Rodriguez, Cesar

Abstract Background Etentamig is a second-generation B-cell maturation antigen (BCMA) x CD3 bispecific antibody that has shown promising efficacy and a favorable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). Etentamig possesses a unique combination of 2 high-affinity BCMA binding domains, coupled to a low-affinity CD3 binding domain that have been shown to reduce the negative impact of soluble BCMA (sBCMA), decrease risk for cytokine release syndrome (CRS), and drive sustained T-cell activation with reduced immune exhaustion in preclinical models of MM (Blood 2023;142 [suppl 1]:4666). Here, we describe correlative biomarker analyses from Phase 1 (NCT03933735) and Phase 1b (NCT05650632) clinical trials of etentamig in RRMM designed to assess the impact of sBCMA on clinical response and pharmacodynamic changes in proinflammatory cytokines, and T-cell redistribution, activation, proliferation, and exhaustion. Methods Peripheral blood and serum samples from patients with RRMM enrolled in Phase 1 and Phase 1b open-label studies who received etentamig monotherapy were collected at baseline, on treatment, and at disease progression. The Phase 1b study consisted of dose-optimization (DO) and dose-expansion (DE) phases. During DO, patients received a single step-up dose (SUD) of intravenous etentamig (2 or 4 mg) on Cycle (C) 1 Day (D) 1, followed by the target dose of 60 mg on D4. In DE, based on DO findings, patients received the recommended etentamig SUD (2 mg) on C1D1, followed by 60 mg on D4 with modified dexamethasone predosing. Samples were analyzed by flow cytometry for immune cell populations, Luminex® for cytokines, and electrochemiluminescence for sBCMA. Peripheral blood mononuclear cells and bone marrow mononuclear cells (BMMC) at baseline and on-treatment were subjected to single-cell Cellular Indexing of Transcriptomes and Epitopes sequencing (scCITEseq) and single-cell T-cell receptors (scTCR) / B-cell receptors clonality analyses. Results While baseline serum sBCMA levels did not correlate with clinical response to etentamig at the selected dose level of 60 mg every 4 weeks (Q4W) with 2 mg SUD, a reduction in sBCMA levels over time was associated with best International Myeloma Working Group response. Etentamig treatment led to a rapid and transient increase of proinflammatory cytokines and promoted T-cell redistribution, activation, and proliferation. Maximum reduction in peak levels of CRS-related cytokines, including (interleukin [IL]-6, IL-8, IL-10, tumor necrosis factor–a), were observed in DE compared with DO and 60 mg Q4W without SUD. Peak induction levels of proinflammatory cytokines during C1 correlated with occurrence of CRS (≥Grade [G] 1) as well as clinical response across dose levels. A modified dexamethasone premedication schedule of 2 mg/60 mg Q4W cohort for C1 resulted in significantly reduced baseline levels of IL-6 and key macrophage-associated cytokine/chemokines (eg, monocyte chemoattractant protein-1 and macrophage inflammatory protein-3 beta). Incidence of CRS was lowest in the 2 mg/60 mg Q4W cohort (26% G1, 4% G2, 0% ≥G3). Higher T-cell to myeloma cell ratio in BMMCs at baseline correlated with better response to etentamig. scCITEseq and scTCR analysis revealed that at baseline, responders also had greater CD8+ T-cell cytotoxic activities, increased TCR clonality, and elevated inflammatory signatures in T-cells from both peripheral blood and bone marrow. Etentamig at a dosage of 60 mg Q4W resulted in significant clonal expansion of CD8+ effector T-cells and enhanced gene expression signatures related to activation and cytotoxicity in both CD8+ T effector and natural killer cells. Along treatment cycles, responders maintained their T-cell fitness, high clonality, and low T-cell exhaustion levels. Frequency of baseline CD4+ or CD8+ T-cell exhaustion (programmed cell death receptor 1+/ T cell immunoglobulin and mucin-domain containing-3 +) did not impact clinical response at optimal dose level of 2 mg/60 mg Q4W etentamig. Conclusions Responses to etentamig were independent of baseline sBCMA levels and resulted in rapid and transient proinflammatory cytokine production that promoted robust T-cell redistribution, activation, and proliferation indicating that the optimal dose of etentamig (2 mg/60 mg Q4W) maximizes its clinical potential as a convenient, safe, and effective therapy for MM.

Introduction ABBV-383 is a differentiated BCMA x CD3 bispecific antibody (fully humanized IgG4) T-cell engager composed of a bivalent BCMA binding domain with high avidity, a low-affinity CD3-binding domain, and a present but silenced-Fc tail retaining the FcRn binding allowing for an extended half-life and thereby, enabling dosing convenience. ABBV-383 monotherapy has shown promising activity and improved CRS safety profile with modified dexamethasone (Dex) premedication in patients (pts) with RRMM (NCT03933735; Rodriguez et al., JCO 2024;42[suppl 16]:7531). Here, ER and CRS PK/PD analyses supporting the selection of optimal SUD for ABBV-383 are reported. Methods ER-efficacy (N=286) and -safety (N=290) analyses were conducted using logistic regression methodology (R version 4.3.2) combining data from escalation (0.025-120 mg Q3W) and expansion (20, 40, 60 mg Q3W and 60 mg Q4W) cohorts of phase 1 study NCT03933735 and Arm A of phase 1b study NCT05650632 evaluating step-up dose (2 or 4 mg on Day 1) with a full dose (60 mg on Day 4) in pts with RRMM. Pts received modified Dex with full dose in expansion cohorts of 60 mg Q4W and 2/60 mg Q4W. In all other cohorts with or without SUD, pts received low Dex. Based on prior knowledge (JCO 2024;42[suppl 16]:7541), the safety endpoints (CRS: any-grade and ≥ G2) were modeled with Cycle 1 total (unbound + bound to soluble BCMA) Cmax, while objective response rate (ORR) was modeled with free (unbound + partially bound to soluble BCMA) Cavg. CRS ER models included a priori selected Dex (low vs. modified) and SUD (yes vs. no) as predictors. Relevant pt-specific covariates were tested in all models. CRS PK/PD analyses included total PK, IL-6, and CRS data (N=199) from the first 3 cycles of the above phase 1/1b studies. A semi-mechanistic indirect response PK/IL-6 model was developed to correlate total PK and IL-6 (NONMEM 7.5). Maximal IL-6 concentrations were derived using post hoc estimates from the PK/IL-6 model and correlated with CRS events (logistic regression; R version 4.3.2). The models included effects of time-dependent Dex (low vs. modified) and SUD (yes vs. no). The overall modeling approach was assessed by comparing observed and predicted CRS rates. Simulations were conducted for various dosing regimens, including one or two SUD and Dex premedication scenarios to support the selection of the optimal SUD. Results Consistent with clinical observations (separate abstract submission), any-grade CRS model predicted probabilities suggested two key outcomes: 1) premedication with modified Dex improves the CRS safety profile compared to the low Dex (42% vs 69% for 60 mg Q4W); 2) modified Dex with SUD further improves the CRS safety profile of ABBV-383 compared to low Dex with SUD (29% vs 43% for 2/60 mg Q4W). Consistent with prior work, no ER relationship was observed for ≥ G2 CRS (p > 0.05). The ORR model resulted in a predicted probability of 68% ORR (closely matching with overall observed 64% ORR) with no impact of SUD and modified Dex. Only soluble BCMA was selected as a covariate in the ORR ER model. The final semi-mechanistic PK/IL-6 model well captured the observed IL-6 data, and the CRS rates (predicted by the logistic regression models) closely matched with the observed data. The CRS PK/PD analyses findings were consistent with the clinical observations and ER analyses key outcomes 1 and 2. The CRS PK/PD analyses predictions comparing the 1-SUD vs 2-SUD (untested) regimens with modified Dex suggested that 1) among the 2-SUD regimens with modified Dex, the 2/3/60 mg regimen would have the maximum reduction of 4% points in any-grade CRS compared to the 2/60 mg 1-SUD regimen, however, with substantial overlap of confidence intervals and with no decrease in ≥ G2 CRS (< 0.5% point); 2) 4 mg as an intermediate SUD in a 2-SUD regimen would lead to higher any-grade and ≥ G2 CRS rates (~9% and 3% points higher, respectively), compared to the 2/60 mg Q4W regimen. Conclusions ER and CRS PK/PD analyses suggested that modified Dex and SUD improve the CRS safety profile of ABBV-383 with no impact on efficacy (ORR) in pts with RRMM. The CRS PK/PD predictions indicated that implementation of 2-SUDs provide minimal additional or no improvement in CRS safety profile compared to 1-SUD. Overall, the 1-SUD dosing regimen of 2 mg with modified premedication prior to the full dose of 60 mg Q4W showed promising results and can be considered for future evaluation and studies.

PURPOSE ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735 ) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. METHODS Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. RESULTS As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. CONCLUSION ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

Abstract Background Prognosis is poor for patients (pts) with relapsed/refractory multiple myeloma (RRMM; median overall survival: <1 year), indicating a clear need to identify agents with novel mechanisms of action. B-cell maturation antigen (BCMA) has recently emerged as a novel treatment target for MM due to its highly selective expression in plasma cells. TNB-383B, a BCMA x CD3 T-cell engaging bispecific antibody, was designed to overcome the toxicity limitations of existing BCMA therapies and has demonstrated promising results in an ongoing first-in-human phase 1 study in pts with RRMM (Rodriguez C, et al. Blood 2020;136[suppl 1]:43-44). Herein, we report the updated efficacy and safety outcomes of this phase 1 study. Methods This multicenter, phase 1, open-label, dose-escalation/expansion study (NCT03933735) enrolled pts with RRMM (≥3 prior lines of therapy that included a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody), estimated glomerular filtration rate ≥30 mL/min as calculated by the Modification of Diet in Renal Disease formula, and ECOG performance status ≤2. Prior BCMA-targeted therapy is prohibited. Primary objectives include safety/tolerability, pharmacokinetics (PK), and determination of recommended phase 2 dose (RP2D); secondary objectives include assessment of clinical activity (per IMWG criteria 2016). TNB-383B is administered intravenously over 1-2 hours every 3 weeks (Q3W) with the first dose administered inpatient. The study uses a 3+3 design with backfilling for dose and permits intrapatient dose escalation to highest safe dose. Dose expansion was initiated on selection of RP2D. Pts are treated until progression, unacceptable toxicity, or other discontinuation criteria are met. The efficacy-evaluable population includes all pts who received at least 1 dose of TNB-383B and have at least 1 postdose assessment. The safety population includes all pts who received at least 1 dose of study drug; adverse events (AEs) are graded according to NCI CTCAE v5.0. Results As of 10 May 2021, 103 pts (dose escalation, n=73; dose expansion, n=30) have been treated with TNB-383B (0.025-120 mg). The RP2D of 60 mg Q3W was selected on the basis of tolerability, safety, PK, and clinical activity. Pt demographics and baseline characteristics are summarized in Table 1. Three dose-limiting toxicities were reported in dose escalation (platelet count decreased: grade [Gr] 4, 60 mg; cytokine release syndrome [CRS]: Gr 3, 90 mg and 120 mg); none were reported as serious. Treatment-related AEs (TRAEs) were reported in 79 (77%) pts, with Gr ≥3 and serious AEs occurring in 33 (32%) and 23 (22%) pts, respectively. The most common TRAEs (Table 2) include CRS (n=54, 52%), neutropenia (n=18, 17%), and fatigue (n=14, 14%). At the RP2D (n=39), the Gr ≥3 CRS rate was 3% (n=1). Onset of CRS typically occurred on the same or next day following the first dose and all pts recovered using tocilizumab or standard supportive care measures. Treatment-emergent AEs (TEAEs) of infusion-related reactions were reported in 8 (8%) pts and infections occurred in 29 (28%) pts; pneumonia (n=5, 5%) and upper respiratory tract infection (n=4, 4%) were the most common. Five deaths from TEAEs were reported; all were unrelated to study drug. Forty-two (40%) pts discontinued treatment due to disease progression. In the dose-escalation cohorts of ≥40 mg Q3W (n=24), the objective response rate (ORR) was 79% (19/24), with a very good partial response or better (≥VGPR) rate of 63% (15/24), and a complete response (CR) rate of 29% (7/24) at the data cutoff date; these pts have the longest follow-up (ie, mature data) with median time on study of 6.1 months (Figure 1). At doses ≥40 mg in the combined dose-escalation and -expansion cohorts (n=44), the observed ORR, ≥VGPR, and CR rates were 64% (28/44), 43% (19/44), and 16% (7/44), respectively; these pts have shorter follow-up (ie, immature data) with median time on study of 3.1 months. Twenty-nine (66%) of the 44 pts administered ≥40 mg were triple-class refractory and reported an ORR of 55% (16/29). Conclusions TNB-383B in pts with RRMM is well tolerated with an ORR of 79% observed at doses ≥40 mg in the dose-escalation cohorts. Despite having a shorter follow-up period, this trend was also observed at doses ≥40 mg in the combined dose-escalation/expansion cohorts (ORR: 64%). Enrollment into the dose-expansion arm is ongoing; updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Kumar: Novartis: Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. D'Souza: Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Janssen, Prothena: Consultancy. Shah: Oncopeptides: Consultancy; Nektar: Research Funding; Poseida: Research Funding; Janssen: Research Funding; Indapta Therapeutics: Consultancy; GSK: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; CSL Behring: Consultancy; Teneobio: Research Funding; Kite: Consultancy; Sutro Biopharma: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy; Precision Biosciences: Research Funding; Sanofi: Consultancy. Rodriguez: Takeda: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau. Voorhees: AbbVie Inc, Bristol-Myers Squibb Company; Consulting Agreement: GlaxoSmithKline, Novartis, Oncopeptides: Other: Advisory Committee; Bristol-Myers Squibb Company.: Other: Data Safety & Monitoring. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Buelow: Teneobio, Inc.: Current Employment, Current holder of stock options in a privately-held company. Freise: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Yue: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Pothacamury: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Polepally: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria.

Background: BCMA targeted immunotherapy has yielded promising results for relapsed/refractory multiple myeloma (RRMM). TNB-383B is a BCMA x CD3 bispecific T-cell redirecting antibody incorporating a unique anti-CD3 moiety that preferentially activates effector over regulatory T-cells and uncouples cytokine release from anti-tumor activity, as well as 2 heavy-chain-only anti-BCMA moieties for a 2:1 tumor associated antigen to CD3 stoichiometry. Results from the ongoing phase 1 dose escalation and expansion First-in-Human (FIH) study of TNB-383B are presented (NCT03933735). Methods: Eligible patients have RRMM and have been exposed to at least 3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Patients have been treated with escalating doses of TNB-383B infused IV over 1-2 hours Q3W (without step-up dosing). The primary objectives are to determine the safety/tolerability and clinical pharmacology of TNB-383B and to identify the MTD/RP2D. The study used a 3+3 design for dose escalation, with additional patients enrolled on cleared dose levels. Patients on earlier dose cohorts were allowed to increase to the highest cleared dose with investigator consensus. Responses were assessed by IMWG criteria and Adverse Events (AEs) were graded according to CTCAE v5.0. Minimal residual disease (MRD) assessment was performed via NGS on bone marrow samples in patients achieving a complete response (CR). Results: As of 13 July 2020, 38 subjects have been dosed with TNB-383B (0.025 - 40 mg). Demographics and disease characteristics at study entry are summarized in Table 1. The most common Gr 3/4 AEs were anemia (6/38; 16%) and thrombocytopenia (5/38; 13%). The most common drug-related AEs were CRS (8/38; 21%) and headache (5/38; 13%). One case of Gr 2 CRS was observed at 0.075 mg; all other CRS events were seen at 5.4 mg and above. Cases of CRS were grade 1 (5/8) or 2 (3/8) and occurred only after the first dose of TNB-383B. All but 3 subjects were managed with fluids and acetaminophen (the other 3 received 1 dose each of tocilizumab). One DLT, Gr3 confusion that resolved within 6 hours without sequelae was seen at the 20 mg dose in an additional patient enrolled on this cohort. No IRRs were observed. Dose modification was necessary in 1 subject for Gr 3 neutropenia associated with CRS; the subject escalated to their full dose after tolerating subsequent doses without incident. 5 subjects died from their underlying disease during follow-up. 15 subjects discontinued treatment, all of them for progressive disease. Preliminary PK data support Q3W dosing of TNB-383B. Activity was observed in one patient each at 0.2 mg and 1.8 mg; at doses of 5.4 - 40 mg an ORR of 52% (12/23) was observed. Depth and duration of response are summarized in Table 2. Conclusions: TNB-383B is well tolerated at doses up to 40 mg, without the need for step/split dosing. A preliminary ORR of 52% (12/23) was observed at doses ≥ 5.4 mg, including deep (6 PR / 3 VGPR / 3 CR) and durable (up to 24 weeks) responses despite dosing only every 3 weeks. Enrollment into the dose escalation arm is ongoing; updated data will be presented at the meeting. Disclosures Rodriguez: BMS, Takeda, Amgen: Consultancy, Speakers Bureau. D'Souza:Amgen: Research Funding; Akcea: Consultancy; Pfizer: Consultancy; Teneobio: Research Funding; Imbrium: Consultancy; Merck: Research Funding; Janssen: Consultancy. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. Voorhees:Bristol-Myers Squibb: Other: Personal fees; Adaptive Biotechnologies: Other: Personal fees; Novartis: Other: Personal fees; Celgene: Other: Personal fees; Janssen: Other: Personal fees; Oncopeptides: Other: Personal fees; TeneoBio: Other: Personal fees; Levine Cancer Institute, Atrium Health: Current Employment. Buelow:Teneobio, Inc.: Current Employment, Current equity holder in private company. Kumar:Karyopharm: Consultancy; Tenebio: Other, Research Funding; Sanofi: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Merck: Consultancy, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Cellectar: Other; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding.