Tarlatamab is a bispecific delta-like ligand 3 (DLL3)-directed CD3 T-cell engager that binds to DLL3 expressed on the surface of tumour cells and CD3 expressed on the surface of T-cells. The bispecific binding of tarlatamab to T-cells and DLL3-positive tumour cells triggers T-cell activation, production of inflammatory cytokines, and release of cytotoxic proteins, which results in redirected lysis of tumour cells.
The pharmacodynamic response after a single infusion of tarlatamab was characterised by T-cell redistribution and activation, and transient cytokine elevation. Peripheral T-cell redistribution (i.e., T-cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred within 24 hours after the initial dose of tarlatamab at 1 mg on day 1. T-cell counts declined within 6 hours post infusion and returned to baseline levels in the majority of the patients prior to the next infusion on day 8.
Serum cytokines IL-2, IL-6, IL-8, IL-10, IFN-γ and TNF-α were transiently elevated following the initial dose of tarlatamab at 1 mg on day 1. Cytokine levels peaked within the first 2 days following the start of tarlatamab infusion and generally returned to baseline levels prior to the next infusion on day 8. In subsequent treatments, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial infusion on day 1.
Tarlatamab population pharmacokinetic (PK) analyses in adult subjects (n=702) with previously treated advanced SCLC were performed to characterise the time course of tarlatamab serum concentrations after intravenous administration, to quantify inter-individual variability and to evaluate effects of subject specific covariates on the PK parameters of tarlatamab.
The peak serum concentration (Cmax), trough serum concentration (Ctrough) and area under the serum concentration versus time curve at steady state (AUCtau) of tarlatamab increased dose proportionally in the evaluated dose range of 1 mg to 100 mg Q2W (10 times the recommended dose). Approximate steady state in serum tarlatamab exposures were achieved by cycle 2 day 15.
The typical value (inter-subject CV%) for central volume of distribution is 3.23 L (38%) and steady state volume of distribution is 8.19 L as estimated by population PK analysis.
The metabolic pathway of tarlatamab has not been characterised. Like other protein therapeutics, tarlatamab is expected to be degraded into small peptides and amino acids via catabolic pathways.
The systemic clearance (inter-subject CV%) was 0.728 L/day (34%) and terminal elimination half-life was approximately 10.6 days in subjects with SCLC as estimated by population PK analysis.
No clinically meaningful differences in the clearance of tarlatamab were observed based on age (range: 20-86 years), bodyweight (range: 35-149 kg), sex, race, mild or moderate renal impairment (eGFR ≥ 30 mL/min), or mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN). Limited data is available in patients with moderate hepatic impairment and no data is available in patients with severe hepatic or severe renal impairment.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.
No genotoxicity or carcinogenicity studies have been conducted with tarlatamab.
No studies have been conducted to evaluate the effects of tarlatamab on fertility.
A reproductive toxicity study conducted in mice using the murine surrogate molecule muS757 showed transplacental transport of muS757 and did not induce embryo-foetal toxicity or teratogenicity.
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