Initial Results from a Phase 1 Study of TQB2934, a BCMA × CD3 Bispecific Antibody, As Monotherapy in Patients with Relapsed/Refractory Multiple

Introduction: Despite significant advances in the treatment of multiple myeloma, triple-class-exposed (TCE) and triple-class-refractory (TCR) patients still have a poor prognosis. Immunotherapies targeting B-cell maturation antigen (BCMA) have shown promise in treating relapsed/refractory multiple myeloma (RRMM). TQB2934 is a 2+1 BCMA × CD3 bispecific antibody with bivalent BCMA domains and monovalent CD3 domain that targets both BCMA-expressing MM cells and CD3-expressing T cells leading to T cell activation and resulting in subsequent myeloma cell death. Here we report initial safety and efficacy results of TQB2934 as a single agent in patients with RRMM from an ongoing phase 1 first-in-human study. Methods: TQB2934-I-01 is an open-label, phase 1 dose escalation and expansion study (NCT05646758). Pts with RRMM aged 18-75 years who had received ≥ 1 standard-of-care regimens, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 agent, were eligible. Patients who received prior BCMA-targeted therapies were excluded from the dose escalation cohort. The study used a Bayesian Optimal Interval design for dose escalation. TQB2934 was administered intravenously QW in C1-3, Q2W in C4-6, and Q4W in C7 and beyond in patients who had achieved a partial response (PR) or better (28-day cycles). Patients received 2 step-up doses 1 week before target doses at 3mg, 10mg, 20mg, and 40mg dose levels. The primary objectives were to assess the safety and tolerability and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) based on dose-limiting toxicity (DLT). The secondary objectives were to assess preliminary anti-myeloma activity and characterize the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed per American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS and ICANS. DLT and other adverse events were assessed per National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. The response was assessed per the International Myeloma Working Group 2016 criteria. Results: As of July 18, 2024, a total of 21 patients with RRMM were enrolled and treated with TQB2934. Among 19 evaluable patients, the median age was 67 years (range 51-75); 53% were female; 84% had a stage of II/III per Revised International Staging System (R-ISS); 63% had at least high-risk cytogenetic abnormality and 42% had extramedullary disease. Patients received a median of 3 prior regimens (range 2-5); all patients had myeloma refractory to the last line of treatment; 95%/37% had TCE/TCR myeloma. TQB2934 doses ranged from 0.09 to 40mg; the median duration of treatment was 1.3 months (range 0.2-12.0) and 6 patients (32%) were continuing TQB2934 treatment. Any grade/grade 3-4 treatment-emergent adverse events (TEAE) were reported in 90%/74% of treated patients. The most common (≥30%) any grade/grade 3-4 treatment-related adverse events (TRAE) were CRS (68%/5%), leukopenia (58%/16%), anemia (53%/26%), thrombocytopenia (47%/26%), lymphopenia (42%/26%), fever (42%/0) and neutropenia (37%/16%). 1 pt reported grade 3 CRS at 3mg without step-up doses while no patients with step-up doses at ≥3mg dose levels experienced ≥grade 3 CRS. CRS occurred most frequently with the first target dose and lasted no more than 3 days. Infections were reported in 47% of patients including pneumonia (21%). MTD has not been reached yet. Of the 19 evaluable patients across all dose levels, 6 patients achieved a partial response or better (the overall response rate, 31.6%), including 4 (21.1%) with a very good partial response (VGPR) or better and 2 (10.5%) with a complete response (CR) or better. No pts achieved response at <3mg dose levels. ORR, ≥VGPR, and ≥CR at ≥10mg dose levels were 50.0%, 25.0%, and 12.5%, respectively. Among pts without extramedullary disease at baseline, ORR and ≥VGPR were 80.0% and 40.0%, respectively. Conclusions: TQB2934, a 2+1 BCMA bispecific antibody, has shown manageable safety profiles and encouraging clinical activity at higher doses in patients with heavily pretreated RRMM. These results support further clinical evaluation and enrollment in the phase 1 study is ongoing.