英文药名：COMETRIQ(CABOZANTINIB Capsules)

中文药名：卡博替尼[混合]胶囊

生产厂家：Exelixis, Inc/Ipsen Pharma GmbH
药品介绍
2013年，甲状腺髓样癌治疗新药cabozantinib(Cometriq,Exelixis, Inc) 获欧洲上市许可的批准。人用药品委员会认为，药物警戒计划将作为此次批准的组成部分之一进行实施。
该药品完整的适应症是对于进展期的，不能手术切除的，局部晚期或者转移性的甲状腺髓样癌患者治疗时使用。在对此类患者的临床试验中，与安慰剂进行对比，cabozantinib可改善无进展生存期。
甲状腺髓样癌是一种罕见的甲状腺癌，人用药品委员会提出意见并指出，cabozantinib有孤儿药地位。
Cabozantinib于2012年12月由美国批准用于甲状腺髓样癌的治疗。
Cabozantinib是多受体酪氨酸激酶抑制剂，并且正用于其他癌症的研究。在治疗前列腺癌的临床试验中已经出现了可观的结果。
适应症和用途
COMETRIQ是激酶抑制剂适用为进展性，转移甲状腺髓样癌(MTC)患者的治疗。
剂量和给药方法
● 推荐剂量：140mg口服，每天1次。
● 指导患者服用COMETRIQ前至少2小时和后至少1小时不要进食。
剂型和规格
20mg和80mg胶囊。
每天140mg，包括3x20mg和1x80mg，一盒共112粒胶囊 为28天疗程

Cometriq 20+80mg capsules (100mg and 140mg per day dose)
1. Name of the medicinal product
COMETRIQ 20 mg hard capsules
COMETRIQ 80 mg hard capsules
2. Qualitative and quantitative composition
One hard capsule contains cabozantinib (S)-malate equivalent to 20 mg or 80 mg cabozantinib.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Hard 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.
The hard capsules are orange with “XL184 80mg” 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 sections 4.4 and 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
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.
Patients with renal impairment
Cabozantinib should be used with caution in patients with renal impairment. Cabozantinib is not recommended for use in patients with severe renal impairment since there is limited data in patients with severe renal impairment, and safety and efficacy have not been established.
Patients with hepatic impairment
Cabozantinib is not recommended for use in patients with hepatic impairment, since there is limited data in patients with hepatic impairment, and safety and efficacy have not been established.
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
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 trial. 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).
Perforations, fistulas, and intra-abdominal abscesses
Serious 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 and events of arterial thromboembolism 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
Hemorrhage 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.
Wound complications
Wound complications have been observed with cabozantinib. Cabozantinib treatment should be stopped at least 28 days prior to scheduled surgery, 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. For invasive dental procedures, cabozantinib treatment should be held at least 28 days prior to scheduled surgery, 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.
Reversible posterior leukoencephalopathy syndrome
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior Reversible Encephalopathy Syndrome (PRES) has been observed with cabozantinib. Cabozantinib treatment should be discontinued in patients with RPLS.
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 μM), 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.
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 co-administration 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.
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.
P-glycoprotein substrates
Cabozantinib was an inhibitor (IC50 = 7.0 μM), 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 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.
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 breast-feeding 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 a 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, hypoalbumenia, and hyperbilirubinemia.
Tabulated summary 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1: Adverse reactions reported with cabozantinib

System Organ Class	Very Common	Common	Uncommon
Infections and infestations		abscess (including visceral, skin, tooth), pneumonia, folliculitis, fungal infection (including skin, oral, genital)	aspergilloma
Endocrine disorders		hypothyroidism
Metabolism and nutrition disorders	decreased appetite, hypocalcaemia, hypophosphataemia, hyperbilirubinemia, hypoalbumenia	dehydration
Psychiatric disorders		anxiety, depression, confusional state	abnormal dreams, delirium
Nervous system disorders	dysgeusia, headache, dizziness	peripheral neuropathy, paraesthesia, ageusia, tremor	ataxia, disturbance in attention, hepatic encephalopathy, loss of consciousness, speech disorder, transient ischaemic attack, posterior reversible encephalopathy syndrome
Eye disorders		vision blurred	cataract, conjunctivitis
Ear and labyrinth disorders		ear pain, tinnitus	hypoacusis
Cardiac disorders		atrial fibrillation	angina pectoris, supraventricular tachycardia
Vascular disorders	hypertension	hypotension, venous thrombosis, pallor, peripheral coldness	arterial thrombosis
Respiratory, thoracic, and mediastinal disorders	dysphonia, oropharyngeal pain	non-gastrointestinal fistula (including tracheal, pneumomediastinum, tracheo-oesophageal), pulmonary embolism, respiratory tract haemorrhage (including pulmonary, bronchial, tracheal), pneumonia aspiration	atelectasis, pharyngeal oedema, pneumonitis
Gastrointestinal disorders	diarrhoea, nausea, stomatitis, constipation, vomiting, abdominal pain, dysphagia, dyspepsia, glossodynia	gastrointestinal perforation, gastrointestinal haemorrhage, pancreatitis, haemorrhoids, anal fissure, anal inflammation, cheilitis	gastrointestinal fistula, oesophagitis
Hepatobiliary disorders		cholelithiasis
Skin and subcutaneous tissue disorders	palmar-plantar erythrodysaesthesia syndrome, hair colour changes, rash, dry skin, alopecia, erythema	hyperkeratosis, acne, blister, hair growth abnormal, skin exfolation, skin hypopigmentation	skin ulcer, telangiectasia
Musculoskeletal and connective tissue disorders	arthralgia, muscle spasms	musculoskeletal chest pain, osteonecrosis of jaw	rhabdomyolysis
Renal and urinary disorders		proteinuria, dysuria, haematuria	renal failure acute
Reproductive system and breast disorders			amenorrhoea, vaginal haemorrhage
General disorders and administration site conditions	fatigue, mucosal inflammation, asthenia	impaired wound healing, chills, face oedema	cyst, facial pain, localised oedema
Investigations	weight decreased, serum ALT, AST, and ALP increased, blood LDH increased, blood TSH increased, lymphopenia, neutropenia, thrombocytopenia	blood creatinine phosphokinase increased, neutrophil count decreased	activated partial thromboplastin time shortened, eosinophil count increased, platelet count increased

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. 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.
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
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
e-mail: medsafety@hpra.ie
Malta
ADR Reporting
Website: www.medicinesauthority.gov.mt/adrportal
4.9 Overdose
There 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: L01XE26.
Mechanism of action
Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodeling, 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, tumor 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, randomized 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.
An interim administrative analysis of OS performed including 75% of total deaths required for the final analysis shows a trend for prolonged OS in the cabozantinib arm compared to placebo: stratified HR (95% CI) 0.83 (0.60, 1,14); median (months) 26.0 cabozantinib vs. 20.3 placebo.
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	26.0 months	20.3 months
	HR: 0.83 (0.60, 1.14)
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
c 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, 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.
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 relationship between prolonged PFS and significant improvement in OS (HR 0.53, p=0.0179) has been demonstrated only in the subgroup of RET M918T mutation positive patients (n=81/219 cabozantinib arm). OS has not yet been analysed in other RET and/or RAS mutation 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).
This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited.
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary
5.2 Pharmacokinetic properties
Absorption
Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 2 to 5 hours post-dose.
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.
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%).
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
A difference in PK in patients with renal impairment cannot be excluded, as data in this population are not yet available.
Hepatic impairment
A difference in PK in patients with hepatic impairment cannot be excluded, as data in this population are not yet available.
Race
No data are available to determine a difference in PK based on race.
5.3 Preclinical safety data
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:
In rat and dog repeat-dose toxicity studies up to 6 months duration, target organs for toxicity were GI tract, bone marrow, lymphoid tissues, kidney, adrenal and reproductive tract tissues. The no observed adverse effect level (NOAEL) for these findings were below human clinical exposure levels at intended therapeutic dose.
Cabozantinib has shown no mutagenic or clastogenic potential in a standard battery of genotoxicity assays. Carcinogenicity studies have not been performed.
Fertility studies in rats have shown reduced male and female fertility. Further, hypospermatogenesis was observe in male dogs at exposure levels below human clinical exposure levels at intended therapeutic dose.
Embryo-foetal development studies were performed in rats and rabbits. In rats, cabozantinib caused postimplantation loss, foetal oedema, cleft palate/lip, dermal aplasia and kinked or rudimentary tail. In rabbits, cabozantinib produced foetal soft tissue changes (reduced spleen size, small or missing intermediate lung lobe) and increased foetal incidence of total malformations. NOAEL for embryo-foetal toxicity and teratogenic findings were below human clinical exposure levels at intended therapeutic dose.
Juvenile rats (comparable to a >2 year old pediatric population) administered cabozantinib showed increased WBC parameters, decreased haematopoiesis, pubescent/immature female reproductive system (without delayed vaginal opening), tooth abnormalities, reduced bone mineral content and density, liver pigmentation and bile duct hyperplasia. Findings in uterus/ovaries and decreased haematopoiesis appeared to be transient, while effects on bone parameters and liver pigmentation were sustained. Evaluations in juvenile rats (comparable to a <2 year old pediatric population) have not been performed.
6. Pharmaceutical particulars
6.1 List of excipients
Capsule content
Microcrystalline cellulose
Croscarmellose sodium
Sodium starch glycoloate
Silica colloidal anhydrous
Stearic acid
Capsule shell
Gelatin
Black iron oxide (E172) (20 mg capsules only)
Red iron oxide (E172) (80 mg capsules only)
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 either:
7 x 20 mg and 7 x 80 mg capsules (100 mg/day dose for a 7-day supply)
21 x 20 mg and 7 x 80 mg capsules (140 mg/day dose for a 7-day supply)
28 day pack containing:
56 capsules (4 blister cards of: 7 x 20 mg and 7 x 80 mg) (100 mg/day dose for a 28 day supply)
112 capsules (4 blister cards of: 21 x 20mg and 7 x 80 mg) (140 mg/day dose for a 28 day supply)
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
TMC Pharma Services Ltd.
Lodge Farm Barn
Elvetham Park Estate
Fleet Road
Hartley Wintney
Hampshire
RG27 8AS
United Kingdom
8. Marketing authorisation number(s)
EU/1/13/890/002
7 x 20 mg and 7 x 80 mg capsules (100 mg/day dose for a 7-day supply)
EU/1/13/890/003
21 x 20 mg and 7 x 80 mg capsules (140 mg/day dose for a 7-day supply)
EU/1/13/890/005
56 capsules (4 blister cards of: 7 x 20 mg and 7 x 80 mg) (100 mg/day dose for 28 day supply)
EU/1/13/890/006
112 capsules (4 blister cards of: 21 x 20mg and 7 x 80 mg) (140 mg/day dose for 28 day supply)
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 21 March 2014
10. Date of revision of the text
18/12/2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
Cometriq 20mg capsules (60mg per day dose)（http://www.medicines.org.uk/emc/medicine/29173）
美国FDA批准Cometriq(cabozantinib)治疗罕见型甲状腺癌
2012年11月29日美国食品药品监督管理局(FDA)批准Cometriq(cabozantinib)治疗已播散至身体其他部分(转移的)甲状腺髓样癌。
甲状腺制造一种有助于维持血中钙健康水平的激素被称为降钙素[calcitonin]细胞中发生甲状腺髓样癌。这性癌自发发生或在有某些基因突变家族，导致内分泌系统1种或更多癌症，包括甲状腺。
美国国立癌症研究所估计在2012年56,460 美国人将诊断有甲状腺癌和1,780将死于此病。约4%甲状腺癌是甲状腺髓癌，为罕见甲状腺癌之一。
FDA的药物评价和研究中心血液学和肿瘤室主任Richard Pazdur，M.D.说：“在过去2年中Cometriq是第二个被批准治疗甲状腺髓样癌和反映FDA承诺发展和批准为治疗罕见病药物，”“在2011年4月批准Caprelsa，有此罕见和难治疾病患者的治疗选择有限。”
美国FDA在其优先审评程序下在6个月内完成Cometriq的申请审评。这个程序为可能提供治疗重要进展或当前没有治疗存在的药物提供一个加快6个月审评。Cometriq因为意向治疗罕见病或情况还获得孤儿产品指定。
Cometriq是激酶抑制剂阻断涉及髓样癌细胞的发育和生长的异常激酶蛋白。在服用Cometriq前至少2小时和后1小时患者不应进食。
在一项涉及330例有甲状腺髓样癌患者临床研究确定Cometriq的安全性和有效性。用Cometriq治疗增加无癌进展生存患者生存时间长度(无进展生存) 而，有些患者，肿瘤大小减小(缓解率)。
被给予Cometriq患者无肿瘤生长生存平均11.2个月与之比较接受糖丸(安慰剂)患者平均4个月。结果还显示用Cometriq治疗患者27%肿瘤大小减小平均持续接近15个月，而who 接受安慰剂患者未见减小。用Cometriq治疗不延长 患者生命。

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注意：下产品美国和德国上市包装，不同包装和不同价格，采购者以咨询为准。
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产地国家：德国
原产地英文商品名:
Cometriq 140mg 112capsules /box(each blister containing a 80mg capsules and three 20MG capsules)
原产地英文药品名:
CABOZANTINIB S-MALATE
中文参考商品译名:
Cometriq混合剂 140毫克 112胶囊/盒（每个吸塑包含1个80毫克胶囊和3个20MG胶囊）
中文参考药品译名:
卡博替尼
生产厂家中文参考译名:
EXELIXIS
生产厂家英文名:
EXELIXIS
-------------------------------------------------
产地国家：德国
原产地英文商品名:
Cometriq 100mg 56capsules/box(Each blister contains 80mg capsules and 20MG capsules)
原产地英文药品名:
CABOZANTINIB S-MALATE
中文参考商品译名:
Cometriq混合剂 100毫克 56胶囊/盒（每个吸塑包含80毫克胶囊和20MG胶囊）
中文参考药品译名:
卡博替尼
生产厂家英文名:
Ipsen Pharma GmbH
-------------------------------------------------
产地国家：德国
原产地英文商品名:
Cometriq 84capsules(each blister containing a 20mg capsules and three 60MG capsules)
原产地英文药品名:
CABOZANTINIB S-MALATE
中文参考商品译名:
Cometriq混合剂  84粒包（每个泡罩包含20mg胶囊和三个60MG胶囊）
中文参考药品译名:
卡博替尼
生产厂家英文名:
Ipsen Pharma GmbH
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产地国家: 美国
原产地英文商品名:
Cometriq 100MG DILY DOSE 4BILISTER CARDS（EACH BLISTER CARD CONTAINS SEVEN 80MG AND SEVEN 20MG CAPSULES)
原产地英文药品名:
CABOZANTINIB S-MALATE
中文参考商品译名:
Cometriq混合剂 100毫克 4吸塑包 （每个吸塑包含七个80毫克和七20MG胶囊）
中文参考药品译名:
卡博替尼
生产厂家中文参考译名:
EXELIXIS
生产厂家英文名:
EXELIXIS
---------------------------------------------------
产地国家: 美国
原产地英文商品名:
Cometriq 60mg 21caps
原产地英文药品名:
CABOZANTINIB S-MALATE
中文参考商品译名:
Cometriq 60mg 21caps
中文参考药品译名:
卡博替尼
生产厂家中文参考译名:
EXELIXIS (US).
生产厂家英文名:
EXELIXIS (US).
--------------------------------------------------
产地国家: 美国
原产地英文商品名:
Cometriq 100mg 14caps
原产地英文药品名:
CABOZANTINIB S-MALATE
中文参考商品译名:
Cometriq 100mg 14caps
中文参考药品译名:
卡博替尼
生产厂家中文参考译名:
EXELIXIS (US).
生产厂家英文名:
EXELIXIS (US).