Osimertinib plasma trough concentration in relation to brain metastases development in patients with advanced EGFR-mutated non-small cell lung cancer

Introduction Brain metastases (BM) are common in patients with advanced EGFR-mutated (EGFRm+) non-small cell lung cancer (NSCLC). Despite good BM-related outcomes of osimertinib several patients still experience intracranial progression. A possible explanation is pharmacological 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/progression. Methods A prospective multicentre cohort study, including patients receiving osimertinib for advanced EGFRm+ NSCLC. At osimertinib start, patients were allocated to the BM or no/unknown BM cohort and were further divided into subgroups based on osimertinib Cmin,SS (low, middle and high exposure). Cumulative incidence of BM progression/development and overall survival were determined for each group. Results 173 patients were included, 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 Cmin,SS-subgroup (>270.7 ng/mL). After 12 months, the cumulative incidence of BM progression for the BM cohort was 20% (95% CI 2.6 – 49.0), 31% (95% CI 10.6 – 53.9) and 31% (95% CI 10.8 – 54.5) per Cmin,SS-subgroups, 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/unknown BM cohort, 4.0% developed BM without differences within Cmin,SS subgroups. Conclusion No relation was found between osimertinib Cmin,SS and BM development/progression in patients with advanced EGFRm+ NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development/progression.