Osimertinib Plasma Trough Concentration in Relation to Brain Metastases Development in Patients With Advanced EGFR-Mutated NSCLC

Judith L Gulikers; G D Marijn Veerman; Merel Jebbink; Paul D Kruithof; Christi M J Steendam; René J Boosman; Ron H J Mathijssen; Vivianne C G Tjan-Heijnen; Johanna H M Driessen; Safiye Dursun; Egbert F Smit; Anne-Marie C Dingemans; Robin M J M van Geel; Sander Croes; Lizza E L Hendriks

doi:10.1016/j.jtocrr.2024.100656

Osimertinib Plasma Trough Concentration in Relation to Brain Metastases Development in Patients With Advanced EGFR-Mutated NSCLC

JTO Clin Res Rep. 2024 Feb 20;5(4):100656. doi: 10.1016/j.jtocrr.2024.100656. eCollection 2024 Apr.

Authors

Judith L Gulikers^{1

2}, G D Marijn Veerman^{3

4}, Merel Jebbink⁵, Paul D Kruithof^{1

2}, Christi M J Steendam^{4

6}, René J Boosman⁷, Ron H J Mathijssen³, Vivianne C G Tjan-Heijnen⁸, Johanna H M Driessen^{1

2

9}, Safiye Dursun¹⁰, Egbert F Smit^{5

11}, Anne-Marie C Dingemans⁵, Robin M J M van Geel^{1

2}, Sander Croes^{1

2}, Lizza E L Hendriks¹⁰

Affiliations

¹ Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Centre+, Maastricht, The Netherlands.
² CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, The Netherlands.
³ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁴ Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
⁵ Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁶ Department of Pulmonary Medicine, Catharina Hospital, Eindhoven, The Netherlands.
⁷ Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁸ Division Medical Oncology, GROW - School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands.
⁹ NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
¹⁰ Department of Pulmonary Diseases, GROW - School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, The Netherlands.
¹¹ Department of Pulmonary Diseases, LUMC, Leiden, The Netherlands.

Abstract

Introduction: Brain metastases (BM) are common in patients with advanced EGFR-mutated (EGFRm+) NSCLC. Despite good BM-related outcomes of osimertinib, several patients still experience intracranial progression. A possible explanation is pharmacologic failure due to low plasma trough levels (C_min,SS) and consequently limited intracranial osimertinib exposure. We investigated the relation between osimertinib C_min,SS and BM development or progression.

Methods: A prospective multicenter cohort study, including patients receiving osimertinib for advanced EGFRm+ NSCLC. At osimertinib start, patients were allocated to the BM or no or unknown BM cohort and were further divided into subgroups based on osimertinib C_min,SS (low, middle, and high exposure). Cumulative incidence of BM progression or development and overall survival were determined for each group.

Results: A total of 173 patients were included, with 49 (28.3%) had baseline BM. Of these patients, 36.7% experienced BM progression, of which 16.7% in the low (<159.3 ng/mL), 40.0% in the middle, and 47.1% in the high (>270.7 ng/mL) C_min,SS subgroups. After 12 months, the cumulative incidence of BM progression for the BM cohort was 20% (95% confidence interval [CI] 2.6-49.0), 31% (95% CI:10.6-53.9), and 31% (95% CI:10.8-54.5) per C_min,SS subgroup, respectively. After 20 months, this was 20% (95% CI:2.6-49.0), 52% (95% CI:23.8-74.2), and 57% (95% CI:24.9-79.7), respectively. For the no or unknown BM cohort, 4.0% developed BM without differences within C_min,SS subgroups.

Conclusions: No relation was found between osimertinib C_min,SS and BM development or progression in patients with advanced EGFRm+ NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development or progression.

Keywords: Brain metastasis; NSCLC; Osimertinib; Plasma trough concentration.