Cabozantinib Tablets

One case of overdosage was reported in the cabozantinib clinical program; a patient inadvertently took twice the intended dose (200 mg daily) of another formulation of cabozantinib product for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

Mechanism Of Action

In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

Pharmacodynamics

The exposure-response or –safety relationship for cabozantinib is unknown.

The effect of orally administered cabozantinib on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled study in patients with medullary thyroid cancer administered a dose of 140 mg. A mean increase in QTcF of 10 -15 ms was observed at 4 weeks after initiating cabozantinib. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No cabozantinibtreated patients in this study had a confirmed QTcF > 500 ms nor did any cabozantinib-treated patients in the RCC study (at a dose of 60 mg).

Pharmacokinetics

Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in 4-to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state was achieved by Day 15.

Following oral administration of cabozantinib, median time to peak cabozantinib plasma concentrations (Tmax ) ranged from 2 to 3 hours post-dose.

A 19% increase in the Cmax of the tablet formulation (CABOMETYX) compared to the capsule formulation (COMETRIQ®) was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations [see DOSAGE AND ADMINISTRATION].

Cabozantinib Cmax and AUC values increased by 41% and 57%, respectively, following a high-fat meal relative to fasted conditions in healthy subjects administered a single 140 mg oral dose of an investigational cabozantinib capsule formulation.

The oral volume of distribution (Vz/F) of cabozantinib is approximately 319 L. Cabozantinib is  highly protein bound in human plasma ( ≥ 99.7%).

The predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at steady-state is estimated to be 2.2 L/hr.

Cabozantinib is a substrate of CYP3A4 in vitro.

Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single 140 mg dose of an investigational 14C-cabozantinib formulation in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72 hour collection.

Specific Populations

The following patient characteristics did not result in a clinically relevant difference in the pharmacokinetics of cabozantinib: age (32-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m² as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics of cabozantinib is unknown in patients with worse than moderate renal impairment (eGFR less than 29 mL/min/1.73m²) as estimated by MDRD equation or renal impairment requiring dialysis.

Hepatic Impairment

Cabozantinib exposure (AUC0-inf ) increased by 81% and 63%, respectively, in patients with mild (C-P A) and moderate (C-P B) hepatic impairment. Patients with severe hepatic impairment have not been studied [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].

Pediatric Population

The pharmacokinetics of cabozantinib has not been studied in the pediatric population [see Use in Specific Populations].

Drug Interactions

Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf ) by 38%.

Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf ) by 77%.

No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma  exposure (Cmax and AUC) was observed when co-administered with cabozantinib at steady-state plasma concentrations ( ≥ 100 mg/day daily for a minimum of 21 days) in patients with solid tumors.  

No clinically-significant effect on plasma cabozantinib exposure (AUC) was observed following co-administration of the proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers.

Metabolic Pathways

Inhibition of CYP3A4 reduced the formation of the oxidative metabolite by > 80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a < 20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.

Although cabozantinib is an inhibitor of CYP2C8 in vitro, a clinical study of this potential interaction concluded that concurrent use did not result in a clinically relevant effect on CYP2C8 substrate exposure. Given this finding, other less sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, and CYP3A4) were not evaluated in a clinical study because, although a clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib does not inhibit CYP1A2 and CYP2D6 isozymes in vitro.

Cabozantinib is an inducer of CYP1A1 mRNA; however, the clinical relevance of this finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4.

Cabozantinib is an inhibitor, but not a substrate, of P-gp transport activities and has the potential to increase plasma concentrations of co-administered substrates of P-gp. The clinical relevance of this finding is unknown.

Cabozantinib is a substrate of MRP2 in vitro and MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. The clinical relevance of this finding is unknown.

Clinical Studies

Study 1 was a randomized (1:1), open-label, multicenter study of CABOMETYX versus everolimus conducted in patients with advanced RCC who had received at least 1 prior antiangiogenic therapy. Patients had to have a Karnofsky Performance Score (KPS) ≥ 70%. Patients were stratified by the number of prior VEGFR tyrosine kinase inhibitors and Memorial Sloan Kettering Cancer Center (MSKCC) Risk Group.

Patients (N=658) were randomized to receive CABOMETYX (N=330) administered orally at 60 mg daily or everolimus (N=328) administered orally at 10 mg daily. The majority of the patients were male (75%), with a median age of 62 years. Sixty-nine percent (69%) received only one prior anti-angiogenic therapy. Patient distribution by MSKCC risk groups was 46% favorable (0 risk factors), 42% intermediate (1 risk factor), and 13% poor (2 or 3 risk factors). Fifty-four percent (54%) of patients had 3 or more organs with metastatic disease, including lung (63%), lymph nodes (62%), liver (29%), and bone (22%).

The main efficacy outcome measure was progression-free survival (PFS) assessed by a blinded independent radiology review committee among the first 375 subjects randomized. Other efficacy endpoints were objective response rate (ORR) and overall survival (OS) in the Intent-to-Treat (ITT) population. Tumor assessments were conducted every 8 weeks for the first 12 months, then every 12 weeks thereafter. Patients received treatment until disease progression or experiencing unacceptable toxicity. Patients on both arms who had disease progression could continue treatment at the discretion of the investigator.

Statistically significant improvements in PFS, OS, and ORR were demonstrated for CABOMETYX compared to everolimus (Figures 1 and 2 and Tables 4 and 5).

Figure 1: Progression-Free Survival in Study 1 (First 375 Randomized)

Table 4: Progression-Free Survival in Study 1 (First 375 Randomized)

Figure 2: Overall Survival in Study 1 (ITT)

Table 5. Overall Survival and Objective Response Rate in Study 1 (ITT)

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take on an empty stomach. Take 1 hour before or 2 hours after meals.
• Swallow whole. Do not chew, break, or crush.
• Take with a full glass of water.
• To gain the most benefit, do not miss doses.
• Keep taking this medicine (cabozantinib tablets) as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it and go back to your normal time.
• If it is less than 12 hours until the next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.