084: Effect of Hepatic Impairment on Single Dose Pharmacokinetics (PK) of Lazertinib

Statement of Purpose: Lazertinib is a mutant selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor in development for treatment of NSCLC. Preclinical findings indicate that lazertinib is predominantly metabolized by hepatic enzymes. Glutathione conjugation by glutathione s-transferase mu 1 (GSTM1) isoform was also identified as one of the contributing metabolic pathways. Hepatic impairment (HI) can alter PK which may impact clinical effectiveness or safety of a drug. As lazertinib can potentially be administered to patients with HI, this study was conducted to evaluate the effect of HI on the single dose PK of lazertinib and to support clinical dosing recommendations for patients with hepatic insufficiency.

Description of Methods & Materials: NCT05112952 was a single dose, open-label, non-randomized, parallel group, multi-center, Phase 1 PK study with lazertinib in participants who either have HI with no other major co-morbidity (Group 1), or healthy participants who qualified for the control group (Group 2). The study was a reduced PK study design with 2 sequential parts based on Child-Pugh categories - Part A (moderate HI) and optional Part B (mild and severe HI). Conduct of Part B was to be based on the safety profile and the magnitude of change in plasma exposure of lazertinib in Part A. In Part A, 8 hepatic impaired participants enrolled in Group 1 were individually-matched (demographically and by GSTM1 status) to 8 healthy participants in Group 2. A single oral dose of 160 mg lazertinib was administered under fed condition in both groups followed by PK and safety assessments

Data & Results: Lazertinib dosing in Group 1 and Group 2 was well tolerated and all 16 participants completed the study. The mean (CV) plasma C_max, AUC_last and t_1/2 of lazertinib administered in Group 1 vs Group 2 were 221 (36%) vs 271 (27%) ng/mL, 4420 (32%) vs 4,574 (22%) h*ng/mL and 93.5 (21.4) vs 80.8 (34.0) hours, respectively. The geometric mean ratios (90% CI) with Group 1 as test treatment and Group 2 as reference treatment for plasma lazertinib C_max and AUC_last were 80% (60%, 105%) and 95% (79%, 113%) respectively.

Interpretation, Conclusion or Significance: The lazertinib plasma exposure in the moderate HI group was comparable to that in matched healthy participant group with overall differences in C_max and AUC_last of < 2-fold suggesting no dose adjustment is required for lazertinib treatment in hepatic impaired patients. Since there was no increase in plasma exposure of lazertinib in Part A Group 1, optional study Part B was not conducted.

Disclosures: