Optimizing lazertinib therapy through GSTM1 genotyping: a strategy to reduce excess drug exposure and potential...

The combination of lazertinib and amivantamab has shown superior efficacy over first line osimertinib in EGFR-mutated metastatic non-small cell lung cancer, but is associated with significant toxicity and high costs. Lazertinib exposure varies widely due to genetic polymorphisms of the encoding for GSTM1, with almost 50% of Caucasians having a non-functional enzyme resulting in an approximate twofold higher systemic drug exposure. Despite this, all patients receive a fixed 240 mg once-daily dose irrespective of GSTM1 status, leading to avoidable toxicity without additional clinical benefit. Our purpose was to develop alternative dosing regimens based on GSTM1 status.

We conducted pharmacokinetic simulations using an existing validated population pharmacokinetic model to evaluate genotype-guided alternative dosing strategies in GSTM1 null individuals.

Two regimens- 160 mg once daily (QD) and 240 mg every other day-were predicted to provide systemic exposures comparable to or exceeding those seen in GSTM1 non-null patients on the standard dose. The 160 mg QD dose resulted in a geometric mean ratio in GSTM1 null patients (GMR) for the trough (Ctrough) and average (Caverage) concentration relative tot he approved dose in GSTM1 non-null patients of 1.43 and 1.19, respectively. The respective GMRs for Ctrough and Caverage associated with 240 mg every-other-day dosing were 0.90 and 0.89, and this dosing regimen could reduce drug expenses up to 50% ($132.860 per year per patient) based on current pricing.

Our findings support the feasibility of individualized lazertinib dosing based on GSTM1 status to reduce toxicity and healthcare costs without compromising effective exposure.