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1911 Teclistamab Population Pharmacokinetics and Exposure-Response Relationship Support 1.5 Mg/Kg Dose Regimen in Relapsed/Refractory Multiple Myeloma

Program: Oral and Poster Abstracts
Session: 652. Multiple Myeloma and Plasma Cell Dyscrasias: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Biological therapies, Clinical Research, Plasma Cell Disorders, Diseases, Therapies, Lymphoid Malignancies
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Xin Miao1*, Liviawati S. Wu2*, Shun Xin Wang Lin1*, Yan Xu1*, Yang Chen1*, Yuki Iwaki3*, Rachel Kobos4, Tara Stephenson1*, Kristy Kemmerer1*, Clarissa M. Uhlar1*, Arnob Banerjee1*, Jenna D. Goldberg4*, Danielle Trancucci4*, Raluca Verona1*, Lixia Pei4*, Yaming Su4*, Daniele Ouellet1*, Alfred L. Garfall5*, Amrita Y. Krishnan, MD, FACP6, Saad Usmani, MD7, Suzette Girgis1 and Honghui Zhou1*

1Janssen Research & Development, Spring House, PA
2Janssen Research & Development, South San Francisco, CA
3Janssen Pharmaceutical KK, Tokyo, Japan
4Janssen Research & Development, Raritan, NJ
5Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
6City of Hope Comprehensive Cancer Center, Duarte, CA
7Memorial Sloan Kettering Cancer Center, New York, NY

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.

Disclosures: 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: Sutro SAB: Speakers Bureau; Takeda, GSK, BMS: Speakers Bureau; Janssen: Research Funding; BMS: Current equity holder in publicly-traded company; BMS, Janssen, Adaptive, GSK, AbbVie, Regeneron, Sanofi, AstraZeneca: Consultancy; Artiva: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding; Regeneron: Consultancy; Adaptive: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Sutro: Consultancy; Bristol Myers Squibb: Consultancy, Other: Stock Ownership (not including stocks owned in a managed portfolio), Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Usmani: Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen Pharmaceuticals, Merck, Pharmacyclics, Sanofi, Seagen Inc., formerly Seattle Genetics, Inc., SkylineDX, Takeda: Consultancy; AbbVie, Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Janssen Pharmaceuticals, Oncopeptides, Sanofi, Seagen Inc., formerly Seattle Genetics, Inc., Secura Bio, Inc., SkylineDX, Takeda, TeneoBio , Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen: Research Funding; Amgen, BMS, Janssen Pharmaceuticals, Sanofi: Speakers Bureau. 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.

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

*signifies non-member of ASH