14 (18)
23 (29)
Objective Response Rate n (%) by Investigator
Complete responses
1 (1)
0
Partial responses
25 (32)
9 (12)
ORR (partial responses only)
26 (33)
9 (12)
Stable disease
34 (43)
29 (37)
Progressive Disease
14 (18)
19 (24)
a in accord with EU censoring
b Stratification factors per IxRS comprise IMDC risk categories (intermediate risk, poor risk and bone metastasis (yes, no)
c Estimated using the Cox proportional hazard model adjusted for stratification factors per IxRS. Hazard ratio < 1 indicates progression-free survival in favor of cabozantinib
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with CABOMETYX in all subsets of the paediatric population in treatment of kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney) (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 3 to 4 hours post-dose. Plasma-concentration time profiles show a second absorption peak approximately 24 hours after administration, which suggests that cabozantinib may undergo enterohepatic recirculation.
Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in an approximately a 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state is achieved by approximately Day 15.
A high-fat meal moderately increased Cmax and AUC values (41% and 57%, respectively) relative to fasted conditions in healthy volunteers administered a single 140 mg oral cabozantinib dose. There is no information on the precise food-effect when taken 1 hour after administration of cabozantinib.
Bioequivalence could not be demonstrated between the cabozantinib capsule and tablet formulations following a single 140 mg dose in healthy subjects. A 19% increase in the Cmax of the tablet formulation (CABOMETYX) compared to the capsule formulation (COMETRIQ) was observed. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations.
Distribution
Cabozantinib is highly protein bound in vitro in human plasma (≥ 99.7%). Based on the population-pharmacokinetic (PK) model, the volume of distribution (Vz) is approximately 319 L (SE: ± 2.7%). Protein binding was not altered in subjects with mild or moderately impaired renal or hepatic function.
Biotransformation
Cabozantinib was metabolized in vivo. Four metabolites were present in plasma at exposures (AUC) greater than 10% of parent: XL184-N-oxide, XL184 amide cleavage product, XL184 monohydroxy sulfate, and 6-desmethyl amide cleavage product sulfate. Two non-conjugated metabolites (XL184-N-oxide and XL184 amide cleavage product), which possess <1% of the on-target kinase inhibition potency of parent cabozantinib, each represent <10% of total drug-related plasma exposure.
Cabozantinib is a substrate for CYP3A4 metabolism in vitro, as a neutralizing antibody to CYP3A4 inhibited formation of metabolite XL184 N-oxide by >80% in a NADPH-catalyzed human liver microsomal (HLM) incubation; in contrast, neutralizing antibodies to CYP1A2, CYP2A6, CYP2B6, C |
