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

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.

Miao:Janssen: Current Employment. Wu:Johnson & Johnson: Current Employment. Wang Lin:Janssen: Current equity holder in private company, Ended employment in the past 24 months. Chen:Janssen Pharmaceuticals: Ended employment in the past 24 months. Iwaki:Janssen Pharmaceutical K.K. of Johnson and Johnson (Japan): Current Employment. Kobos:Janssen: Current equity holder in private company, Current holder of stock options in a privately-held company. Kemmerer:Janssen: Current Employment, Current holder of stock options in a privately-held company. Uhlar:Janssen R&D: Current Employment, Current equity holder in private company. Banerjee:Janssen R&D: Current Employment, Current equity holder in publicly-traded company. Goldberg:Janssen: Current Employment, Current equity holder in private company. Trancucci:Janssen: Current Employment. Verona:Janssen R&D, Johnson and Johnson: Current Employment. Pei:Janssen R&D: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Ouellet:Johnson & Johnson (Janssen): Current Employment, Current holder of stock options in a privately-held company; Abbvie: Current equity holder in private company; Pfizer Inc: Ended employment in the past 24 months. Garfall:Janssen, GSK, Amgen, Legend: Consultancy; Janssen: Other: Independent data monitoring committee; Janssen, Novartis, Tmunity, CRISPR Therapeutics: Research Funding. Krishnan:Takeda: Speakers Bureau; Amgen: Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Other: Stock Ownership (not including stocks owned in a managed portfolio), Speakers Bureau; Sutro: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Adaptive: Consultancy; Regeneron: Consultancy; Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy; Artiva: Consultancy; BMS, Janssen, Adaptive, GSK, AbbVie, Regeneron, Sanofi, AstraZeneca: Consultancy; BMS: Current equity holder in publicly-traded company; Janssen: Research Funding; Takeda, GSK, BMS: Speakers Bureau; Sutro SAB: Speakers Bureau. Usmani:Abbvie, Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Janssen,Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, TeneoBio: Consultancy; Amgen, BMS, Janssen, Sanofi: Speakers Bureau; Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, Takeda: Research Funding. Girgis:Janssen Research & Development, Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Zhou:Johnson & Johnson: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Elevar Therapeutics: Current Employment, Current equity holder in publicly-traded company.

at the time of abstract submission, teclistamab is being investigated for the treatment of multiple myeloma but is not yet not approved