Summary Basis of Decision for Cabometyx

Clinical Pharmacology

Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases implicated in tumour growth and angiogenesis, pathologic bone remodeling, drug resistance, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of hepatocyte growth factor receptor protein (MET) and vascular endothelial growth factor (VEGF) receptors. Additionally, cabozantinib inhibits other tyrosine kinases including ROS1, TYRO3, MER, TRKB, TIE-2, the GAS6 receptor (AXL), the rearranged during transfection (RET) protein, the stem cell factor receptor (KIT), and Fms-like tyrosine kinase-3 (FLT3).

Pharmacokinetic studies for cabozantinib were conducted mainly with suspension or capsule formulations. However, a study was included in this submission which demonstrates bioequivalence between the capsule and tablet formulations. Given cabozantinib was originally developed as a treatment for thyroid cancer; several studies included in this submission were conducted in patients with conditions other than renal cell carcinoma (RCC). As a result, information on pharmacokinetics after multiple dosing with 20 mg, 40 mg and 60 mg tablets is limited.

The food effects study, XL184-004, was conducted with a capsule formulation rather than the tablet formulation intended for marketing of Cabometyx. Results of this study demonstrated that administration of cabozantinib following a high-fat meal significantly increased systemic exposure in healthy subjects. Patients taking Cabometyx are therefore advised not to take it with food, and not to eat for at least two hours before and one hour after administration.

The bioequivalence between the capsule and tablet formulations of Cabometyx was evaluated in study XL184-001. Results of this study demonstrated that the rate of absorption and extent of exposure to cabozantinib were similar between the two formulations. Based on these results, the conclusions drawn from the food effects study using the capsule formulation are considered applicable to the tablet formulation.

The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Cabometyx have been well characterized in patients and healthy volunteers. Pharmacokinetic data suggests that cabozantinib may undergo enterohepatic recirculation, which may extend the half-life of the drug. Terminal half-life was calculated as approximately 99 hours following administration of 20 mg, 40 mg, and 60 mg doses. Additionally, four metabolites of cabozantinib were detected in plasma at concentrations greater than 10% of the parent concentration. Overall the pharmacokinetic data support use of Cabometyx for the approved indication.

Compared to healthy subjects, exposure to cabozantinib was 81% higher in patients with mild hepatic impairment and 63% higher in patients with moderate hepatic impairment. Elevated exposure levels correlated with lower clearance rates, and together, these extend the mean terminal half-life by 70-75% in patients with hepatic impairment. A decreased starting dose of 40 mg is therefore recommended for patients with mild to moderate hepatic impairment. Cabometyx is not recommended for individuals with severe hepatic impairment, as it has not been studied in this population.

Higher values were also reported for peak plasma concentration and exposure to cabozantinib in patients with renal impairment versus healthy subjects. The ratios of geometric least squares mean for plasma cabozantinib, C_max and AUC_0-inf, were 19% and 30% higher in patients with mild renal impairment, and 2% and 6-7% higher in patients with moderate renal impairment. Patients with mild to moderate renal impairment are advised to use Cabometyx with caution. Additionally, it is not recommended for patients with severe renal impairment, as it has not been studied in this population.

Drug-Drug Interactions

Co-administration of Cabometyx and strong cytochrome P450 (CYP) 3A4 inhibitors must be done cautiously, as this decreases cabozantinib clearance by 29% and increases single dose plasma cabozantinib exposure by 38%. Chronic concurrent use of Cabometyx with CYP3A4 inducers should be avoided, as this increases cabozantinib clearance 4.3-fold and decreases cabozantinib exposure by 77%.

Results of in vitro experiments have shown that cabozantinib is a substrate of multidrug resistance-associated protein 2 (MRP2), and inhibits pump P-glycoprotein (P-gp).

Co-administration of Cabometyx with MRP2 inhibitors or substrates of P-gp may result in increased cabozantinib exposure.

For further details, please refer to the Cabometyx Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Cabometyx in patients with advanced renal cell carcinoma (RCC) was based primarily on one pivotal study referred to as METEOR. METEOR was a randomized, open-label, Phase III study comparing Cabometyx against the standard second-line treatment for advanced RCC, everolimus. All 658 patients enrolled in this study had advanced RCC, and had previously received at least one VEGF receptor tyrosine kinase inhibitor. Patients were randomized in a 1:1 ratio to one of two treatment groups, to receive either 60 mg cabozantinib or 10 mg everolimus once daily. Treatment continued until the patient's condition progressed, or until the patient experienced an unacceptable level of toxicity. Tumour assessments occurred every eight weeks for the first 12 months, and every 12 weeks thereafter.

The primary efficacy endpoint was progression-free survival (PFS). A blinded independent radiology review committee conducted the primary analysis of PFS among the first 375 patients randomized. A statistically significant increase in PFS was reported in patients treated with cabozantinib, compared to those treated with everolimus (7.4 months and 3.8 months, respectively). Results of an analysis in the complete patient population were consistent with those from the primary population.

Objective response rate (ORR) was assessed as a secondary endpoint in the whole patient population, and was significantly higher in patients receiving cabozantinib than in patients receiving everolimus. As determined by clinical investigators, the ORR was 24% for cabozantinib and 4% for everolimus. An independent review committee calculated corresponding values of 17% and 3% for cabozantinib and everolimus.

Overall survival was also a secondary efficacy endpoint, and was analyzed three times during the course of the study. The first analysis was carried out at the time of the PFS analysis in the primary population. Results did not meet the threshold for statistical significance, but a trend towards prolonged overall survival was detected in patients receiving cabozantinib. The second analysis revealed a statistically significant increase in overall survival in patients treated with cabozantinib. Median overall survival values of 21.4 months and 16.5 months were reported for patients treated with cabozantinib and everolimus, respectively. The third and final analysis yielded median values of 21.4 months and 17.1 months in connection with cabozantinib and everolimus, respectively. This increase of 4.3 months was statistically significant, and confirmed that the overall survival benefit of cabozantinib treatment was maintained.

Indication

For more information, refer to the Cabometyx Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Cabometyx was based primarily on safety data derived from the pivotal Phase III METEOR study previously described in the Clinical Efficacy section. The outcomes of this study demonstrated that PFS, overall survival, and ORR are higher for cabozantinib (the medicinal ingredient in Cabometyx), than for the standard second-line treatment for advanced RCC, everolimus.

Adverse events were experienced by all patients enrolled in this study, with similar incidences of serious adverse events observed in both treatment groups. Severe adverse events (worst related adverse event, Grade 3 or 4) were more often associated with Cabometyx than with everolimus (68% versus 58% of patients). Adverse events associated with death within 30 days of the last drug administration were more frequent among everolimus-treated patients (7.1%) than Cabometyx-treated patients (4.5%).

Dose modifications were needed to manage adverse events in 76% of patients receiving Cabometyx and 61% of patients receiving everolimus. Diarrhea, palmar-plantar erythrodysaesthesia syndrome (PPES), and fatigue required dose interruption in at least 10% of Cabometyx-treated patients. These three adverse events, along with hypertension, were also the most frequently associated with dose reduction. Decreased appetite and fatigue led to treatment discontinuation in more than 1% of patients.

The most common adverse events, experienced by 10% or more of Cabometyx-treated patients, were diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (PPES), hypertension, vomiting, decreased weight, constipation, dysgeusia, stomatitis, hypothyroidism, dysphonia, mucosal inflammation, dyspnea, asthenia, cough, increased aspartate aminotransferase (AST), anemia, back pain, abdominal pain, increased alanine aminotransferase (ALT), hypomagnesemia, rash, pain in extremities, muscle spasms, proteinuria, dyspepsia, arthralgia, hypokalemia, dry skin, headache, and hypophosphatemia.

Several clinically significant adverse events have been associated with Cabometyx, which are also characteristic of other tyrosine kinase inhibitors. These include gastrointestinal (GI) perforation, GI and non-GI fistulas, thromboembolic events, severe hemorrhage (Grade 3 or above), wound complications, reversible posterior leukoencephalopathy syndrome, hypertension, and hepatotoxicity, which are all highlighted in a Serious Warnings and Precautions box in the Cabometyx Product Monograph. Other adverse events associated with tyrosine kinase inhibitors include diarrhea, PPES, hypothyroidism, osteonecrosis, proteinuria, and QT prolongation.

A Notice of Deficiency (NOD) was issued for the initial new drug submission for Cabometyx. Two major objections were identified: insufficient information to conduct a thorough analysis of cardiac safety, and the absence of a Phase I dose-finding study to justify the recommended starting dose of 60 mg. The sponsor supplied the outstanding data in a response to the NOD. These were found to be acceptable upon review, and the objections are considered resolved.

Health Canada has determined that appropriate measures are in place to address the safety concerns identified for Cabometyx, and to promote its safe and effective use. Overall, the risk-benefit profile of Cabometyx is favourable and there are no issues within this submission which preclude authorization of the product. For more information, refer to the Cabometyx Product Monograph, approved by Health Canada and available through the Drug Product Database.