Association of Cabozantinib Dose Reductions for Toxicity with Clinical Effectiveness in Metastatic Renal Cell Carcinoma (mRCC): Results from the Canadian Kidney Cancer Information System (CKCis)

Background Cabozantinib, an oral multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated efficacy in metastatic renal cell carcinoma (mRCC). The association between toxicity and therapeutic effectiveness has been established with other TKIs. We investigated whether cabozantinib dose reductions, a surrogate for toxicity and adequate drug exposure, were associated with improved clinical outcomes in mRCC. Methods Employing the CKCis database, we analyzed patients treated with cabozantinib in the second line or later between 2011-2021. The cohort was stratified into those needing dose reductions (DR) during treatment and those not (no DR). Outcomes, including objective response rate (ORR), time to treatment failure (TTF), and overall survival (OS), were compared based on dose reduction status. The influence of the initial dose on outcomes was also explored. Results Among 319 cabozantinib-treated patients, 48.3% underwent dose reductions. Response rates exhibited no significant difference between the DR and no-DR groups (15.1% vs. 18.2%, p=0.55). Patients with DR had superior median OS (26.15 vs. 15.47 months, p=0.019) and TTF (12.74 vs. 6.44 months, p=0.022) compared to no-DR patients. These differences retained significance following adjustment for IMDC risk group (OS HR=0.67, p=0.032; TTF HR=0.65, p=0.008). There was no association between the initial dose and ORR, OS, or TTF. Conclusion This study highlights the link between cabozantinib dose reductions due to toxicity and improved survival and time to treatment failure in mRCC patients. These findings underscore the potential of using on-treatment toxicity as an indicator of adequate drug exposure to individualize dosing and optimize treatment effectiveness. Larger studies are warranted to validate these results and develop individualized strategies for cabozantinib when given alone or in combination with immunotherapy. Micro-abstract This retrospective study assessed the impact of cabozantinib dose reductions on outcomes in metastatic renal cell carcinoma (mRCC). Patients requiring dose reductions experienced significantly better overall survival and time to treatment failure. These findings underscore the potential of using on-treatment toxicity as an indicator of adequate drug exposure to individualize dosing and optimize treatment effectiveness. Further validation through larger studies is needed.