A Systematic Intracranial Exposure‐Response Evaluation of Brain‐Penetrant Inhibitors: Informing Dose Selection for Brain Metastases

ABSTRACT Brain metastases (BMs) represent a major clinical challenge due to their high incidence in cancers such as non‐small cell lung cancer (NSCLC) and breast cancer, and the limited efficacy of systemic therapies resulting from inadequate drug penetration across the blood–brain barrier. Although several brain‐penetrant tyrosine kinase inhibitors (TKIs) have been developed, the quantitative relationship between intracranial drug exposure and intracranial clinical response has not been well established, leaving an important gap in dose selection strategies. In this study, we systematically evaluated the intracranial exposure‐response relationship across brain‐penetrant small‐molecule TKIs. Fourteen TKIs were identified based on guideline‐recommended therapies for BMs. For each drug, plasma and cerebrospinal fluid (CSF) pharmacokinetic profiles were simulated using published population pharmacokinetic models, with CSF exposures extrapolated using known unbound plasma fractions and CSF‐to‐plasma unbound concentration ratios ( K p,uu,CSF ) in humans. Key intracranial exposure metrics, including the CSF steady‐state trough and average concentrations relative to IC 50 ( C min,ss /IC 50 and C ave,ss /IC 50 ) and the percentage of the steady‐state dosing interval during which CSF concentrations remained above IC 50 (T% > IC 50 ), were derived and correlated with intracranial outcomes from published clinical studies. Overall, significant positive correlations were observed between intracranial exposure metrics and both intracranial objective response rate (ORR) and complete response rate (CR). Greater exposure coverage above IC 50 was associated with improved intracranial efficacy. This work demonstrates a positive intracranial exposure‐response relationship across brain‐penetrant TKIs and provides a quantitative benchmark to inform dose selection beyond traditional plasma exposure metrics. These findings highlight the importance of achieving sufficient CNS drug concentrations to optimize the therapeutic effect in patients with BMs.