Population Pharmacokinetics and Exposure–Response with Teclistamab in Patients With Relapsed/Refractory Multiple Myeloma: Results From MajesTEC-1.

Background: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. Objective: We report the population pharmacokinetics of teclistamab administered intravenously and subcutaneously (SC) and exposure–response relationships from the phase I/II, first-in-human, open-label, multicenter MajesTEC-1 study. Methods: Phase I of MajesTEC-1 consisted of dose escalation and expansion at the recommended phase II dose (RP2D; 1.5 mg/kg SC weekly, preceded by step-up doses of 0.06 and 0.3 mg/kg); phase II investigated the efficacy of teclistamab RP2D in patients with RRMM. Population pharmacokinetics and the impact of covariates on teclistamab systemic exposure were assessed using a 2-compartment model with first-order absorption for SC and parallel time-independent and time-dependent elimination pathways. Exposure–response analyses were conducted, including overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the incidence of grade ≥ 3 anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection. Results: In total, 4840 measurable serum concentration samples from 338 pharmacokinetics-evaluable patients who received teclistamab were analyzed. The typical population value of time-independent and time-dependent clearance were 0.449 L/day and 0.547 L/day, respectively. The time-dependent clearance decreased rapidly to < 10% after 8 weeks of teclistamab treatment. Patients who discontinue teclistamab after the 13th dose are expected to have a 50% reduction from C_max in teclistamab concentration at a median (5th to 95th percentile) time of 15 days (7–33 days) after T_max and a 97% reduction from C_max in teclistamab concentration at a median time of 69 days (32–163 days) after T_max. Body weight, multiple myeloma type (immunoglobulin G vs non–immunoglobulin G), and International Staging System (ISS) stage (II vs I and III vs I) were statistically significant covariates on teclistamab pharmacokinetics; however, these covariates had no clinically relevant effect on the efficacy of teclistamab at the RP2D. Across all doses, ORR approached a plateau at the concentration range associated with RP2D, and in patients who received the RP2D, a flat exposure–response curve was observed. No apparent relationship was observed between DoR, PFS, OS, and the incidence of grade ≥3 adverse events across the predicted exposure quartiles. Conclusion: Body weight, myeloma type, and ISS stage impacted systemic teclistamab exposure without any clinically relevant effect on efficacy. The exposure–response analyses for ORR showed a positive trend with increasing teclistamab systemic exposure, with a plateau at the RP2D, and there was no apparent exposure–response trend for safety or other efficacy endpoints. These analyses support the RP2D of teclistamab in patients with RRMM. Clinical Trial Registration: NCT03145181 (phase I, 09 May 2017); NCT04557098 (phase II, 21 September 2020). [ABSTRACT FROM AUTHOR]