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Purpose <p>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 <i>GSTM1</i>, 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&#xa0;mg once-daily dose irrespective of <i>GSTM1</i> status, leading to avoidable toxicity without additional clinical benefit. Our purpose was to develop alternative dosing regimens based on GSTM1 status.</p> Methods <p>We conducted pharmacokinetic simulations using an existing validated population pharmacokinetic model to evaluate genotype-guided alternative dosing strategies in <i>GSTM1</i> null individuals.</p> Results <p>Two regimens— 160&#xa0;mg once daily (QD) and 240&#xa0;mg every other day—were predicted to provide systemic exposures comparable to or exceeding those seen in <i>GSTM1</i> non-null patients on the standard dose. The 160&#xa0;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 <i>GSTM1</i> non-null patients of 1.43 and 1.19, respectively. The respective GMRs for Ctrough and Caverage associated with 240&#xa0;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.</p> Conclusion <p>Our findings support the feasibility of individualized lazertinib dosing based on <i>GSTM1</i> status to reduce toxicity and healthcare costs without compromising effective exposure.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月7日

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  • Rob ter Heine,
  • Bianca J. C. van den Bosch,
  • Robin M. van Geel,
  • Wouter H. van Geffen,
  • Lizza E. L. Hendriks,
  • Michel M. van den Heuvel,
  • Simon E. Koele,
  • Adrianus J. de Langen,
  • Thijs H. Oude Munnink,
  • Anthonie J. van der Wekken

摘要

Purpose

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.

Methods

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

Results

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.

Conclusion

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