Exposure-toxicity relationship of cabozantinib in patients with renal cell cancer and salivary gland cancer.

Abstract

Cabozantinib is registered in fixed 60\u2009mg dose. However, 46-62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure >750\u2009μg/L. In this study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured Cmin at steady-state. The geometric mean (GM) Cmin at the starting dose, at 40\u2009mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n\xa0=\xa022) started with 60\u2009mg, while 52% of RCC patients started with 40\u2009mg. GM Cmin at the start dose was 1456\u2009μg/L(95%CI:1185-1789) vs 682\u2009μg/L(95%CI:572-812)(P\xa0<\u2009.001) for SGC and RCC patients, respectively. When dose-normalized to 40\u2009mg, SGC patients had a significantly higher cabozantinib exposure compared to RCC patients(Cmin 971\u2009μg/L(95%CI:790-1193) vs 669\u2009μg/L(95%CI:568-788)(P\xa0=\u2009.005). Dose reductions due to toxicity were needed in 91% and 60% of SGC and RCC patients, respectively. Median BTD was ~20-30\u2009mg for SGC and 40\u2009mg for RCC patients. GM Cmin at BTD were comparable between the SGC and the RCC group, 694\u2009μg/L(95%CI:584-824) vs 583\u2009μg/L(95%CI:496-671)(P\xa0=\u2009.1). The observed cabozantinib exposure at BTD of ~600\u2009μg/L is below the previously proposed target. Surprisingly, a comparable exposure at BTD was reached at different dosages of cabozantinib for SGC patients compared to RCC patients Further research is warranted to identify the optimal exposure and starting dose to balance efficacy and toxicity. This article is protected by copyright. All rights reserved.