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

Introduction: Brain metastases (BM) are common in patients with advanced EGFR -mutated ( EGFR m+) 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 EGFR m + 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 EGFR m + NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development or progression.
Competing Interests: Dr. Veerman reports receiving payment or honoraria for lectures from Eli Lilly (payed to the institute). Dr. Steendam reports receiving an unrestricted research grant from AstraZeneca (payed to the institute), payment or honoraria for lectures from Academic Pharmaceutical, supporting for attending meetings from Eli Lilly and Rochte and fullfilling unpaid roles at NVALT and CieBOD. Prof. dr. Mathijssen reports receiving grants of contracts for investigator initiated research from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi and Sevier (all payed to the institute). Prof. dr. Tjan-Heijnen reports receiving grants or contracts from Pfizer, Novartis, Eli Lilly, Gilead, Roche, AstraZeneca and Daiichi Sankyo (all payed to the institute), and receiving consulting fees from Eli Lilly, Novartis and AstraZeneca. Drs. Dursun reports receiving payment or honoraria a presentation at Novartis. Prof. dr. Smit reports receiving grants or contracts from AstraZeneca and Daiichi Sankyo (payed to the institute), receiving consulting fees from AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi Sankyo, Sanofi, Eli Lilly, Roche Genentech, Merck, Novartis, Pfizer, Takeda and Taiho (all payed to the institute), participation on a data safety monitoring board or advisory board from DSI and Taiho and receiving payment of honoraria for lectures from Boehringer-Ingelheim. Prof. dr. Dingemans reports receiving grants or contracts from Amgen, Dutch Cancer Society and HANART (all payed to the institute), receiving consulting fees from AMGEN, Bayer, Boehringer-Ingelheim, Sanofy, Roche, Janssen and AstraZeneca (all payed to the institute), and receiving payment or honoraria for lectures from Janssen, Pfizer, AstraZeneca, Eli Lilly and Takeda (all payed to the institute), participation on a data and safety monitoring board or advisory board from Takeda and Roche and is unpaid char at EORTC LCG. Dr. van Geel reports receiving grants or contracts from Academic Alliance Fund (payed to the institute). Dr. Hendriks reports receiving grants or contracts from Roche Genentech, AstraZeneca, Boehringer-Ingelheim, Takeda, Merck, Pfizer and Novartis (all payed to the institute), receiving payment or honoraria for lectures from MSD, Eli Lilly, Sanofi, GSK and High5oncology (all payed to the institute), and personal payments from Benecke, Medtalks, Medimix, VJOncology, participation on a data safety monitoring board or advisory board from BMS, Eli Lilly, Roche Genetech, Pfizer, Takeda, MSD, Merck, Novartis, Boehringer-Ingelheim, Amgen, Janssen and Anhearts (all payed to the institute), and interview sessions funded by Roche Genentech, Bayer and Eli Lilly (all payed to the institute). All other authors declare no conflict of interest.
(© 2024 The Authors.)