Summary of medicine characteristics - COMETRIQ 20 MG HARD CAPSULES
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One hard capsule contains cabozantinib (S)-malate equivalent to 20 mg cabozantinib.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
3 PHARMACEUTICAL FORMHard capsule.
The hard capsules are grey with “XL184 20mg” printed in black on the body of the capsule. The capsule contains an off-white to white powder.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
COMETRIQ is indicated for the treatment of adult patients with progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma.
For patients in whom rearranged during transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decision (see important information in section 5.1).
4.2 Posology and method of administration
Therapy with COMETRIQ should be initiated by a physician experienced in the administration of anticancer medicinal products.
Posology
COMETRIQ (cabozantinib) capsules and CABOMETYX (cabozantinib) tablets are not bioequivalent and should not be used interchangeably (see section 5.2).
The recommended dose of COMETRIQ is 140 mg once daily, taken as one 80 mg orange capsule and three 20 mg grey capsules. Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.
It should be expected that a majority of patients treated with COMETRIQ will require one or more dose adjustments (reduction and/or interruption) due to toxicity. Patients should therefore be closely monitored during the first eight weeks of therapy (see section 4.4).
Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of COMETRIQ therapy. When dose reduction is necessary, it is recommended to reduce to 100 mg daily, taken as one 80 mg orange capsule and one 20 mg grey capsule, and then to 60 mg daily, taken as three 20 mg grey capsules.
Dose interruptions are recommended for management of CTCAE grade 3 or greater toxicities or intolerable grade 2 toxicities.
Dose reductions are recommended for events that, if persistent, could become serious or intolerable.
As most events can occur early in the course of treatment, the physician should evaluate the patient closely during the first eight weeks of treatment to determine if dose modifications are warranted. Events that generally have early onset include hypocalcaemia, hypokalaemia, thrombocytopenia, hypertension, palmar-plantar erythrodysaesthesia syndrome (PPES), and gastrointestinal (GI) events (abdominal or mouth pain, mucosal inflammation, constipation, diarrhoea, vomiting).
The occurrence of some serious adverse reactions (like GI fistula) might be dependent on the cumulative dose and might present in a later stage of treatment.
If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose.
Concomitant medicinal products
Concomitant medicinal products that are strong inhibitors of CYP3A4 should be used with caution, and chronic use of concomitant medicinal products that are strong inducers of CYP3A4 should be avoided (see sections 4.4 and 4.5).
Selection of an alternative concomitant medicinal product with no or minimal potential to induce or inhibit CYP3A4 should be considered.
Elderly patients
No specific dose adjustment for the use of cabozantinib in older people (> 65 years) is recommended. However, a trend in increased rate of SAEs has been observed in subjects aged 75 years and older.
Race
There is little experience with cabozantinib in non-White patients.
Renal impairment
Cabozantinib should be used with caution in patients with mild or moderate renal impairment.
Cabozantinib is not recommended for use in patients with severe renal impairment as safety and efficacy have not been established in this population.
Hepatic impairment
In patients with mild or moderate hepatic impairment the recommended dose of cabozantinib is 60 mg once daily. Close monitoring of overall safety is recommended in these patients (see section 5.2) as dose adjustment or interruption may be required. Cabozantinib is not recommended for use in patients with severe hepatic impairment as safety and efficacy have not been established in this population.
Patients with cardiac impairment
There is limited data in patients with cardiac impairment. No specific dosing recommendations can be made.
Paediatric population
The safety and efficacy of cabozantinib in children aged <18 years have not yet been established. No data are available.
Method of administration
COMETRIQ is for oral use. The capsules should be swallowed whole and not opened. Patients should be instructed to not eat anything for at least 2 hours before through 1 hour after taking COMETRIQ.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4
Special warnings and precautions for use
Dose reductions and dose interruptions occurred in 79% and 72%, respectively, of cabozantinib-treated patients in the pivotal clinical study. Two dose reductions were required in 41% of patients. The median time to first dose reduction was 43 days, and to first dose interruption was 33 days. Close monitoring of patients is therefore recommended during the first eight weeks of therapy (see section 4.2).
Hepatotoxicity
Abnormalities of liver function tests (increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin) have been frequently observed in patients treated with cabozantinib. It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of cabozantinib treatment and to monitor closely during treatment. For patients with worsening of liver function tests considered related to cabozantinb treatment (i.e where no alternative cause is evident), the dose should be reduced or treatment interrupted following recommendations provided in section 4.2.
Perforations, fistulas, and intra-abdominal abscesses
Serious gastrointestinal (GI) perforations and fistulas, sometimes fatal, and intra-abdominal abscesses have been observed with cabozantinib. Patients who have had recent radiotherapy, have inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, peritonitis, or diverticulitis), have tumour infiltration of trachea, bronchi, or oesophagus, have complications from prior GI surgery (particularly when associated with delayed or incomplete healing), or have complications from prior radiation therapy to the thoracic cavity (including mediastinum) should be carefully evaluated before initiating cabozantinib therapy and subsequently they should be monitored closely for symptoms of perforations and fistulas. Non-GI fistula should be ruled out as appropriate in cases of onset of mucositis after start of therapy. Cabozantinib should be discontinued in patients who experience a GI perforation or a GI or non-GI fistula.
Thromboembolic events
Events of venous thromboembolism, including pulmonary embolism and events of arterial thromboembolism, sometimes fatal, have been observed with cabozantinib. Cabozantinib should be used with caution in patients who are at risk for, or who have a history of, these events. Cabozantinib should be discontinued in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.
Haemorrhage
Severe haemorrhage, sometimes fatal, has been observed with cabozantinib. Patients who have evidence of involvement of the trachea or bronchi by tumour or a history of haemoptysis prior to treatment initiation should be carefully evaluated before initiating cabozantinib therapy. Cabozantinib should not be administered to patients with serious haemorrhage or recent haemoptysis.
Aneurysms and artery dissections
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating cabozantinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.
Gastrointestinal (GI) disorders
Diarrhoea, nausea/vomiting, decreased appetite, and stomatitis/oral pain were some of the most commonly reported GI adverse reactions (see section 4.8). Prompt medical management, including supportive care with antiemetics, antidiarrhoeals, or antacids, should be instituted to prevent dehydration, electrolyte imbalances and weight loss. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant GI adverse reactions (see section 4.2).
Wound complications
Wound complications have been observed with cabozantinib. Cabozantinib treatment should be stopped at least 28 days prior to scheduled surgery, including dental surgery or invasive dental procedures, if possible. The decision to resume cabozantinib therapy after surgery should be based on clinical judgment of adequate wound healing. Cabozantinib should be discontinued in patients with wound healing complications requiring medical intervention.
Hypertension
Hypertension has been observed with cabozantinib. All patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensives, the cabozantinib dose should be reduced. Cabozantinib should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of cabozantinib. In case of hypertensive crisis, cabozantinib should be discontinued.
Osteonecrosis
Events of osteonecrosis of the jaw (ONJ) have been observed with cabozantinib. An oral examination should be performed prior to initiation of cabozantinib and periodically during cabozantinib therapy. Patients should be advised regarding oral hygiene practice. Cabozantinib treatment should be held at least 28 days prior to scheduled dental surgery or invasive dental procedures, if possible. Caution should be used in patients receiving agents associated with ONJ, such as bisphosphonates. Cabozantinib should be discontinued in patients who experience ONJ.
Palmar-plantar erythrodysaesthesia syndrome
Palmar-plantar erythrodysaesthesia syndrome (PPES) has been observed with cabozantinib. When PPES is severe, interruption of treatment with cabozantinib should be considered. Cabozantinib should be restarted with a lower dose when PPES has been resolved to grade 1.
Proteinuria
Proteinuria has been observed with cabozantinib. Urine protein should be monitored regularly during cabozantinib treatment. Cabozantinib should be discontinued in patients who develop nephrotic syndrome.
Posterior reversible encephalopathy syndrome
Posterior reversible encephalopathy syndrome (PRES) has been observed with cabozantinib. PRES should be considered in any patient presenting with symptoms suggestive of the diagnosis, including seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued in patients with PRES.
Prolongation of QT interval
Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using cabozantinib, periodic monitoring with on-treatment ECGs and electrolytes (serum calcium, potassium, and magnesium) should be considered. Concomitant treatment with strong CYP3A4 inhibitors, which may increase cabozantinib plasma concentrations, should be used with caution.
CYP3A4 inducers and inhibitors
Cabozantinib is a CYP3A4 substrate. Concurrent administration of cabozantinib with the strong CYP3A4 inhibitor ketoconazole resulted in an increase in cabozantinib plasma exposure. Caution is required when administering cabozantinib with agents that are strong CYP3A4 inhibitors. Concurrent administration of cabozantinib with the strong CYP3A4 inducer rifampicin resulted in a decrease in cabozantinib plasma exposure. Therefore chronic administration of agents that are strong CYP3A4 inducers with cabozantinib should be avoided (see sections 4.2 and 4.5).
P-glycoprotein substrates
Cabozantinib was an inhibitor (IC50 = 7.0 jiM), but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib.
MRP2 inhibitors
Administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors (e.g. cyclosporine, efavirenz, emtricitabine) should be approached with caution.
Excipient
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially “sodium-free”.
4.5 Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on cabozantinib
CYP3A4 inhibitors and inducers
Administration of the strong CYP3A4 inhibitor ketoconazole (400 mg daily for 27 days) to healthy volunteers decreased cabozantinib clearance (by 29%) and increased single-dose plasma cabozantinib exposure (AUC) by 38%. Therefore coadministration of strong CYP3A4 inhibitors (e.g., ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) with cabozantinib should be approached with caution.
Administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 31 days) to healthy volunteers increased cabozantinib clearance (4.3-fold) and decreased single-dose plasma cabozantinib exposure (AUC) by 77%. Chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing St. John’s Wort [Hypericum perforatum]) with cabozantinib should therefore be avoided.
Gastric pH modifying agents
Co-administration of proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers resulted in no clinically-significant effect on plasma cabozantinib exposure (AUC). No dose adjustment is indicated when gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, and antacids) are co-administered with cabozantinib.
MRP2 inhibitors
In vitro data demonstrate that cabozantinib is a substrate of MRP2. Therefore, administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations.
Bile salt-sequestering agents
Bile salt-sequestering agents such as cholestyramine and cholestagel may interact with cabozantinib and may impact absorption (or reabsorption) resulting in potentially decreased exposure (see section 5.2). The clinical significance of these potential interactions is unknown.
Effect of cabozantinib on other medicinal products
The effect of cabozantinib on the pharmacokinetics of contraceptive steroids has not been investigated. As unchanged contraceptive effect may not be guaranteed, an additional contraceptive method, such as a barrier method, is recommended.
Because of high plasma protein binding levels of cabozantinib (section 5.2) a plasma protein displacement interaction with warfarin may be possible. In case of such combination, INR values should be monitored.
P-glycoprotein substrates
Cabozantinib was an inhibitor (IC50 = 7.0 jiM), but not a substrate, of P-gp transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of coadministered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in males and females
Women of childbearing potential must be advised to avoid pregnancy while on cabozantinib. Female partners of male patients taking cabozantinib must also avoid pregnancy. Effective methods of contraception should be used by male and female patients and their partners during therapy, and for at least 4 months after completing therapy. Because oral contraceptives might possibly not be considered as “effective methods of contraception,” they should be used together with another method, such as a barrier method (see section 4.5).
Pregnancy
There are no studies in pregnant women using cabozantinib. Studies in animals have shown embryo-foetal and teratogenic effects (see section 5.3). The potential risk for humans is unknown. Cabozantinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with cabozantinib.
Breast-feeding
It is not known whether cabozantinib and/or its metabolites are excreted in human milk. Because of the potential harm to the infant, mothers should discontinue breastfeeding during treatment with cabozantinib, and for at least 4 months after completing therapy.
Fertility
There are no data on human fertility. Based on non-clinical safety findings, male and female fertility may be compromised by treatment with cabozantinib (see section 5.3). Both men and women should be advised to seek advice and consider fertility preservation before treatment.
4.7 Effects on ability to drive and use machines
Cabozantinib has minor influence on the ability to drive and use machines. Adverse reactions such as fatigue and weakness have been associated with cabozantinib.
Therefore, caution should be recommended when driving or operating machines.
4.8 Undesirable effects
Summary of safety profile
The most common serious adverse reactions associated with cabozantinib are pneumonia, mucosal inflammation, hypocalcaemia, dysphagia, dehydration, pulmonary embolism, and hypertension. The most frequent adverse reactions of any grade (experienced by at least 20% of patients) included diarrhoea, PPES, weight decreased, decreased appetite, nausea, fatigue, dysgeusia, hair colour changes, hypertension, stomatitis, constipation, vomiting, mucosal inflammation, asthenia, and dysphonia.
The most common laboratory abnormalities were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased alkaline phosphatase (ALP), lymphopenia, hypocalcaemia, neutropenia, thrombocytopenia, hypophosphatemia, hyperbilirubinemia, hypomagnesaemia, and hypokalaemia.
Tabulated list of adverse reactions
Adverse reactions are listed in Table 1 according to MedDRA system organ class and frequency categories. Frequencies are based on all grades and defined as very common (>1/10), common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1: Adverse reactions reported with cabozantinib
Infections and in | ’estations |
Common | abscess (including visceral, skin, tooth), pneumonia, folliculitis, fungal infection (including skin, oral, genital) |
Uncommon | aspergilloma |
Endocrine disorc | ers |
Common | hypothyroidism |
Metabolism and nutrition disorders | |
Very Common | decreased appetite, hypocalcaemiac, hypokalaemiac, hypomagnesaemiac |
Common | dehydration*, hypoalbuminaemiac, hyperbilirubinaemiad, hypophosphatemia0 |
Psychiatric disorders | |
Common | anxiety, depression, confusional state |
Uncommon | abnormal dreams, delirium |
Nervous system c | isorders |
Very Common | dysgeusia, headache, dizziness |
Common | cerebrovascular accident, peripheral neuropathy, paraesthesia, ageusia, tremor |
Uncommon | ataxia, disturbance in attention, hepatic encephalopathy, loss of consciousness, speech disorder, posterior reversible encephalopathy syndrome |
Eye disorders | |
Common | vision blurred |
Uncommon | cataract, conjunctivitis |
Ear and labyrint | h disorders |
Common | ear pain, tinnitus |
Uncommon | hypoacusis |
Cardiac disorders | |
Common | atrial fibrillation |
Uncommon | angina pectoris, supraventricular tachycardia |
Not Known | myocardial infarction |
Vascular disorders | |
Very Common | , . f hypertension |
Common | hypotensiong, deep vein thrombosis , venous thrombosis , arterial thrombosis , pallor, peripheral coldness |
Not Known | aneurysms and artery dissections |
Respiratory, thoracic, and mediastinal disorders | |
Very Common | dysphonia, oropharyngeal pain |
Common | non-gastrointestinal fistula (including tracheal, pneumomediastinum, tracheo-oesophageal), pulmonary embolism , respiratory tract haemorrhage (including pulmonary, bronchial, tracheal), pneumonia aspiration |
Uncommon | atelectasis, pharyngeal oedema, pneumonitis |
Gastrointestinal disorders | |
Very Common | diarrhoea, nausea*, stomatitis, constipation, vomiting*, abdominal paine, dyspepsia, dysphagia, glossodynia |
Common | gastrointestinal perforation , gastrointestinal fistula , gastrointestinal haemorrhage , pancreatitis, haemorrhoids, anal fissure, anal inflammation, cheilitis |
Uncommon | oesophagitis |
Hepatobiliary disorders | |
Common | cholelithiasis |
Skin and subcutaneous tissue disorders |
Very Common | palmar-plantar erythrodysaesthesia syndrome*, hair colour changes, rash, dry skin, alopecia, erythema |
Common | hyperkeratosis, acne, blister, hair growth abnormal, skin exfoliation, skin hypopigmentation |
Uncommon | skin ulcer, telangiectasia |
Musculoskeletal and connective tissue disorders | |
Very Common | arthralgia, muscle spasms, pain in extremity |
Common | musculoskeletal chest pain, osteonecrosis of jaw |
Uncommon | rhabdomyolysis |
Renal and urinary disorders | |
Common | proteinuria*, dysuria, haematuria |
Uncommon | renal failure acute |
Reproductive system and breast disorders | |
Uncommon | amenorrhoea, vaginal haemorrhage |
General disorders and administration site conditions | |
Very Common | fatigue, mucosal inflammation, asthenia |
Common | impaired wound healing , chills, face oedema |
Uncommon | cyst, facial pain, localised oedema |
Investigations | |
Very Common | weight decreased, serum ALT, AST, and ALP increased, blood LDH increased, blood TSH increased*d, thrombocytopenia3 |
Common | blood creatinine increased, lymphopeniaa, neutropeniaa, lipase increased |
Uncommon | activated partial thromboplastin time shortened, eosinophil count increasedb, platelet count increasedb |
*n
See section 4.8 Description of selected adverse reactions for further characterisation.
The following terms have been combined to derive appropriate frequency categorisation:
a Lowered haematology parameters: Lymphopenia and lymphocyte count decreased; Neutropenia and neutrophil count decreased; Thrombocytopenia and platelet count decreased.
bElevated haematology parameters: Eosinophil count increased and eosinophilia; Platelet count increased and thrombocytosis
c Lowered biochemistry parameters: Hypoalbuminaemia and blood albumin decreased; Hypocalcaemia and blood calcium decreased; Hypokalaemia and blood potassium decreased; Hypomagnesaemia and blood magnesium decreased; Hypohosphatemia and blood phosphorus decreased.
d Elevated biochemistry parameters: Hyperbilirubinaemia and blood bilirubin increased; Hypothyroidism and blood thyroid stimulating hormone increased.
e Abdominal pain, abdominal discomfort, abdominal pain upper and abdominal pain lower f Hypertension and blood pressure increased.
g Hypotension and blood pressure decreased.
Description of selected adverse reactions
A thyroid stimulating hormone (TSH) value above normal after first dose was observed in 57% of patients on cabozantinib versus 19% of patients on placebo (regardless of baseline values). Ninety-two percent of patients on the cabozantinib arm had a prior thyroidectomy, and 89% were taking thyroid hormones prior to first dose.
An increase from baseline in corrected QT interval by Fridericia (QTcF) of 10 – 15 ms on Day 29 (but not on Day 1) following initiation of cabozantinib treatment (at a dose of 140 mg qd) was observed in a controlled clinical study in cancer patients (see section 4.4). This effect was not associated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treated subjects had a QTcF >500 ms.
Please refer to section 4.4 for recommendations about the monitoring and management of the following adverse events: perforations, fistulas, and intra-abdominal abscesses; thromboembolic events; haemorrhage; aneurysms and artery dissections; gastrointestinal disorders; wound complications; hypertension; osteonecrosis; palmar-plantar erythrodysaesthesia syndrome; proteinuria; and posterior reversible encephalopathy syndrome.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed below.
United Kingdom (Great Britain)
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseThere is no specific treatment for cabozantinib overdose and possible symptoms of overdose have not been established.
In the event of suspected overdose, cabozantinib should be withheld and supportive care instituted. Metabolic clinical laboratory parameters should be monitored at least weekly or as deemed clinically appropriate to assess any possible changing trends. Adverse reactions associated with overdose are to be treated symptomatically.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01EX07.
Mechanism of action
Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodelling, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine kinases including RET, the GAS6 receptor (AXL), the stem cell factor receptor (KIT), and Fms-like tyrosine kinase-3 (FLT3).
Pharmacodynamic effects
Cabozantinib exhibited dose-related tumour growth inhibition, tumour regression, and/or inhibited metastasis in a broad range of preclinical tumour models.
Efficacy with cabozantinib was observed in medullary thyroid cancer patients with wild-type or mutant RET.
Clinical data in medullary thyroid cancer
A multi-center, randomised double-blind study comparing cabozantinib (N = 219) with placebo (N = 111) was conducted in patients with unresectable locally advanced or metastatic MTC and documented radiographic disease progression within 14 months prior to study entry. The primary objective was to compare progression-free survival (PFS) in patients receiving cabozantinib versus patients receiving placebo. The secondary objectives were to compare overall response rate (ORR) and overall survival (OS). Centralized, independent, blinded review of the imaging data was used in the assessment of PFS and ORR. Patients were treated until disease progression or unacceptable toxicity.
The result of the PFS analysis, based on the central review RECIST assessment, demonstrated a statistically significant difference in the duration of PFS with cabozantinib versus placebo: the median duration was 11.2 months for subjects in the cabozantinib arm versus 4.0 months for subjects in the placebo arm (stratified Hazard Ratio [HR] = 0.28; 95% CI: 0.19, 0.40; p<0.0001; Figure 1). The PFS results were consistent across all baseline and demographic subgroups evaluated, including prior therapy with tyrosine kinase inhibitors (which may have consisted of agents targeting pathways associated with anti-angiogenesis), RET mutational status (including subjects documented not to have RET mutations), prior anticancer or radiotherapy status, or the existence of bone metastases.
The ORR was 27.9% and 0% for subjects in the cabozantinib arm and placebo arm, respectively (p<0.0001; Table 2). The median duration of objective responses was 14.6 months (95% CI: 11.1, 17.5) for subjects in the cabozantinib arm.
Figure 1: Kaplan Meier curve of progression free survival
Number of | subjects at risk | |||||||
Month | 0 | 3 | 6 | 9 | 12 | 15 | 18 | 21 |
Cometriq | 219 | 121 | 78 | 55 | 31 | 12 | 2 | 1 |
Placebo | 111 | 35 | 11 | 6 | 3 | 2 | 0 | 0 |
The final analysis of OS was conducted after 218 events (deaths) occurred and shows a trend for an increase in median survival of 5.5 months in the cabozantinib arm: median (months) 26.6 cabozantinib vs. 21.1 placebo (HR = 0.85 [95% CI: 0.64, 1.12], p = 0.2409).
Figure 2: Kaplan-Meier curve of overall survival
Table 2: Summary of key efficacy findings
Cabozantinib | Placebo | |
Median progression-free survival | 11.2 months | 4.0 months |
HR: 0.28 (0.19, 0.40) p <0.0001 | ||
Median overall survival | 26.6 months | 21.1 months |
HR: 0.85 (0.64, 1.12) p = 0.2409 | ||
Overall response ratea (95% CI) | 27.9% (21.9%, 34.5%) | 0% |
p <0.0001 | ||
Duration of response; median (95% CI) | 14.6 months (11.1, 17.5) | N/A |
Disease control rate b (95% CI) | 55.3% (48.3%, 62.2%) | 13.5% (7.6%, 21.6%) |
Calcitonin responsea | 47% (49/104)c | 3% (1/40) c |
CEA responsea | 33% (47/143) c | 2% (1/55)c |
a Response = CR + PR
b Disease Control Rate = SD+ ORR
Includes patients who were evaluable for response
RET mutation status
Of the 215 subjects with sufficient data to determine mutational status, 78.6% (n=169) were classified as RET mutation positive (126 of which were positive for the M918T mutation), and 21.4% (n=46) were classified as RET mutation negative. For an additional 115 subjects the RET mutational status could not be determined or was unclear. All three subgroups showed increased PFS in the cabozantinib arm compared to the placebo arm (HRs of 0.23, 0.53, and 0.30 for RET mutation positive, negative, and unknown subgroups, respectively). The objective response rates measured in these subgroups were generally consistent with the PFS results, with the RET mutation positive, negative, and unknown subgroups showing tumour response rates of 32%, 22%, and 25%, respectively.
Cometriq 81 77 73 67 65 59 56 54 50 48 45 43 42 39 38 27 24 21 14 7 3 2 1 0
Placebo 45 42 38 34 31 26 24 20 19 17 17 17 15 14 14 10 9 7 6 4 2 0 0 0
Further genetic analysis showed that a small proportion of patients harboured somatic tumour mutations in HRAS, KRAS, or NRAS. These patients (n=16) showed significant prolongation of PFS (HR of 0.15) and an objective response rate of 31%. RET mutation negative patients with no evidence of RAS mutation (n=33) showed a decreased PFS benefit on cabozantinib (HR of 0.87) and a lower response rate of 18% compared to other mutational subgroups.
A significant improvement in OS was observed in the subgroup of RET M918T mutation positive patients (n=81/219 cabozantinib arm): 44.3 months in the cabozantinib arm vs.
18.9 months in the placebo arm (HR = 0.60, p = 0.0255). There was no improvement in OS for the RET M918T negative and unknown subgroups.
Figure 3: Kaplan-Meier analysis of OS among subjects with a RET M918T mutation
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with cabozantinib in one or more subsets of the paediatric population in the treatment of malignant solid tumours (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 2 to 5 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. AUC were similar between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations (<10% difference).
Distribution
Cabozantinib is highly protein bound in vitro in human plasma (> 99.7%). Based on the population-pharmacokinetic (PK) model, the volume of distribution (V/F) is approximately 349 L (SE: ± 2.73%). 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, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. A neutralizing antibody to CYP2C9 showed a minimal effect on cabozantinib metabolite formation (ie, a <20% reduction).
Elimination
The plasma terminal half-life of cabozantinib in single dose studies in healthy volunteers is approximately 120 hours. Mean clearance (CL/F) at steady-state in cancer patients was estimated to be 4.4 L/hr in a population PK analysis. Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy volunteers, approximately 81% of the total administered radioactivity was recovered with 54% in faeces and 27% in urine.
Pharmacokinetics in special patient populations
Renal impairment
Results from a study in patients with renal impairment indicate that the ratios of geometric LS mean for plasma cabozantinib, Cmax and AUC0-inf were 19% and 30% higher, for subjects with mild renal impairment (90% CI for Cmax 91.60% to 155.51%; AUC0-inf 98.79% to 171.26%) and 2% and 6–7% higher (90% CI for Cmax 78.64% to 133.52%; AUC0-inf 79.61% to 140.11%), for subjects with moderate renal impairment, compared to subjects with normal renal function. Patients with severe renal impairment have not been studied.
Hepatic impairment
Results from a study in patients with hepatic impairment indicate that exposure (AUC0-inf) increased by 81% and 63% in subjects with mild and moderate hepatic impairment, respectively (90% CI for AUC0-inf: 121.44% to 270.34% for mild and 107.37% to 246.67% for moderate). Patients with severe hepatic impairment have not been studied.
Race
No data are available to determine a difference in PK based on race.
5.3 Preclinical safety data
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule content
Microcrystalline cellulose
Croscarmellose sodium
Sodium starch glycolate
Silica colloidal anhydrous
Stearic acid
Capsule shell
Gelatin
Black iron oxide (E172)
Titanium dioxide (E171)
Printing ink
Shellac
Black iron oxide (E172)
Propylene glycol
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25 °C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PVC/PE/PCTFE-Al blisters with foil backing, sealed into a secondary heat-sealed card packaging.
Blister cards containing:
21 × 20 mg capsules (60 mg/day dose for a 7-day supply)
28 day pack containing:
84 capsules (4 blister cards of 21 × 20 mg) (60 mg/day dose for a 28 day supply)