The study explores the potential of high-dose regimens of tyrosine kinase inhibitors (TKIs) to improve efficacy in treating metastatic colorectal cancer (mCRC), given that most TKIs have failed in clinical trials. The researchers investigated the relationship between drug exposure and response in vitro using patient-derived tumor organoids (PDTOs) from mCRC patients. This work enhances the understanding of the correlation between TKI exposure and patient response, aiding in determining patient-specific sensitivity. The findings could guide both mechanistic investigations in organotypic translational models and the application of targeted drug exposure to clinical dosing strategies. Additionally, the study highlights the potential clinical benefits of high-dose short-term (HDST) treatment with osimertinib for mCRC and suggests further clinical exploration.