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Osimertinib Plasma Trough Concentration in Relation to Brain Metastases Development in Patients With Advanced
Judith L Gulikers1,2, G D Marijn Veerman3,4, Merel Jebbink5
1Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Centre+, Maastricht, The Netherlands.
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 (Cmin,SS) and consequently limited intracranial osimertinib exposure. We investigated the relation between osimertinib Cmin,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 Cmin,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) Cmin,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 Cmin,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 Cmin,SS subgroups.
Conclusions:
No relation was found between osimertinib Cmin,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.
Insights
Osimertinib plasma levels did not correlate with brain metastases (BM) development or progression in advanced EGFR-mutated NSCLC patients. This indicates that systemic drug exposure is not a reliable predictor for intracranial disease in this population.
Area of Science:
- Oncology
- Pharmacology
- Medical Research
Background:
- Brain metastases (BM) are a significant clinical challenge in advanced EGFR-mutated (EGFRm+) non-small cell lung cancer (NSCLC).
- While osimertinib demonstrates efficacy, some patients experience intracranial progression, potentially linked to insufficient drug exposure in the brain.
Purpose of the Study:
- To investigate the relationship between osimertinib plasma trough levels (Cmin,SS) and the development or progression of brain metastases in patients with advanced EGFRm+ NSCLC.
- To determine if systemic osimertinib exposure serves as a predictor for intracranial disease outcomes.
Main Methods:
- A prospective multicenter cohort study included 173 patients with advanced EGFRm+ NSCLC receiving osimertinib.
- Patients were stratified by baseline BM status and categorized into low, middle, and high Cmin,SS subgroups.
- Cumulative incidence of BM progression/development and overall survival were analyzed across Cmin,SS subgroups.
Main Results:
- No significant association was found between osimertinib Cmin,SS and the development or progression of BM in the overall cohort.
- In patients with baseline BM, BM progression rates varied across Cmin,SS subgroups, but no clear trend linked higher exposure to better outcomes.
- The development of new BM in patients without baseline BM showed no difference across Cmin,SS subgroups.
Conclusions:
- Osimertinib Cmin,SS is not a reliable predictor of BM development or progression in advanced EGFRm+ NSCLC.
- Systemic osimertinib exposure does not appear to be a surrogate marker for intracranial disease control.
- Further research may be needed to identify other factors influencing intracranial response to osimertinib.
