Clinical Pharmacokinetic Assessment of Lazertinib in Healthy Adult Participants: Effects of GSTM1 Genotype

Clin Drug Investig. 2025 Oct 12. doi: 10.1007/s40261-025-01494-z. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Lazertinib, a potent and irreversible third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has shown promising efficacy and favorable tolerability in EGFR-mutated non-small cell lung cancer (NSCLC). On the basis of in vitro findings, lazertinib is primarily metabolized by glutathione conjugation via glutathione-S-transferase mu 1 (GSTM1), occurring via enzymatic activity of GST or non-enzymatic processes, as well as through cytochrome P450 3A4. Here, we report the effect of GSTM1 on lazertinib pharmacokinetics (PK) using clinical evaluations.

METHODS: The effect of GSTM1 on lazertinib PK was evaluated in multiple phase 1 pharmacology studies. Clinical studies (NCT03556436, NCT04410081, and NCT05076877) involving healthy adult participants given lazertinib were analyzed on the basis of GSTM1 genotype (null [i.e., no expression] or non-null [i.e., expression]).

RESULTS: In a clinical study where participants were genotyped and analyzed to determine the association of lazertinib plasma maximum concentration (C_max) and area under curve (AUC) with a panel of genes known to affect PK, GSTM1 genotype showed a statistically significant association with AUC. Compared with null GSTM1 participants, non-null GSTM1 participants had relatively lower plasma exposure owing to increased GSTM1-mediated clearance. The mean single-dose and steady-state plasma C_max and AUC of lazertinib was 1.1- to 1.8-fold and 1.4- to 2.2-fold higher in null GSTM1 participants, respectively. The safety profiles of lazertinib were generally comparable across null and non-null GSTM1 participants.

CONCLUSIONS: Overall, GSTM1 status affected lazertinib PK in healthy participants and hence further research is warranted to determine the magnitude of PK differences and whether they are clinically meaningful in the NSCLC patient population intended to be treated with lazertinib.

PMID:41076618 | DOI:10.1007/s40261-025-01494-z