Amivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immune cell-directing activity that targets tumours with activating EGFR mutations such as Exon 19 deletions, L858R substitution, and Exon 20 insertion mutations. Amivantamab binds to the extracellular domains of EGFR and MET.
Amivantamab disrupts EGFR and MET signalling functions through blocking ligand binding and enhancing degradation of EGFR and MET, thereby preventing tumour growth and progression. The presence of EGFR and MET on the surface of tumour cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.
Amivantamab decreased serum albumin concentration, a pharmacodynamic effect of MET inhibition, typically during the first 8 weeks; thereafter, albumin concentration stabilised for the remainder of amivantamab treatment.
Based on amivantamab monotherapy data, amivantamab area under the concentration-time curve (AUC1week) increases proportionally over a dose range from 350 to 1750 mg.
Based on simulations from the population pharmacokinetic model, AUC1week was approximately 2.8-fold higher after the fifth dose for the 2-week dosing regimen and 2.6-fold higher after the fourth dose for the 3-week dosing regimen. Steady-state concentrations of amivantamab were reached by Week 13 for both the 3-week and 2-week dosing regimen and the systemic accumulation was 1.9-fold.
Based on the individual amivantamab PK parameter estimates in population PK analysis, the geometric mean (CV%) total volume of distribution, is 5.12 (27.8%) L, following administration of the recommended dose of amivantamab.
Based on the individual amivantamab PK parameter estimates in population PK analysis, the geometric mean (CV%) linear clearance (CL) and terminal half-life associated with linear clearance is 0.266 (30.4%) L/day and 13.7 (31.9%) days respectively.
No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on age (27-87 years).
No clinically meaningful effect on the pharmacokinetics of amivantamab was observed in patients with mild (60 ≤ creatinine clearance [CrCl] < 90 mL/min) and moderate (29 ≤ CrCl < 60 mL/min) renal impairment. The effect of severe renal impairment (15 ≤ CrCl < 29 mL/min) on amivantamab pharmacokinetics is unknown.
Changes in hepatic function are unlikely to have any effect on the elimination of amivantamab since IgG1-based molecules such as amivantamab are not metabolised through hepatic pathways.
No clinically meaningful effect in the pharmacokinetics of amivantamab was observed based on mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 x ULN)]. The effect of moderate (total bilirubin 1.5 to 3 times ULN) and severe (total bilirubin > 3 times ULN) hepatic impairment on amivantamab pharmacokinetics is unknown.
The pharmacokinetics of amivantamab in paediatric patients have not been investigated.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.
No animal studies have been performed to establish the carcinogenic potential of amivantamab. Routine genotoxicity and carcinogenicity studies are generally not applicable to biologic pharmaceuticals as large proteins cannot diffuse into cells and cannot interact with DNA or chromosomal material.
No animal studies have been conducted to evaluate the effects on reproduction and foetal development; however, based on its mechanism of action, amivantamab can cause foetal harm or developmental anomalies. As reported in the literature, reduction, elimination, or disruption of embryo foetal or maternal EGFR signaling can prevent implantation, cause embryo foetal loss during various stages of gestation (through effects on placental development), cause developmental anomalies in multiple organs or early death in surviving foetuses. Similarly, knock out of MET or its ligand hepatocyte growth factor (HGF) was embryonic lethal due to severe defects in placental development, and foetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab has the potential to be transmitted from the mother to the developing foetus.
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