Teclistamab Population Pharmacokinetics and Exposure-Response Relationship Support 1.5 Mg/Kg Dose Regimen in Relapsed/Refractory Multiple Myeloma

Abstract

Background: Teclistamab (JNJ-64007957) is a B-cell maturation antigen (BCMA) × CD3 bispecific antibody that redirects CD3+ T cells to induce cytotoxicity of BCMA-expressing multiple myeloma (MM) cells. The objectives of this work were to develop a population pharmacokinetics (PK) model for serum teclistamab concentrations after intravenous (IV) infusion and subcutaneous (SC) administration, evaluate the effects of patients' demographic characteristics and other covariates (such as soluble BCMA [sBCMA]) on PK, and explore the exposure-efficacy/safety relationships in patients with relapsed/refractory MM (RRMM). Methods: Analyses were conducted using data from the phase 1/2 study MajesTEC-1 (NCT03145181/NCT04557098) in eligible patients with RRMM. A population PK model was developed using serum teclistamab concentrations from 338 patients who received IV (range, 0.0003-0.0192 mg/kg every 2 weeks and 0.0192-0.72 mg/kg weekly; n=83) or SC doses (range, 0.08 mg/kg weekly to 6 mg/kg [weekly in cycles 1-2, biweekly in cycles 3-6, monthly in cycle 7+]; n=255). Exposure-response (E-R) analyses for efficacy were evaluated based on the predicted exposure metrics (average concentration of the first treatment dose and trough concentration after the first 4 weekly treatment doses) on overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) at the recommended phase 2 dose (RP2D; 1.5 mg/kg teclistamab SC administered weekly with the first treatment dose preceded by step-up doses of 0.06 and 0.3 mg/kg) as well as 0.08 to 6 mg/kg SC doses in Phase 1. Safety E-R analyses were conducted based on the predicted maximum concentrations (after the first treatment dose and the first 4 weekly treatment doses) on Grade ≥3 treatment-emergent adverse events of anemia, neutropenia, lymphopenia, thrombocytopenia, and infection. Results: The PK of teclistamab was adequately described by a 2-compartment model with first-order absorption (associated with SC administration) and parallel time-independent (CL1) and time-dependent (CL2; decreased over time to reflect the change in tumor burden) elimination pathways. The covariate effects in the final model included the effect of body weight on CL1, volume of distribution in the central compartment (V1), and volume of distribution in the peripheral compartment (V2); the effects of International Staging System stage on CL1; and the effect of type of myeloma (IgG vs non-IgG) on CL1 and CL2. A rapid decrease in sBCMA was observed in the majority of responders within the first month of treatment. At 1.5 mg/kg, E-R for ORR was near flat, and DOR, PFS, and OS were not significantly correlated with teclistamab exposures. For 0.08 to 6 mg/kg SC doses in phase 1, a positive E-R relationship was observed for ORR and the response rate at the concentration range associated with 1.5 mg/kg weekly was approaching the plateau (or maximum response). No apparent positive E-R trend was observed in the incidence of grade ≥3 anemia, neutropenia, lymphopenia, thrombocytopenia, and infections across the predicted exposure quartiles in patients who received teclistamab SC. Conclusions: Teclistamab population PK following IV and SC dosing has been well characterized. The E-R analyses for ORR showed positive trend with a plateau at the RP2D, while there was no apparent E-R trend between teclistamab exposure and the grade ≥3 hematologic and infection treatment-emergent adverse events. These results support 1.5 mg/kg teclistamab SC weekly as the recommended dose regimen for the treatment of RRMM.