Background and Objective <p>Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma. The current patient-unfriendly advice to ingest cabozantinib in a fasted state is based on an increase of 57% in the area under the concentration–time curve after ingestion with a high-fat meal. Taking cabozantinib with a meal that is suitable for daily practice to increase bioavailability could aid in developing alternative dosing strategies. In this study, we aim to investigate the impact of taking cabozantinib with a light breakfast on exposure and toxicity.</p> Methods <p>An open-label, randomized, cross-over, pharmacokinetic evaluation study was performed. In the standard regimen, patients took cabozantinib in a fasted state. In the experimental regimen, patients took cabozantinib with a light breakfast. After 4 weeks, pharmacokinetic samples were obtained for area under the concentration–time curve from 0 to 24 h estimation and patients thereafter switched to the other regimen. Patients were monitored for serious adverse events.</p> Results <p>Twelve patients completed study procedures. The area under the concentration–time curve for taking cabozantinib in a fasted state and with a light breakfast showed a mean difference of + 8.3% (geometric mean ratio, 90% confidence interval 101–117). Similar results were obtained for trough concentration (mean difference 2.5%, geometric mean ratio, 90% confidence interval 90.7–116.0) and maximum concentration (mean difference 14%, geometric mean ratio, 90% confidence interval 103.7–127.6). No differences in serious adverse events were observed.</p> Conclusions <p>Taking cabozantinib with a light breakfast leads to a small increase in exposure. Patients for whom taking cabozantinib in a fasted state is unpleasant are now able to take it with a light breakfast, without an increased risk for exposure-related toxicity.</p> Clinical Trial Registration <p>This study was registered at ClinicalTrials.gov under the number NCT05263245.</p>