Exposure-response modeling of cabozantinib in patients with renal cell carcinoma: Implications for patient care

Abstract

Cabozantinib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of patients with advanced renal cell carcinoma (RCC) at a dose of 60 mg/day. As with other TKIs, cabozantinib is associated with high interpatient variability in drug clearance and exposure that can significantly impact safety and tolerability across a patient population. To optimize cabozantinib exposure (maintaining efficacy and tolerability) for the individual, patients may require treatment interruption with dose reduction (40 mg/day and then 20 mg/day). In the pivotal Phase 3 METEOR trial, cabozantinib significantly improved overall survival, progression-free survival and the objective response rate compared with everolimus in patients with advanced RCC who had received previous treatment with a VEGFR TKI. Dose reductions were common for patients receiving cabozantinib (60%) but effective as only 9% discontinued treatment due to adverse events (AEs). In this review, we discuss pharmacometric analyses that evaluated the impact of cabozantinib dose on efficacy and safety outcomes during the METEOR study. Exposure-response models demonstrate that the risk of experiencing adverse events and dose reduction is increased in patients with low cabozantinib clearance versus typical clearance and decreased in patients with high clearance. Dose reduction of cabozantinib to manage AEs is predicted to have minimal impact on efficacy as AEs are more likely to occur in patients with low clearance and higher exposure to cabozantinib. These analyses further support a dose modification strategy to optimize cabozantinib exposure for individual patients.

Association of cabozantinib pharmacokinetics, progression and toxicity in metastatic renal cell carcinoma patients: results from a pharmacokinetics/pharmacodynamics study

“…Noticeably, only a trend towards a lower Cl/F ( P = 0.1) was associated with relevant toxicity in our study, whereas a low Cl/F has been previously described as a key determinant of toxicity. 7 , 15 This finding may be explained both by our definition of relevant toxicity as a combined endpoint that pooled poorly tolerated G2 and G3 toxicities, whereas most PK/PD studies published considered only G3-4 toxicity, and by the relatively small number of patients included.…”

Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

“…However, CAB accumulates five-fold by day 15 following daily dosing based on AUC, which should be considered in the treatment of these patients. As no clinical data after multiple-dose administration were available, predicted C ss after multiple dosing for the 60 mg tablet was compared to the C ss published by Castellano et al [ 56 ], to evaluate the ability of the model to simulate multiple dosing correctly. A good agreement between the predicted and published value was found (1197 ng/mL vs. 1123 ng/mL).…”

Cabozantinib: An evolving therapy for hepatocellular carcinoma

“…In an exposure-response analysis of patients with HCC, low cabozantinib clearance and its corresponding increase in cabozantinib exposure was predicted to increase the probability of dose modification compared with typical clearance [51]. In a separate exposure-response analysis of patients with RCC, dose reductions in patients with low clearance were predicted to have minimal impact on cabozantinib efficacy [52,53]. Thus, patients with low clearance are more likely to require a dose reduction to improve tolerability, but this will not significantly impact the clinical efficacy of cabozantinib.…”