated for their potential to explain Mosun PK variability. The Mosun CD20 RO% time course for each pt was derived by integrating the Mosun, R, and G model predicted concentration-time courses and their respective CD20 affinities (Kds) into the popPK model. R and G concentration-time courses were predicted by the model using their baseline values and published half-lives, and binding kinetics were assumed to be at equilibrium. PopPK model simulations (n=1000) were done with the final model to establish Mosun concentration ranges for the approved 1/2/60/30 mg dose regimen, given that this regimen was designed to mitigate cytokine release syndrome (CRS) through its step-up Cycle 1 design. Additional popPK model simulations, incorporating Mosun dose delays, were conducted and compared to the 1/2/60/30 mg nominal dose regimen to inform treatment resumption protocols necessary to mitigate CRS. Results : A two-compartment PK model with time-dependent clearance (CL) best described Mosun PK. Mosun CL decreased from an initial value of 1.08 L/day transitioning to a steady state clearance of 0.584 L/day by Cycle 4 (Figure 1A). Mosun terminal phase half-life at steady state was 16.1 days. Concentrations of R/G were present in 50% of patients prior to Mosun therapy (Figure 1A), and the median predose R/G concentration for these patients was 10.0 µg/mL. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline concentrations of R/G; however, no covariate was deemed to have a clinically relevant impact on PK at the recommended dose of 1/2/60/30mg. Mosun CD20 RO% was more variable than Mosun PK (Figure 1B), attributed to the large variability in baseline R/G concentrations. The 60mg loading doses increased Mosun CD20 RO% to steady-state ranges by Cycle 1 (Figure 1B), thereby providing Mosun efficacious exposure in the presence of competing residual, transient R/G concentrations from prior treatment therapies (Figure 1A). From the popPK model simulations, patients with dose delays greater than or equal to 6 weeks had Mosun concentrations that fell below levels after the Day 1 (1mg) and Day 8 (2mg) doses; as such, these pts are instructed to repeat these doses prior to treatment continuation. For Mosun dose delays less than 6 weeks, popPK simulations supported pts either to repeat the last Mosun dose administered, or to continue along with the planned regimen [Lunsumio ® USPI]. Conclusions: Mosun PK was characterized using a two-compartment model with time dependent CL. R/G PK and CD20 binding kinetics were incorporated into the Mosun popPK model to calculate Mosun CD20 RO% over time. The use of two 60mg loading doses enables early achievement of Mosun steady-state target CD20 RO% range, especially benefitting those pts with high levels of precirculating R or G. Simulations with the popPK model supported labeling recommendations for restarting Mosun treatment after dose delays. Acknowledgments: This study was sponsored by F. Hoffmann-La Roche Ltd / Genentech, Inc

Evaluating Tumor-Intrinsic and Patient-Specific Mechanisms of Resistance to Teclistamab in Anti-BCMA Exposed and Naïve Multiple Myeloma

Background: Teclistamab (Tec) is a CD3 x BCMA bispecific antibody granted accelerated FDA approval for treating relapsed/refractory (RR) multiple myeloma (MM) based off the results of the MajesTEC-1 trial (Usmani S, et al. Lancet 2021, Moreau P, et al. N Engl J Med 2022). However, patients with prior exposure to anti-BCMA therapies were excluded from this trial and there is no published data evaluating Tec efficacy in this setting. Additionally, little is known about tumor-intrinsic and patient-specific immunologic predictors of response to Tec. Methods: We performed an IRB-approved analysis of clinical outcomes for 52 commercially treated Tec patients treated as of 07/28/2023 at our center. Results were correlated to pre-treatment BCMA expression measured by immunohistochemistry (IHC). We also profiled peripheral blood T-cells from pre-treatment peripheral blood mononuclear cell (PBMC) samples from a sub cohort of patients via high-dimensional spectral cytometry using a 37-color panel including lineage, exhaustion, and activation markers. Results: Our commercial cohort was older (median age 70 vs 64), more heavily pretreated (median prior lines of therapy 7 vs 5) and had higher incidence of both high-risk cytogenetic abnormalities (33% vs 26%) and extramedullary disease (35% vs 17%) than the MajesTEC-1 population. Additionally, 52% had prior exposure to anti-BCMA therapies, including belantamab mafodotin (31%), anti-BCMA CAR T-cell therapies (37%), and anti-BCMA bispecific antibody therapies (4%), with some having exposure to multiple prior anti-BCMA therapies (17%). Among response evaluable patients (90%), with a median follow-up time of 100 days, the overall response rate (ORR) to Tec was 64% (36% ≥VGPR). Progression free survival (PFS) in patients without prior BCMA therapy was higher than in the anti-BCMA exposed population (median PFS NR vs 102 days, p = 0.032, Figure Panel A). However, the anti-BCMA therapy exposed population was more heavily pretreated (8 vs 5 median prior lines of therapy) and had more patients with high-risk cytogenetic abnormalities (46% vs 19%) and extramedullary disease (42% vs 27%) than the anti-BCMA therapy naïve cohort. No major differences in BCMA expression were noted between responding and non-responding patients or between anti-BCMA exposed and anti-BCMA naïve patients. However, two patients had absent BCMA expression following prior treatment with other BCMA targeting agents and did not respond to Tec. Cytokine release syndrome (CRS) during step-up dosing was strongly associated with Tec efficacy (median PFS NR vs 27 days, p <0.0001), with a 100% ORR for patients with CRS. Immune profiling experiments (Figure Panel B) revealed that Tec responders had peripheral blood enriched for both CD8 + effector memory T-cells (TEM, >6-fold increase, p = 0.0499) and CD8 + effector memory T-cells re-expressing CD45RA (TEMRA, >5-fold increase, p = 0.012) when compared to Tec non-responders. Tec non-responders had peripheral blood enriched for TIGIT + regulatory T-cells (Tregs, 3-fold increase, p = 0.03) when compared to Tec responders. No differences in PD-1, CTLA-4, LAG-3 or TIM-3 expression were observed in Tec responders vs non-responders. Patients with recent relapse from non-BCMA targeting bispecific antibodies (including products targeting FcRH5 or GPRC5D) had peripheral blood enriched for γδ T-cells with high TIGIT expression. Conclusion: Tec is an effective therapy in RRMM with a slightly lower efficacy observed in patients with prior anti-BCMA therapy exposure. PFS reductions among these anti-BCMA exposed patients may be partly due to independent disease associated risk factors. A pre-Tec peripheral blood T-cell population enriched with highly cytotoxic effector T-cells was associated with response to therapy, while suppressive TIGIT +Tregs were associated with nonresponse, suggesting a potential therapeutic role for TIGIT blockade or CD25 + cell depletion to enhance the therapeutic efficacy of bispecific antibodies. Clinical and translational data from additional patients will be presented at the meeting.

EX103, a Novel CD20xCD3 Bispecific Antibody, Showed a Favorable Safety and Potent Single-Agent Antitumor Activity in Heavily Pretreated Relapsed/Refractory Patients with B-Cell Non-Hodgkin Lymphoma

Introduction Non-Hodgkin lymphoma (NHL) is one of the most common cancers in the United States, and relapsed or refractory (R/R) B cell NHL had a poor prognosis. In recent years, T cell engaging bispecific antibody (TCB) emerged as a promising therapy. Nevertheless, severe cytokine release syndrome (CRS) remains to be a significant challenge in TCB treatment. To overcome this issue, we designed a new CD20xCD3 bispecific antibody (EX103) with a lower affinity to CD3. In the non-human primate tox study, EX103 induced much lower IL-6 release. Preliminary data from dose escalation part of Phase I clinical study demonstrates that EX103 has an encouraging safety and robust single-agent antitumor activity trend, even at low doses, in heavily pretreated R/R B-NHL patients. Method The dose-escalation part (8 dose cohorts, ranging from 1.2 to 36 mg) of this Phase I, multicenter, single-arm, open-label clinical trial has enrolled R/R CD20+ B-cell non-Hodgkin lymphoma subjects at 4 study sites in China. Objectives include safety, dose finding (RP2D), and antitumor activity. Eligible patients in each cohort received intravenous(iv) step-up doses of EX103 (with 1 priming dose and 2 intermediate doses followed by 1 target dose of EX103) administered in a 28-day dose limiting toxicity (DLT) observation period, and then received a target dose every 2 weeks for up to 12 cycles until disease progression or unacceptable toxicity. Response rates reported are based on the Lugano criteria (2014). Results As of June 2023, 5 cohorts (target dose from 1.2 to 18 mg) of the dose-escalation were completed. Among 13 evaluable patients , 9 of them are aggressive B-NHL (5 Diffuse large B-cell lymphoma (DLBCL), 3 Follicular lymphoma (FL) grade 3B, and 1 Mantle cell lymphoma (MCL)), 2 of them are indolent B-NHL (1 FL grade 1-3A, 1 Marginal zone lymphoma (MZL)), and 2 of them are Chronic lymphocytic leukemia (CLL). No DLT was observed, and the maximum tolerated dose (MTD) was not reached. The most common adverse events (AEs) were CRS, pyrexia, neutropenia, thrombocytopenia. All CRS were grade (Gr) 1-2, no Gr 3 or higher CRS. Most CRS events occurred in first or second treatment cycle, and all CRS related clinical symptoms were resolved within 48 hours. No Immune effector cell-associated neurotoxicity syndrome (ICANS) or other clinically significant neurologic AEs were reported. Among those patients, the median age was 51 years (range 43-66) and median number of prior lines of treatment was 5 (range 2-8). The preliminary Disease Control Rate (DCR) is 84.6% (11/13). Among 9 aggressive NHL patients, the overall response rate (ORR) was 67.7 % (6/9), including 3 DLBCL patients (1 each in 6 or 12 or 18 mg cohorts) and 1 MCL patient (in 3 mg cohort) achieving CR, and 2 grade 3B FL patients achieving PR (1 each in 6 or 18 mg cohorts). Both indolent NHL patients (1 FL (Grade 1-3A) and 1 MZL in 12 mg cohort) achieved PR and the preliminary ORR for indolent NHL was 100.0 % (2/2). Of 2 CLL patients, 1 achieved SD (3mg cohort). It is worth mentioning that two of the patients who failed prior CAR-T treatment had achieved PR after received 6-14 week treatment of EX103. Both patients are still under EX103 treatment. Conclusions Although this study has a limited number of subjects so far and the findings are preliminary, the available dose-escalation data demonstrate that single-agent EX103, even at low doses (3 or 6 mg), exhibits remarkable antitumor activity and favorable safety. Furthermore, EX103 demonstrates promising efficacy in heavily pretreated patients with R/R B-NHL, including some who have previously failed CAR-T treatment. The safety and efficacy of EX103 will be further evaluated in an ongoing clinical study.

EPCORE FL-1: Phase 3 Trial of Subcutaneous Epcoritamab with Rituximab and Lenalidomide (R 2) Vs R 2 Alone in Patients with Relapsed or Refractory Follicular Lymphoma

Background: Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma (NHL). Several treatment options are approved by the US Food and Drug Administration for second- or later-line FL therapy, including rituximab + lenalidomide (R 2). However, advanced-stage FL remains incurable and new treatment options for relapsed or refractory (R/R) disease are needed. Epcoritamab, a subcutaneously administered, bispecific antibody that binds CD3 on T lymphocytes and CD20 on B cells, induces potent and selective T-cell-mediated killing of malignant CD20 + B cells (van der Horst et al, Blood Cancer J 2021). In the first-in-human, phase 1/2 EPCORE NHL-1 trial (NCT03625037) in heavily pretreated patients with B-cell NHL (N=68), epcoritamab showed manageable safety and promising single-agent anti-tumor activity (Hutchings et al, Lancet 2021). Among 10 patients with R/R FL, objective response rate (ORR) was 90% (95% CI: 55-100) and complete response (CR) rate was 50%. In the ongoing phase 1b/2 trial evaluating epcoritamab + R 2 for R/R FL (EPCORE NHL-2 arms 2a and 2b; NCT04663347), ORR was 98% among 104 efficacy-evaluable patients, with a complete metabolic response in 87%. Most cytokine release syndrome (CRS) events were low grade (n=111; grade 1-2, 46%; grade 3, 2%) and occurred in cycle 1; all CRS events resolved with routine management. These encouraging data, and the distinct mechanisms of action of epcoritamab and R 2, support ongoing evaluation of this combination for its potential to improve clinical outcomes in patients with R/R FL. The phase 3 EPCORE FL-1 trial was designed to evaluate epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL with ≥1 prior line of anti-lymphoma therapy. We present an updated protocol, reflecting recent developments and revisions implemented in this study. Study Design and Methods: EPCORE FL-1 (NCT05409066) is a global, randomized, open-label, multicenter phase 3 trial designed to evaluate efficacy and safety of epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL. Adult patients must have histologically confirmed classic FL (previously grades 1 to 3a FL) stage II, III, or IV with a CD20 + tumor on a representative biopsy based on local pathology report and no evidence of histologic transformation. Patients must have R/R disease after ≥1 prior anti-lymphoma regimen that contained an anti-CD20 monoclonal antibody in combination with chemotherapy; patients receiving only prior anti-CD20 monoclonal antibody monotherapy and/or radiation are not eligible. Other key eligibility criteria include Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose positron emission tomography-avid disease, and ≥1 measurable disease site per Lugano 2014 criteria. Lenalidomide-refractory FL (best response to lenalidomide of stable or progressive disease or progressive disease within 6 months of completion of lenalidomide) is excluded. Approximately 520 patients will be enrolled and randomized 1:1 to receive a full dose of epcoritamab in combination with R 2 or R 2 alone ( Figure); the trial is currently enrolling in 2 arms, Arms A & C. Based on emerging safety and efficacy data, Arm B has been closed to enrollment and the recommended dose of epcoritamab in combination with R 2 is 48 mg. Epcoritamab will be subcutaneously administered using a step-up dosing regimen to full dose in cycle 1 (28 days/cycle). Full dose of epcoritamab will be administered weekly in cycles 2-3 and monthly from cycle 4 onward for up to 12 cycles of treatment. Patients will be serially assessed for disease progression at prespecified intervals. The primary endpoint is progression-free survival assessed by independent review committee (IRC) per Lugano criteria. Key secondary efficacy endpoints include CR rate (by IRC per Lugano criteria), overall survival, and minimal residual disease negativity. Other efficacy endpoints include best overall response, duration of response, duration of complete response, time to progression, event-free survival, time to next anti-lymphoma treatment, and patient-reported outcomes. Safety endpoints include incidence and severity of treatment-emergent adverse events and adverse events of special interest. Exploratory endpoints include assessments of pharmacodynamic and pharmacokinetic data. The study opened for enrollment in 2022 in North America, South America, Europe, Africa, Asia, and Australia.

Clinical Factors Associated with Cytokine Release Syndrome and Dosing Recommendations for Restarting Elranatamab Following an Interruption

BACKGROUND In the MagnetisMM-3 (NCT04649359) study, elranatamab (ELRA) administered at a dose of 76 mg once-weekly (QW) with 2 step-up priming doses of 12 mg on day 1 and 32 mg on day 4 had a manageable safety profile, with 56.3% of patients developing cytokine release syndrome (CRS) and 98.8% of events occurring with the first 3 doses. Here, we report clinical factors associated with CRS and dosing recommendations for restarting treatment after dose interruptions in patients with relapsed or refractory multiple myeloma (RRMM) undergoing treatment with ELRA. METHODS Eligible patients received ELRA subcutaneously in step-up priming doses of 12 and 32 mg on days 1 and 4 of cycle 1, respectively, followed by 76 mg of ELRA QW. CRS events were graded according to the criteria of the American Society for Transplantation and Cellular Therapy and managed according to published guidelines. Multivariable analyses were performed to identify clinical factors associated with CRS. Baseline factors (extramedullary disease by BICR, prior antibody-drug conjugate, prior CAR-T, number of prior lines of therapy [≤5, >5], sex, and age [continuous variable]) were included in the model for CRS after the initial dose, and only post-baseline factors (time to previous CRS and time to initial tocilizumab use) were included in the model for CRS after the second dose. A previously described population pharmacokinetic (PK) model was used to simulate different interruption scenarios and determine how long it takes for ELRA exposure to drop below the threshold associated with CRS events (Hibma J, et al. Poster presented at PAGE 31 2023 [abstract 10648]). The data used to develop this model was collected from the following open-label elranatamab trials: MagnetisMM-1 (NCT03269136; phase 1), MagnetisMM-2 (NCT04798586; phase 1), MagnetisMM-3 (NCT04649359; phase 2), and MagnetisMM-9 (NCT05014412; phase 1/2). Of 183 patients who were treated in MagnetisMM-3 with the 2 step-up priming dosing, 106 patients (57.9%) experienced CRS, 43.7% grade 1, 13.7% grade 2, and 0.5% grade 3. Tocilizumab was used to manage CRS. Of the 130 CRS events, 37 (28.5%; 20 grade 1 and 17 grade ≥2) were treated with tocilizumab, and 93 (71.5%; 82 grade 1 and 11 grade ≥2) were not. After the initial elranatamab dose, 79/183 patients had CRS. The presence of extramedullary disease was predictive of a decreased risk of CRS after the initial dose. Of the 180 who received a second elranatamab dose, 35 had CRS afterwards. In a multivariable model also adjusting for CRS after the initial dose, prior tocilizumab use was predictive of a decreased risk of CRS after the second dose. After receiving doses of 76 mg of ELRA, 16 instances of dose delays lasting >6 to ≤12 weeks were observed. In most of these instances (11/16; 68.8%), patients did not repeat the 32-mg step-up dose. In 5 instances, patients restarted treatment with 32 mg of ELRA. No patients experienced CRS after retreatment. For the 4 instances of dose delays lasting >12 weeks after a 76-mg dose, patients repeated the 32-mg step-up dose in 2 instances, and patients received >32 mg ELRA after the interruption in the other 2 instances, with none experiencing CRS after retreatment. With dose delays of 6-12 weeks, ELRA exposure decreases below the C max after a 32-mg dose but not less than that for the 12-mg dose. With dose delays >12 weeks, ELRA exposure decreases below the C max after a 12-mg dose. To minimize the risk of CRS events after dose interruptions, clinical and PK data and modeling were used to develop recommendations for restarting therapy (Figure). CONCLUSIONS Extramedullary disease and use of tocilizumab were associated with a decreased risk of CRS. Based on clinical and PK data and modeling, it is recommended that patients receiving 76 mg ELRA who then experience dose delays lasting 6-12 or >12 weeks should restart treatment at doses of 32 or 12 mg, respectively.

A Single Center Real-World Data Comparing Salvage Autologous Hematopoietic Stem-Cell Transplantation, Selinexor Combo and Elranatamab Alone Among Triple Class Refractory Myeloma Patients: Better Efficacy with Elranatamab

Introduction: A vast majority of multiple myeloma (MM) patients may experience relapse and require multiple lines of therapy. The choice of the next treatment depends on multiple factors including the response, tolerance to prior therapies, as well as access to novel treatments. Among triple-class refractory patients, in real-world settings where CAR-T therapies are not available, options are limited. Here we report a single-center experience comparing salvage autologous hematopoietic stem-cell transplantation (sAHCT), selinexor combinations, and elranatamab in this highly unmet needed group. Patients & Methods: Between January 2015 and June 2023, 50 patients at our center underwent sAHCT for treatment of refractoriness to all available drugs. Salvage AHCT is defined as being transplanted for treatment of MM after evidence of disease progression not responding to second-generation proteasome inhibitors (PI), immunomodulating agents (IMID), or antiCD38 monoclonal antibody. We compared the outcomes of these patients with RRMM patients who had exhausted their treatment options and were progressing on their last line of therapy to receive single agent Elranatamab at a step-up dosing starting with escalating to 72 mg once a week for six months and on alternate weeks thereafter. Selinexor was administered with either Bortezomib(n:8) or Pomalidomide(n:9) at a dose of 60-100 mg/week every 5-6 weeks. Response and disease progression were assessed according to the IMWG criteria. Results: Patients' characteristics and the outcomes are shown in Table. The median age of patients was similar in both groups. Patients were heavily treated with a median of 4 prior lines of therapy (1-17) and 7 out of 13 carried high-risk cytogenetics in elranatamab group. All patients were triple-class refractory. Five patients responded to DCEP bridging therapy prior to sAHCT. Selinexor (n: 11, 64.7%) and elranatamab (n:5 patients,38.5%) were administered after sAHCT. One patient underwent sAHCT due to progression under Selinexor treatment. In the sAHCT group, 68% of patients relapsed within a median of 7.4 months. Median DFS was significantly prolonged with single agent elranatamab (NR) compared to sAHCT (7.3 mos) and Selinexor-combos (7.3 mos) (p=0.4) (Figure). Adverse events on selinexor regimens included fatigue, nausea, and thrombocytopenia which were managed with Selinexor dose adjustment and supportive care. All patients received the recommended step-up priming dose elranatamab regimen, 69.2% of our patients experienced a Grade 1 cytokine release syndrome (CRS) during the first cycle. None of these patients had to stop treatment due to toxicity. Early sAHSCT mortality was not observed either. At the time of the analysis, all patients on Selinexor have progressed after a median follow-up of 14.7 months. Elranatamab patients are currently at 5 months follow-up and 7/ 13 are still on treatment. Conclusion: Upfront AHCT is a cost-effective treatment option with a decreasing efficacy in late relapses. In this RWE study, we have been able to confirm the inferiority of AHCT at late stages. As seen in our series cytogenetic profile worsens with an increase in the prior number of lines of treatment which are both highest among patients who have received elranatamab. Despite these unfavorable features, single-agent elranatamab has been able to attain the highest overall response rates, unfortunately not reflecting on PFS yet, due to short follow-up. Furthermore, two of these had progressed while on a BCMA immunotoxin Rx and have responded to elranatamab. In conclusion, even with short follow-up single-agent elranatamab is a tolerable and highly effective regimen

Real-World Treatment Outcomes of Teclistamab Under an Outpatient Model for Step-up Dosing Administration

Background Teclistamab, the first-in-class B-cell maturation antigen (BCMA) x CD3 bispecific therapy was recently approved by the FDA for the treatment of triple-class exposed relapsed or refractory multiple myeloma (MM) after ≥ 4 prior lines of therapy. Because of the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the step-up dosing (SUD) of teclistamab is commonly administered in an inpatient setting among early users. Mayo Clinic has a well-established hospital-based outpatient program for novel immunotherapies. Since the FDA approval, teclistamab SUD has been administered as part of this program. Each dose of the SUD is administered in an outpatient setting, and the patient is given a remote monitoring kit to regularly measure vital signs and stay connected with the command center for signs and symptoms of CRS and ICANS throughout the entire SUD period. This study aimed to evaluate early safety outcomes and healthcare resource utilization during SUD in real-world (RW) patients who initiated teclistamab under the outpatient administration model across 3 Mayo Clinic locations (Rochester, MN, Phoenix/Scottsdale, AZ, Jacksonville, FL). Methods This was a retrospective study using Mayo Clinic's electronic medical records from October 26, 2022 to June 12, 2023. Eligible patients were adults diagnosed with MM who had initiated commercial teclistamab at any of the 3 Mayo Clinic locations. Patient characteristics, rates and severity of CRS and ICANS, as well as healthcare resource utilization during SUD were described. Time between teclistamab administration and patient check-out was reported for SUD and treatment doses, respectively. Results At the time of data cutoff, 39 patients received at least 1 teclistamab dose across the 3 locations (median age 67.2 years; male: 74%; White: 87%; non-Hispanic: 92%), including 36 patients who initiated teclistamab SUD directly in an outpatient setting. A total of 8 (21%) patients had MM with high-risk cytogenetics and 14 (36%) had prior exposure to other BCMA-targeted therapies. Prevalent comorbidities prior to receiving teclistamab included anemia (77%), hypertension (56%), lytic bone lesions (51%), neutropenia (49%), and hypogammaglobulinemia (41%). Renal impairment or failure was observed in 31% of the patients (Table 1). Almost all patients received acetaminophen (95%), diphenhydramine (95%), and dexamethasone (92%) as pre-medications on the same day as teclistamab administrations during SUD. Of the teclistamab doses with clinic time data, the majority (62%) of doses during SUD required 30 minutes to 1 hour of clinic time for monitoring between administration and check-out. After SUD, the clinic time for weekly treatment doses decreased to less than 30 minutes for most (79%) doses (Figure 1). In patients who completed SUD by data cutoff (n = 37), most patients (70%) received the SUD on a 3-day dose interval (i.e., day 1, 4, 7). The mean time between the first and third doses was 6.3 days. Among the 37 patients with complete SUD, 12 (32%) developed CRS. The highest CRS grade was grade 1 for 10 patients; 1 patient had a grade 2 CRS, and 1 patient had a grade 4 CRS. The patient with grade 4 CRS concurrently decompensated during a dialysis session and all symptoms were considered for CRS grading. A total of 6 patients had recurrent CRS, including 1 patient with 3 events during SUD. All patients who developed CRS during SUD (n=12) were admitted to the hospital for treatment, with a total of 19 admissions across all patients and a median length of stay of 1.7 days per admission. Among patients who were admitted for CRS (n=12), the majority were treated with acetaminophen (92%), diphenhydramine (83%) and dexamethasone (83%); tocilizumab was given to the 2 patients with CRS grade 2 or higher. Only 1 ICANS event (grade 2) was observed in 1 patient during SUD, after dose 3, and the patient was admitted to the hospital for treatment. Conclusion This study evaluated early RW safety outcomes of teclistamab under an outpatient administration model and found the CRS rate and severity to be comparable with other RW evidence generated from various data sources. Outcomes related to teclistamab SUD from Mayo Clinic supported the safety and feasibility of outpatient administration model as a potential option to reduce healthcare resource utilization and improve treatment experiences.

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.

French Monocentric Experience of Outpatient Step-up Dosing of Teclistamab in Relapsed Refractory Multiple Myeloma

Background Teclistamab is the first approved BCMAxCD3 bispecific antibody for relapsed/refractory multiple myeloma and is available in France since October 2022 through a procedure facilitating patient access to innovation addressing high unmet medical needs (Acces Precoce, AP). Given specific toxicities, associated with novel bispecific therapies, including cytokine release syndrome (CRS), inpatient step-up dosing is usually considered. However, the favorable toxicity profile of teclistamab may be conducive to outpatient administration. Our center is already experienced in outpatient stem cell transplantation for newly diagnosed transplant eligible myeloma patients. Here, we report the characteristics and outcomes of patients treated with teclistamab exclusively in an outpatient setting, including the step-up dosing phase. Methods Among the 32 patients who completed the step-up dosing schedule of teclistamab in our center between January 2021 and July 2023, 15 were treated outside of clinical trials and 8 patients received teclistamab exclusively in an outpatient unit. Eligibility for outpatient step-up dose administration was based on (1) clinical and (2) logistical criteria: 1) general condition maintained, no active infection, no high tumor burden or very rapidly progressing disease; 2) patient agreeing to stay within 30 minutes of transportation to the site for 48 hours after each step-up dose and after the first full dose. The 8 eligible patients underwent specific monitoring at home: consisting of measurement of temperature, blood pressure and oxygen saturation by a homecare nurse twice a day for 15 days. Patients and careers were trained in self-monitoring of the CRS and were provided with a blood pressure monitor and an oxymeter. In addition to the regulatory documents of the French AP, patients were given a practical drug information sheet. Oral dexamethasone was available at home in case of emergency with hospital 24-hour contacts in the event of grade ≥ 2 CRS or any other complication. Results In addition to one patient treated in the MajesTEC3 trial, 7 of the 15 patients treated outside clinical trials since January 2023 (47%) were dosed exclusively in outpatient setting. Median age was 69 years (43-81). Isotype of myeloma was FLC in 5/8 patients. Teclistamab was given after a median of 4 previous lines of therapy (3-7). Dose escalation was carried out in accordance with FDA and EMA recommendations after premedication with dexamethasone. CRS was reported in 3 patients (2 grade 1, 1 grade 2 treated with dexamethasone and tocilizumab). No ICANS or infections G ≥ 2 were reported. ORR was VGPR or better in the majority of the patients (6/8). To date, only one patient required an unplanned admission, of 10 days to manage both grade 2 CRS and CMV reactivation occurred simultaneously. There were no toxicity-related deaths. According to local procedures, all the patients received prophylaxis with antibiotics and antivirals as well as polyvalent immunoglobulins. Cost analysis is ongoing and all the data will be updated at the time of the presentation. Conclusion Outpatient teclistamab step-up dose is feasible with careful patient selection and close at home monitoring, and seems associated with similar safety profiles and efficacy outcomes as inpatient treatment. Outpatient management is cost-effective and may help optimize healthcare resource utilization.

Mitigating the Risk of Cytokine Release Syndrome (CRS): Preliminary Results from a DLBCL Cohort of Epcore NHL-1

Background: Epcoritamab SC, a CD3xCD20 T-cell-engaging bispecific antibody, has recently been approved by the US FDA for the treatment of adults with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. As a single agent, epcoritamab SC has demonstrated deep, durable responses with a manageable safety profile in patients with R/R large B-cell lymphoma in the expansion portion of the phase 1/2 EPCORE ™ NHL-1 trial (NCT03625037). Cytokine release syndrome (CRS) events in the dose expansion part of the trial were primarily low grade (49.7% overall; 31.8% grade [G] 1, 15.3% G2, 2.5% G3); timing was predictable, and the majority of events occurred following the first full dose at cycle 1 day 15 (C1D15). To mitigate CRS in dose expansion, subcutaneous administration, step-up dosing, and premedication, including prednisolone, were used. Here, we present preliminary results from a DLBCL optimization cohort of the EPCORE NHL-1 trial that further investigates mitigating the risk of CRS in patients treated with epcoritamab SC monotherapy. Methods: Adult patients with R/R CD20 + DLBCL (previously treated with ≥2 lines of systemic therapy) were enrolled to receive epcoritamab SC in 28-d cycles as follows: weekly, C1-3; every 2 weeks, C4-9; every 4 weeks, C≥10 until progressive disease or unacceptable toxicity. Patients received 2 step-up doses (step-up dose 1, 0.16 mg, and step-up dose 2, 0.8 mg) followed by 48-mg full doses. To further mitigate CRS, C1 of the optimization cohort included mandatory administration of dexamethasone 15 mg as premedication on D1, D8, D15, and D22 and as prophylaxis on D2-4, D9-11, D16-18, and D23-25, and diphenhydramine and acetaminophen as premedication on D1, D8, D15, and D22 with each dose. In C1, it was strongly recommended that patients be well hydrated and that antihypertensive medications be held for 24 h prior to epcoritamab SC administration. Patients were also encouraged to monitor their temperatures following the first 4 doses. Hospitalization and inpatient observation were optional. The primary endpoint was rate of G2 or higher CRS and all CRS events. Secondary pharmacokinetic/pharmacodynamic (PK/PD) analyses were performed. Results: As of April 21, 2023, 24 patients (median age, 65 y) had been treated in this DLBCL optimization cohort. The median number of prior lines of treatment was 3 (range, 2-10), 75% of patients were primary refractory, 71% had stage IV disease, and 58% had prior CAR T. With a median follow-up of 1.3 mo, 18 patients (75%) remained on treatment. The most common treatment-emergent AEs (TEAEs) of any grade were infections (38%; COVID-19, 8%), fatigue (21%), CRS (17%), headache (17%), anemia (13%), constipation (13%), decreased platelet count (13%), dyspnea (13%), hyponatremia (13%), insomnia (13%), and neutropenia (13%; febrile neutropenia, 4%). All CRS events were G1; 1 patient was treated with anticytokine therapy (tocilizumab); there were no treatment discontinuations due to CRS. The most commonly observed CRS symptom was fever (100%). Most CRS events (3/5 events) occurred following the first full dose on C1D15. The median time to CRS resolution was 3.5 d (range, 1-25) and all events resolved. Compared with the DLBCL expansion cohort, circulating interleukin 6 (IL-6) levels were decreased 24 h after the first full dose (C1D15) of epcoritamab SC ( Figure). The median circulating IL-6 level at C1D16 was lower in the dose optimization cohort at 6.92 pg/mL (2.97 pg/mL at C1D1 predose), compared with 21.24 pg/mL (2.45 pg/mL at C1D1 predose) in the DLBCL expansion cohort. The addition of dexamethasone and fluids in optimization did not appear to interfere with T-cell margination or T-cell activation, given that the fold-change values of T-cell absolute counts and percentage of activated T cells were similar between DLBCL optimization and expansion cohorts at C1D16. No patients experienced ICANS, clinical tumor lysis syndrome, or fatal TEAEs. Conclusions: Encouraging preliminary data from this DLBCL CRS optimization cohort, which incorporates prophylactic dexamethasone and hydration of patients during cycle 1, indicate that this approach is effective in decreasing rates and severity of CRS. Data with additional patients and follow-up will be presented.

Outpatient Management of CAR-T and Teclistamab for Patients with Lymphoma and Multiple Myeloma

Background: Patients (pts) receiving FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy or Bispecific antibody Teclistamab (Tec) are commonly managed in the inpatient setting given the common adverse events such as cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome ICANS. We have previously reported that hospital-based outpatient (HBO) management of pts receiving CAR-T is feasible and safe (Bansal et al, ASH2022). In 2023, HBO management at our institution began incorporating home health visits and management of grade 1 CRS in outpatient setting for select pts receiving standard of care (SOC) CAR-T. Here, we report outcomes of our updated practice. Methods: We retrospectively analyzed medical records and remote monitoring data of adult pts who received SOC CAR-T or Tec between 10/2020 and 7/2023 at Mayo Clinic, Rochester under an IRB approved protocol. Results: In 3/2023, pts deemed to be low risk for severe CRS (fever onset >= 3 days from infusion, CRP<100) received HBO management for grade 1 CRS, including outpatient administration of tocilizumab. If CRS improved or resolved, outpatient monitoring was continued. If CRS persisted within the observation period on HBO, pts were admitted. Recurrent CRS after the first episode were all managed inpatient. Nine pts met these criteria for HBO CRS management and their outcomes were compared to those who received initial inpatient (INPT) CRS management (INPT, n=17) during the same timeframe, as well as the outcome of 164 pts who had CRS management INPT prior to our practice change (Table 1). Two-third of the pts with initial management of CRS outpatient did not require hospitalization. Median time to hospitalization trended later than those managed inpatient at the onset of CRS. The duration of hospitalization was comparable for all pts admitted between initial HBO and INPT CRS management. However with fewer admissions in the initial CRS HBO group, the average hospitalization days (LOS) per patient treated for that group was lower compared to initial INPT CRS management. Data on additional pts will be presented at ASH. In 1/2023, pts on RPM with no ongoing CRS symptoms, no language barriers, and no compliance concerns received home health visits during weeks 3 and 4 post CAR-T infusion in place of clinic visits on HBO. Home health visit team communicated with HBO staff to review assessment and plan. Changes in HBO utilization will be presented. Finally, 24 pts received 223 Tec infusions on HBO. Median age was 66 years, 15 (61%) were males, 9 (38%) had high risk cytogenetics. The median prior lines of therapy was 5. Among these pts, 220/223 (99%) doses were performed on HBO and 204/220 (93%) infusions never required admission for management. Twenty pts enrolled in RPM (Figure 1). An average of 2 alerts were generated per patient during the 2 week period and median time from infusion to alert was 1.5 days. Majority of alerts were resolved over a phone call and only 13/114 (11%) alerts required a physician visit/hospital admission. Of the 16 Tec infusions resulting in admission, 4/16 (25%) required re-admission resulting in a total of 20 hospitalizations. Admissions mostly occurred during step-up dosing (18/20; 90%). Most common reason for first admission was fever (13/16, 85%) and median time to admission was 1 day from infusion. Median LOS was 1.5 days (range, 0-12). In terms of CRS, majority were Grade 1 (12/13, 93%) which were managed with steroids (dexamethasone/ prednisone) alone. One patient had CRS grade 4 event, in the setting of concurrent decompensation during dialysis, and was treated with steroids, tocilizumab, vasopressor, CRRT, thoracentesis, intubation and mechanical ventilation. The rate of second CRS event after management of first CRS with steroid (dexamethasone/ prednisone) was 15% (2/13). These second CRS episodes also resolved with steroid alone. Data on additional pts receiving Tec will be presented at ASH. Conclusion: Our data showed that additional advances in outpatient practice, including initial outpatient management of CRS and outpatient administration of Tec step up dosing are feasible, safe and reduce hospital resource utilization.

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.

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.

Alnuctamab (ALNUC; BMS-986349; CC-93269), a 2+1 B-Cell Maturation Antigen (BCMA) × CD3 T-Cell Engager (TCE), Administered Subcutaneously (SC) in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from a Phase 1 First-in-Human Clinical Study

Introduction : ALNUC, a 2+1 TCE with bivalent binding to BCMA, is under investigation in a phase 1 trial (NCT03486067) in pts with triple-class exposed RRMM previously treated with ≥ 3 lines of therapy (LOTs). IV-administered ALNUC demonstrated durable responses (median duration of response, 33.6 mo). However, due to a high frequency of cytokine release syndrome (CRS; 76% of pts), including grade ≥ 3 events (7% of pts), the trial pivoted to SC administration of ALNUC. This resulted in a markedly improved safety profile, allowing escalation to higher target doses, while showing promising antitumor activity (Wong SW et al. EHA 2023. Abstract P883). We present updated data for SC ALNUC in pts with RRMM treated in the phase 1 study. Methods : Pts with RRMM who had received ≥ 3 LOTs, including an immunomodulatory drug (IMiD ®), a proteasome inhibitor, and an anti-CD38 therapy, were eligible. SC ALNUC was given on day (D) 1, 4, 8, 15, and 22 of cycle 1 (C1), QW in C2-3, Q2W in C4-6, and Q4W in C7 and beyond (28-d cycles). Step-up doses were given on C1D1 (3 mg) and C1D4 (6 mg), and target doses (10, 15, 30, or 60 mg) on C1D8 and thereafter. Target doses of 10, 30, and 60 mg were tested in dose expansion. Safety and tolerability were primary objectives. Secondary objectives included preliminary efficacy and pharmacokinetics. The data cutoff for the results included herein was Apr 3, 2023; updated data will be presented. Results : Of 73 pts treated with SC ALNUC in dose escalation (target dose: 10 mg, n = 6; 15 mg, n = 4; 30 mg, n = 6; 60 mg, n = 7) and dose expansion (target dose: 10 mg, n = 19; 30 mg, n = 21; 60 mg, n = 10), median age was 64 y; 58% were male. Pts had median of 4 prior regimens (range, 3-14); 96% were refractory to last LOT, 100%/78% had triple-class/penta-drug exposed MM, and 63%/19% had triple-class/penta-drug refractory MM. Median follow-up was 7.4 mo (range, 0.5-19.9). All-grade/grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 99%/81% of pts; most common were CRS (56%/0%), neutropenia (55%/45%), anemia (47%/27%), and thrombocytopenia (37%/16%). All-grade/grade ≥ 3 infections occurred in 62%/16% of pts; infections occurring in ≥ 10% of pts were COVID-19 (23%/3%) and upper respiratory tract infections (12%/0%). Infections of special interest included grade 2 cytomegalovirus reactivation in 1 pt (1.3%); there were no grade ≥ 3 infections of special interest. Median time to CRS was 3 d (range, 1-20), with a median duration of 2 d (range, 1-11). CRS was most common after the first step-up dose (40% of pts). Of 887 doses administered at the fourth dose and beyond, the frequency of CRS per dose was < 1%. Two pts had grade 1 neurotoxicity suspected related to SC ALNUC; no grade ≥ 2 neurotoxicity was observed. One pt discontinued treatment due to a TEAE (grade 3 metastatic colon cancer not suspected related to treatment); 1 treatment-related death (cerebral hemorrhage) occurred at the 60-mg target dose. Overall response rate (ORR) was 54% (39 of 72 efficacy-evaluable pts treated with SC ALNUC) across all doses, with responses deepening over time (Figure). ORR was 63% (27/43) at target doses ≥ 30 mg and 69% (18/26) at the 30-mg target dose. Median time to response was 1.2 mo (range, 0.9-4.0) and 77% (30/39) of responses were ongoing at data cutoff. Among efficacy-evaluable pts, median PFS was 10.1 mo (95% CI, 2.8-16.6) across all dose levels. For the 30-mg target dose, at a median follow up of 9.3 mo, median PFS was not reached (95% CI, 4.7-NA) with a 12-mo PFS of 53% (95% CI, 30-71). Among the 39 pts who achieved a response, 28/28 pts (100%) with evaluable minimal residual disease (MRD) samples were MRD-negative (10 −5 sensitivity by flow cytometry) at C2D1, C4D1, C6D1, or C8D1; of the 18 pts who achieved a response at the 30-mg target dose, 14/14 pts (100%) with available MRD data were MRD-negative. Preliminary population pharmacokinetic analysis estimated ~60% SC ALNUC bioavailability with a 14-d half-life. Observed trough concentrations at the 30-mg target dose exceeded levels predicted for efficacy by C2D1. Hallmark pharmacodynamic effects of TCEs were observed. Conclusions : SC ALNUC continued to demonstrate a safety profile consistent with the drug class and a low rate of severe infections. Across doses, responses were durable and deepened over time, with a high proportion of responders achieving MRD negativity. High antitumor activity was observed at target doses ≥ 30 mg and specifically at the 30-mg target dose. Enrollment in the phase 1 study is ongoing.

Mosunetuzumab Monotherapy Demonstrates Activity and a Manageable Safety Profile in Patients with Relapsed or Refractory Richter's Transformation

Background: Richter's transformation (RT) is characterized by the development of chronic lymphocytic leukemia to an aggressive lymphoma, most commonly CD20+ large B-cell lymphoma. RT remains an unmet medical need with a poor prognosis and no standard of care. Mosunetuzumab is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. In a Phase I/II study (NCT02500407), fixed-duration mosunetuzumab monotherapy demonstrated notable efficacy and a manageable safety profile in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (Bartlett et al. Blood Advances 2023). We report the efficacy and safety of mosunetuzumab monotherapy in patients with R/R RT after a median follow-up of 8.7 (range: 1-37) months. Methods: Eligible patients with R/R RT and ≥1 prior therapies were enrolled. Patients with lymphocyte counts of ≥5000/µL were excluded. Mosunetuzumab was administered intravenously in 21-day cycles with step-up dosing in Cycle (C) 1 (C1 Day [D] 1, 1mg; C1D8, 2mg; C1D15/C2D1, 60mg; C3D1 and onwards, 30mg). Hospitalization for treatment was not required. Patients achieving a complete response (CR) by C8 completed treatment without additional cycles; patients with a partial response (PR) or stable disease received a total of 17 cycles. The primary endpoints were safety and tolerability. Efficacy was a secondary endpoint and was assessed according to Cheson 2007 criteria. Cytokine release syndrome (CRS) events were graded using the American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: Twenty patients with R/R RT were enrolled. Median age was 70 (range: 49-87) years, 95.0% of patients had Ann Arbor stage III/IV disease, and 70.0% had an International Prognostic Index score of ≥3. Median number of prior therapies was 2.5 (range: 1-10), 65.0% of patients had ≥2 prior therapies, and 45.0% had received prior treatment with a Bruton tyrosine kinase inhibitor. Overall, 80.0% of patients were refractory to their last therapy. Investigator-assessed overall response and CR rates were 40.0% and 20.0%, respectively. Of four patients with a CR, two had a CR ongoing for ≥20 months at data cut-off (duration of CR [DOCR] at data cut-off: 21.2 months [patient had disease progression at a later timepoint] and 34.2 months), and the other two patients had received a subsequent stem-cell transplant (DOCR with mosunetuzumab: 0.1 and 4.2 months) ( Figure). The four patients with a PR had individual durations of response of: 1.7, 2.1, 2.3, and 2.8 months. The most common adverse event (AE) was CRS (65.0%), and events were predominantly Grade (Gr) 1 (20.0%) or Gr 2 (40.0%); a Gr 3 event was reported after C1D15 in one patient (5.0%). CRS was primarily associated with treatment administration during C1 (C1D1, 15.0%; C1D15, 50.0%); a Gr 1 CRS event was reported in one patient (5.0%) during C2. Of the 14 patients with CRS, six (42.9%) received tocilizumab, three (21.4%) received low-flow oxygen, one (7.1%) received a single pressor, and four (28.6%) received steroids; of the patients who received steroids, two (14.3%) received both tocilizumab and steroids. One patient was admitted to the intensive care unit for the management of Gr 3 CRS. The median duration of CRS was 3 (range: 1‒9) days. All CRS events resolved. Neurologic AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and considered treatment-related, occurred in two patients (Gr 1 ICANS and Gr 2 lethargy, each n=1); both events resolved. ICANS occurred one day after a Gr 2 CRS event. No Gr 5 (fatal) AEs, or AEs leading to treatment discontinuation were reported. AEs of special interest included infections (35.0%), neutropenia (15.0%), thrombocytopenia (20.0%), and tumor flare events (10.0%). Conclusions: In patients with R/R RT, fixed-duration mosunetuzumab monotherapy demonstrates activity with durable responses and a manageable safety profile in a limited sample size of 20 patients. Treatment with mosunetuzumab warrants further study in this patient population with a high unmet medical need.

Glofitamab Plus R-CHOP Induces High Response Rates with a Manageable Safety Profile in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A 12-Month Analysis from a Phase Ib Study

Background: Over a third of patients (pts) with DLBCL do not respond or relapse after first-line (1L) treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; Sarkozy and Sehn. Ann Lymphoma 2019); these pts have limited curative options. Glofitamab (Glofit) is a T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format that allows bivalent binding to CD20 on B cells; this enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy has shown durable responses in pts with relapsed/refractory DLBCL (Dickinson et al. NEJM 2022). In the safety run-in and expansion phases of the ongoing NP40126 trial (NCT03467373), Glofit + R-CHOP demonstrated promising efficacy and manageable safety in pts with 1L DLBCL (Topp et al. ASH 2022). Here, we report durability of response beyond 12 months in Glofit + R-CHOP-treated pts with 1L DLBCL from the NP40126 trial. Methods: Pts received R-CHOP for 6-8 three-weekly cycles. Intravenous Glofit was given with step-up dosing during Cycle (C)2 (Day [D]8, 2.5mg; D15, 10mg) and at the target dose (30mg) from C3D8 onwards. Glofit maintenance was allowed for up to one year. Efficacy was analyzed in all pts who had been on the study long enough to have a protocol scheduled end-of-treatment response assessment. Safety was analyzed in all pts who received at least one dose of any study drug. Response was assessed by PET-CT using Lugano criteria (Cheson et al. JCO 2014). Cytokine release syndrome (CRS) events were graded using the American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019) and other adverse events (AEs) by the Common Terminology Criteria for Adverse Events (v4.0). Hospitalization was not mandated for Glofit. Results: As of April 4, 2023, 56 pts were enrolled in this cohort. Median age was 68 years (range: 21-84), 54 pts (96.4%) had Ann Arbor stage III/IV disease, and median International Prognostic Index (IPI) score was 3 (IPI 1: 3.6% [2/56], IPI 2: 33.9% [19/56], IPI 3: 35.7% [20/56], IPI 4: 23.2% [13/56], IPI 5: 3.6% [2/56]). The cell of origin was germinal center B-cell (GCB) in 25 (44.6%) pts and non-GCB in 11 (19.6%) pts. After 17.1 (range: 0-26) months of median follow-up, the best overall response rate was 92.9% (52/56) and the complete metabolic response (CMR) rate was 83.9% (47/56). Median time to CMR was 1.8 months (95% confidence interval [CI]: 1.6-4.7). Most CMRs (44/47; 93.6%) were ongoing at data cut-off ( Figure). Among complete responders, the Kaplan-Meier estimated probability of ongoing responses at 12 months was 91.5% (95% CI: 82.2-100). Median duration of response and duration of complete response were not reached at data cut-off. The incidence of AEs and serious AEs (SAEs) were similar compared with earlier analyses. Grade (Gr) ≥3 AEs occurred in 42 (75.0%) pts and Gr ≥3 AEs related to Glofit in 14 (25.0%) pts. SAEs were reported in 20 (35.7%) pts and SAEs related to Glofit in six (10.7%) pts. Gr 5 AEs were reported in four (7.1%) pts (COVID-19 pneumonia, n=3; infusion related reaction associated with rituximab, n=1). AEs leading to dose interruption of Glofit occurred in 12 (21.4%) pts. Median dose intensity was 100% for all R-CHOP components. AEs leading to discontinuation of Glofit occurred in one (1.8%) patient. CRS events were reported in six (10.7%) pts: Gr 1, n=4; Gr 2, n=2; no Gr 3/4 CRS events were reported. All CRS events occurred during C2-3. Tocilizumab was used in two (33.3%) pts with CRS. Neurologic AEs (NAEs) occurred in 23 (41.1%) pts (most common NAEs (>5%) were peripheral neuropathy, n=7 [12.5%]; paraesthesia, n=5 [8.9%]; insomnia, n=4 [7.1%]; headache, n=3 [5.4%]); Gr 3 NAEs included cerebrovascular accident (n=1) and herpes zoster (n=1). No Glofit-related NAEs consistent with immune effector cell-associated neurotoxicity syndrome were reported. Neutropenia was reported in 26 (46.4%) pts (Gr ≥3 neutropenia: Gr 3, n=5; Gr 4, n=19). Infections and infestations were reported in 27 (48.2%) pts (of which the majority were Gr ≤2 [17/27]); Gr 3, n=7; Gr 5, n=3. Conclusions: Glofit + R-CHOP had a manageable safety profile with a low incidence of CRS, and continued to demonstrate durable responses with an improved CMR rate since the last data cut-off. These findings support the potential for favorable long-term outcomes with Glofit + R-CHOP as 1L treatment of DLBCL. Further analyses, including circulating tumor DNA data, will be presented.

Double Step-up Dosing (2SUD) Regimen Mitigates Severe Icans and CRS While Maintaining High Efficacy in Subjects with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL) Treated with AZD0486, a Novel CD19xCD3 T-Cell Engager (TCE): Updated Safety and Efficacy Data from the Ongoing First-in-Human (FIH) Phase 1 Trial

Background: AZD0486 (formerly TNB-486) is a novel, IgG4 fully human CD19xCD3 bispecific TCE incorporating a unique low affinity anti-CD3 moiety designed to reduce cytokine release while retaining potent T-cell mediated cytotoxicity of malignant B cells. A silenced Fc prevents nonspecific binding, antibody-dependent cellular cytotoxicity, and confers a long half-life suitable for intermittent administration. Preliminary clinical activity in Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) was reported [ Hou et al, Blood 2022; Jacobs et al, HemaSphere 2023] following fixed and single step-up dosing (1SUD). We now present focused updated safety data following implementation of 2SUD in the ongoing FIH phase 1 study (NCT04594642). Methods: Patients with R/R CD19+ B-NHL failing ≥2 prior lines of therapy, including prior CD19 CART and/or CD20 TCE, were enrolled. AZD0486 was administered in escalating doses in either no SUD (Day (D)1, D15 0.03-2.4mg), 1SUD (D1 0.27-1 mg, D15 2.4-10 mg), or 2SUD (D1 0.27 mg, D8 1 mg, D15 2.4-7.2 mg, FL/DLBCL only) schedules. AZD0486 was given IV every 2 weeks in 28D Cycles (C) up to 2 years. Monthly dosing was considered for patients in complete response (CR) at C6. Responses were assessed by RECIL 2017 by Central Imaging Review, AEs by CTCAE v5.0, and CRS/ICANS by 2019 ASTCT criteria. Results: As of 03 July 2023, 62 patients (27 DLBCL, 25 FL, 5 mantle cell lymphoma, 4 marginal zone lymphoma, 1 other) received AZD0486 and were evaluable for safety. Median age was 68 (range 22-86), with 58% male, 81% stage III/IV. Median prior lines of therapy was 3 (range 2-16) including 23 (37%) failing CART and 3 (4.8%) failing CD20 TCE. Fifteen (24%) were CD20 negative at study entry. The complete response (CR) rate was 91% (10/11) in patients with FL treated in 2.4 mg dose cohorts and for all FL efficacy evaluable subjects dosed at 2.4mg or above, CR was achieved in 14/17 (83%) with an overall response rate (ORR) of 88%. Median duration of response (DOR) has not beenreached. With the implementation of 2SUD regimen, no Grade 3+ CRS or ICANS events were observed (Table 1). Grade 1-2 CRS events decreased from 62.5% to 22.2% (fixed/1SUD, 15/24 and 2SUD, 4/18). Grade 1-2 ICANS events decreased from 20% (5/24) to 5.6% (1/18), presented mainly as confusion, and typically resolved in 1-2 days. The most common AEs (occurring in >20%) of any grade and regardless of drug causality were CRS (48%), anemia (34%), neutropenia (32%), lymphopenia (29%), ICANS (27%) and decreased WBC (20.9%). Treatment-related events of Grade ≥3 included lymphopenia (24%), neutropenia (15%), ICANS (9.7%) and anemia (3.2%). No treatment related deaths were reported (1 death due to COVID19, unrelated) and no treatment-related AEs lead to discontinuation (1 patient discontinued due to COVID-19, unrelated). Preliminary analysis (TNF-a, IL-6, IL-8, IL-10) suggests a decrease in cytokine levels after target dose with 2 SUD compared to fixed dosing and 1SUD, regardless of target dose. Conclusions: AZD0486 (formerly TNB-486) is an active treatment in patients with advanced R/R B-NHL and has a predictable safety profile characterized by mainly low-grade AEs and fully transient and reversible CRS/ICANS events. The 2 SUD schedule reduced the overall rate of low grade CRS and ICANS (Grade 1-2) and abrogated Grade 3 events further improving the risk/benefit profile of AZD0486. Dose escalation is ongoing to identify the RP2D.

Dexamethasone is Associated with a Lower Incidence and Severity of Cytokine Release Syndrome Compared with Other Corticosteroid Regimens When Given as Premedication for Glofitamab Monotherapy in Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Background: Glofitamab, a CD20xCD3 T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format, induced frequent and durable complete responses (CRs) with a manageable safety profile in pivotal expansion cohorts of an ongoing Phase I/II study (NCT03075696) in patients (pts) with R/R LBCL (Dickinson et al. NEJM 2022, Falchi et al. ASCO 2023). Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation that can be triggered non-specifically by T-cell engaging therapies. As previously reported, corticosteroid (steroid) premedication was required to prevent or mitigate CRS in pts treated with glofitamab. Dexamethasone (Dex) was mandated in one expansion cohort to assess if this could reduce the rate and severity of CRS versus other steroids. Here, we report data from the dose-escalation and expansion cohorts in pts with R/R LBCL who received Dex only versus non-Dex premedication. Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [DLBCL NOS], high-grade B-cell lymphoma [HGBCL], primary mediastinal LBCL [PMBCL], or LBCL arising from follicular lymphoma [trFL]) and ≥2 prior therapies received 1000mg obinutuzumab pretreatment (Gpt) 7 days prior to the first glofitamab dose. IV glofitamab was administered with step-up dosing during Cycle (C) 1 (Day 8, 2.5mg; Day 15, 10mg) followed by the target dose (30mg) on Day 1 of C2-12 (21-day cycles; 8.4 months). Steroid premedication (80mg IV methylprednisolone, or equivalent dose of prednisone [100mg] or prednisolone [100mg], or 20mg IV Dex) was given at least 60 minutes prior to Gpt and each glofitamab dose. Responses were assessed using Lugano criteria (Cheson et al. JCO 2014). CRS events were graded by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of May 1, 2023, 145 pts with R/R LBCL had received glofitamab, including 33 (22.8%) pts (DLBCL NOS, n=24 [72.7%]; HGBCL, n=2 [6.1%]; trFL, n=7 [21.2%]) who received Dex premedication before each glofitamab dose (Dex only cohort) and 112 (77.2%) pts (DLBCL NOS, n=81 [72.3%]; HGBCL, n=5 [4.5%]; PMBCL, n=6 [5.4%]; trFL, n=20 [17.9%]) who had not received Dex premedication before each glofitamab dose (non-Dex cohort). In the Dex only and non-Dex cohorts, median age was 73.0 years (range: 27-86) and 66.0 years (range: 21-90), and 26/33 (78.8%) pts and 83/112 (74.1%) pts had Ann Arbor stage III/IV disease, respectively. Median number of prior therapies was 3.0 for both cohorts. Ten (30.3%) and 37 (33.0%) pts had previously received chimeric antigen receptor T-cell therapy, and 6 (18.3%) and 22 (19.6%) pts had received autologous stem cell transplant in the Dex only and non-Dex cohorts, respectively. Median number of glofitamab cycles was 5.0 in both cohorts. CRS of any grade occurred in 48.5% of pts in the Dex only cohort and 73.2% of pts in the non-Dex cohort, and CRS leading to serious adverse events occurred in 5 (15.2%) and 27 (24.1%) pts, respectively. In both cohorts, CRS events were mostly low grade and primarily occurred during C1 (Table; Figure). Recurring Grade (Gr) ≥2 CRS was not observed in the Dex only cohort and 6 (5.4%) pts had recurring Gr ≥2 CRS in the non-Dex cohort. Median time to CRS onset and median time to resolution were similar in the two cohorts. Treatment discontinuation rate was lower in the Dex only cohort (n=21, 63.6%) versus the non-Dex cohort (n=80, 71.4%), mainly due to progressive disease (Dex only cohort, n=12 [36.4%]; non-Dex cohort, n=52 [46.4%]). In the DLBCL NOS and trFL population, the best overall response assessed by Independent Review Committee was similar between the Dex only (n=31) and non-Dex (n=101) cohorts, with CR reported in 14 (45.2%) and 44 (43.6%) pts, and 12 (38.7%) and 34 (33.7%) pts remaining in CR at data cutoff, respectively. The estimated event-free rate among complete responders at 12 months after the first CR was 83.1% (95% CI: 61.5-100.0) in the Dex only cohort and 77% (95% CI: 63.8-90.2) in the non-Dex cohort. Conclusions: The incidence, severity, and seriousness of CRS after glofitamab administration in pts with R/R LBCL were numerically lower with Dex premedication versus premedication with other steroid regimens. Response rates in the Dex only cohort were similar to those reported in the non-Dex cohort. We therefore propose Dex as the steroid of choice for premedication to prevent or mitigate CRS in pts with LBCL treated with glofitamab monotherapy, considering its half-life and potency.