Pharmacokinetics of Tarlatamab, a Delta-Like Ligand-3 (DLL3) Targeted Half-Life Extended Bispecific T-Cell Engager (BiTE ® ) Immunotherapy in Adult Patients with Previously Treated Small-Cell Lung Cancer: Results from DeLLphi-300, a Phase I Multiple-Dose-Escalation Study.

Autor: Minocha M; Clinical Pharmacology Modeling & Simulation, Amgen, Thousand Oaks, CA, USA., Thompson CG; Clinical Pharmacology Modeling & Simulation, Amgen, Thousand Oaks, CA, USA., Murphy A; Clinical Pharmacology Modeling & Simulation, Amgen, Thousand Oaks, CA, USA., Zhou Y; Clinical Immunology, Amgen, South San Francisco, CA, USA., Brandl C; Bioanalytical Science, Amgen Research (Munich) GmbH, Munich, Germany., Parkes A; Early Development Oncology, Amgen, Thousand Oaks, CA, USA., Chen X; Early Development Oncology, Amgen, Thousand Oaks, CA, USA., Yu B; Early Development Oncology, Amgen, Thousand Oaks, CA, USA., Martinez P; Global Development Oncology, Amgen, Thousand Oaks, CA, USA., Houk BE; Clinical Pharmacology Modeling & Simulation, Amgen, Thousand Oaks, CA, USA. bhouk@amgen.com.
Jazyk: angličtina
Zdroj: Clinical pharmacokinetics [Clin Pharmacokinet] 2024 Dec; Vol. 63 (12), pp. 1757-1768. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1007/s40262-024-01451-7
Abstrakt: Background: Tarlatamab binds to delta-like ligand 3 on cancer cells and cluster of differentiation-3 on T cells, leading to T-cell-mediated tumor lysis, and has demonstrated a promising safety and efficacy profile in patients with previously treated small-cell lung cancer (SCLC). Here, we present pharmacokinetic results from DeLLphi-300 (NCT03319940), an ongoing international, open-label, first-in-human study in previously treated adult patients with SCLC.
Methods: Multiple escalating doses of tarlatamab were administered every 2 weeks (Q2W; 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 mg) in a 28-day cycle. To reduce the risk of cytokine-release syndrome, starting at the 3 mg dose level, a step dose regimen was employed consisting of a 1 mg infusion on cycle 1 day 1 (C1D1), followed by the target dose on C1D8, C1D15, and Q2W thereafter. All doses were infused over 1 h. Other tarlatamab dosing regimens were also explored, either for patient convenience (every 3 weeks) or to mitigate cytokine-release syndrome (extended intravenous infusion over a period of 3 days). Intensive pharmacokinetic samples were collected during cycles 1 and 2, and additional samples for pharmacokinetic and immunogenicity measurement were collected at regular intervals in later cycles. Pharmacokinetic data were analyzed using noncompartmental analysis, and antidrug antibody (ADA) incidence, including any effect on tarlatamab pharmacokinetic parameters, was summarized.
Results: Pharmacokinetic data were available from 203 patients. The median age was 62 years (range 32-80), and 55.7% (n = 113) of patients were male, 78.3% (n = 159) were white, and 8.3% (n = 17) were of Japanese descent. Following intravenous infusion, serum tarlatamab concentrations declined with time in a biphasic manner. Serum exposures increased in an approximately dose-proportional manner across the evaluated target dose range with a mean (standard deviation) estimated terminal phase elimination half-life of 5.8 (1.6) days, and steady state achieved by approximately C2D15. Of the 183 evaluable patients, 12 (6.6%) developed treatment-emergent ADAs; the distribution of dose-normalized serum concentrations were similar between patients who were ADA positive and ADA negative. In addition, the distribution of exposures was comparable in Japanese and non-Japanese patients.
Conclusion: In patients with previously treated SCLC, tarlatamab demonstrated dose-proportional pharmacokinetic and extended half-life characteristics that support a Q2W dosing interval. Neither Japanese race nor ADA had a clinically relevant impact on exposures.
Competing Interests: Declarations. Funding: This study was funded by Amgen Inc. Conflicts of Interest: All authors are employees and shareholders of Amgen. The authors have no additional conflicts of interest to declare. Availability of Data and Material: Electronic records and data are stored at Amgen Inc., Thousand Oaks, CA, USA. Qualified researchers may request data from Amgen clinical studies. Complete details are available at https://wwwext.amgen.com/science/clinical-trials/clinical-data-transparency-practices/clinical-trial-data-sharing-request/ . Ethics Approval: The protocol and amendments were approved by the institutional review board or ethics committee at each participating site. The trial was conducted in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Consent to Participate: All patients provided written informed consent. Consent for Publication: Not applicable. Code Availability: Not applicable. Author Contributions: PM, BY, XC, AP, YZ, MM, and BH were responsible for the conception and design of the clinical study. CB performed the bioanalysis. AM, CT, MM, and BH performed the pharmacokinetic analysis and wrote the manuscript. All authors read and approved the final version of this manuscript.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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