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英文药名：Stivarga（Regorafenib film-coated tablets） 中文药名：瑞格菲尼薄膜包衣片 生产厂家：拜尔制药
Table 2: Recommended measures and dose modifications in case of drug-related liver function test abnormalities
Regorafenib is eliminated mainly via the hepatic route. In clinical studies, no relevant differences in exposure, safety or efficacy were observed between patients with mild hepatic impairment (Child-Pugh A) and normal hepatic function. No dose adjustment is required in patients with mild hepatic impairment. Since only limited data are available for patients with moderate hepatic impairment (Child Pugh B), no dose recommendation can be provided. Close monitoring of overall safety is recommended in these patients (see sections 4.4 and 5.2). Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population. Renal impairment Available clinical data indicate similar exposure of regorafenib and its metabolites M-2 and M-5 in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. No dose adjustment is required in patients with mild, moderate or severe renal impairment (see also section 5.2). Elderly population In clinical studies, no relevant differences in exposure, safety or efficacy were observed between elderly (aged 65 years and above) and younger patients (see also section 5.2). Gender In clinical studies, no relevant differences in exposure, safety or efficacy were observed between male and female patients. No dose adjustment is necessary based on gender (see also section 5.2). Ethnic differences In clinical studies, no relevant differences in exposure or efficacy were observed between patients of different ethnic groups. A higher incidence of hand foot skin reaction (HFSR) / palmar-plantar erythrodysesthesia syndrome, severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Stivarga compared with Caucasians. The Asian patients treated with Stivarga in clinical studies were primarily from East Asia (~90%). There is limited data on regorafenib in the black patient population. No dose adjustment is necessary based on ethnicity (see section 5.2). Paediatric population There is no relevant use of Stivarga in the paediatric population in the indication of metastatic colorectal cancer. The safety and efficacy of regorafenib in patients below 18 years of age in the indication gastrointestinal stromal tumors (GIST) have not been established. No data are available. Method of administration Stivarga is for oral use. Stivarga should be taken at the same time each day. The tablets should be swallowed whole with water after a light meal that contains less than 30% fat. An example of a light (low-fat) meal would include 1 portion of cereal (about 30 g), 1 glass of skimmed milk, 1 slice of toast with jam, 1 glass of apple juice, and 1 cup of coffee or tea (520 calories, 2 g fat). 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 Hepatic effects Abnormalities of liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) have been frequently observed in patients treated with Stivarga. Severe liver function test abnormalities (Grade 3 to 4) and hepatic dysfunction with clinical manifestations (including fatal outcomes) have been reported in a small proportion of patients (see section 4.8). In clinical trials, a higher incidence of severe liver function test abnormalities and hepatic dysfunction was observed in Asian (in particular Japanese) patients treated with Stivarga as compared with Caucasians (see section 4.2). It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of treatment with Stivarga and monitor closely (at least every two weeks) during the first 2 months of treatment. Thereafter, periodic monitoring should be continued at least monthly and as clinically indicated. Regorafenib is a uridine diphosphate glucuronosyl transferase (UGT) 1A1 inhibitor (see section 4.5). Mild, indirect (unconjugated) hyperbilirubinaemia may occur in patients with Gilbert's syndrome. For patients with observed worsening of liver function tests considered related to treatment with Stivarga (i.e. where no alternative cause is evident, such as post-hepatic cholestasis or disease progression), the dose modification and monitoring advice in Table 2 should be followed (see section 4.2). Regorafenib is eliminated mainly via the hepatic route. Close monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment (see also sections 4.2 and 5.2). Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as Stivarga has not been studied in this population and exposure might be increased in these patients. Haemorrhage Stivarga has been associated with an increased incidence of haemorrhagic events, some of which were fatal (see section 4.8). Blood counts and coagulation parameters should be monitored in patients with conditions predisposing to bleeding, and in those treated with anticoagulants (e.g. warfarin and phenprocoumon) or other concomitant medicinal products that increase the risk of bleeding. In the event of severe bleeding necessitating urgent medical intervention, permanent discontinuation of Stivarga should be considered. Cardiac ischaemia and infarction Stivarga has been associated with an increased incidence of myocardial ischaemia and infarction (see section 4.8). Patients with unstable angina or new onset angina (within 3 months of starting Stivarga therapy), recent myocardial infarction (within 6 months of starting Stivarga therapy) and those with cardiac failure New York Heart Association (NYHA) Classification 2 or higher were excluded from the clinical studies. Patients with a history of ischaemic heart disease should be monitored for clinical signs and symptoms of myocardial ischaemia. In patients who develop cardiac ischaemia and/or infarction, interruption of Stivarga is recommended until resolution. The decision to re-start Stivarga therapy should be based on careful consideration of the potential benefits and risks of the individual patient. Stivarga should be permanently discontinued if there is no resolution. Posterior reversible encephalopathy syndrome (PRES) PRES has been reported in association with Stivarga treatment (see section 4.8). Signs and symptoms of PRES include seizures, headache, altered mental status, visual disturbance or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging. In patients developing PRES, discontinuation of Stivarga, along with control of hypertension and supportive medical management of other symptoms is recommended. Gastrointestinal perforation and fistula Gastrointestinal perforation (including fatal outcome) and fistulae have been reported in patients treated with Stivarga (see section 4.8). These events are also known to be common disease-related complications in patients with intra-abdominal malignancies. Discontinuation of Stivarga is recommended in patients developing gastrointestinal perforation or fistula. Arterial hypertension Stivarga has been associated with an increased incidence of arterial hypertension (see section 4.8). Blood pressure should be controlled prior to initiation of treatment with Stivarga. It is recommended to monitor blood pressure and to treat hypertension in accordance with standard medical practice. In cases of severe or persistent hypertension despite adequate medical management, treatment should be temporarily interrupted and/or the dose reduced at the discretion of the physician (see section 4.2). In case of hypertensive crisis, Stivarga should be discontinued. Wound healing complications As medicinal products with anti-angiogenic properties may suppress or interfere with wound healing, temporary interruption of Stivarga is recommended for precautionary reasons in patients undergoing major surgical procedures. The decision to resume treatment with Stivarga following major surgical intervention should be based on clinical judgment of adequate wound healing. Dermatological toxicity Hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia syndrome and rash represent the most frequently observed dermatological adverse reactions with Stivarga (see section 4.8). ). In clinical trials, a higher incidence of HFSR was observed in Asian (in particular Japanese) patients treated with Stivarga as compared with Caucasians (see section 4.2). Measures for the prevention of HFSR include control of calluses and use of shoe cushions and gloves to prevent pressure stress to soles and palms. Management of HFSR may include the use of keratolytic creams (e.g. urea-, salicylic acid-, or alpha hydroxyl acid-based creams applied sparingly only on affected areas) and moisturizing creams (applied liberally) for symptomatic relief. Dose reduction and/or temporary interruption of Stivarga, or in severe or persistent cases, permanent discontinuation of Stivarga should be considered (see section 4.2). Biochemical and metabolic laboratory test abnormalities Stivarga has been associated with an increased incidence of electrolyte abnormalities (including hypophosphatemia, hypocalcaemia, hyponatraemia and hypokalaemia) and metabolic abnormalities (including increases in thyroid stimulating hormone, lipase and amylase). The abnormalities are generally of mild to moderate severity, not associated with clinical manifestations, and do not usually require dose interruptions or reductions. It is recommended to monitor biochemical and metabolic parameters during Stivarga treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Dose interruption or reduction, or permanent discontinuation of Stivarga should be considered in case of persistent or recurrent significant abnormalities (see section 4.2). Important information about some of the ingredients Each daily dose of 160 mg contains 2.427 mmol (or 55.8 mg) of sodium. To be taken into consideration by patients on a controlled sodium diet. Each daily dose of 160 mg contains 1.68 mg of lecithin (derived from soya). 4.5 Interaction with other medicinal products and other forms of interaction Inhibitors of CYP3A4 and UGT1A9 / inducers of CYP3A4 In vitro data indicate that regorafenib is metabolized by cytochrome CYP3A4 and uridine diphosphate glucuronosyl transferase UGT1A9. Administration of ketoconazole (400 mg for 18 days), a strong CYP3A4 inhibitor, with a single dose of regorafenib (160 mg on day 5) resulted in an increase in mean exposure (AUC) of regorafenib of approximately 33%, and a decrease in mean exposure of the active metabolites, M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), of approximately 90%. It is recommended to avoid concomitant use of strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin and voriconazole) as their influence on the steady-state exposure of regorafenib and its metabolites has not been studied. Co-administration of a strong UGT1A9 inhibitor (e.g. mefenamic acid, diflunisal, and niflumic acid) during regorafenib treatment should be avoided, as their influence on the steady-state exposure of regorafenib and its metabolites has not been studied. Administration of rifampicin (600 mg for 9 days), a strong CYP3A4 inducer, with a single dose of regorafenib (160 mg on day 7) resulted in a reduction in AUC of regorafenib of approximately 50%, a 3- to 4-fold increase in mean exposure of the active metabolite M-5, and no change in exposure of active metabolite M-2. Other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital and St. John's wort) may also increase metabolism of regorafenib. Strong inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered. UGT1A1 and UGT1A9 substrates In vitro data indicate that regorafenib as well as its active metabolite M-2 inhibit glucuronidation mediated by UGT1A1 and UGT1A9 whereas M-5 only inhibits UGT1A1 at concentrations which are achieved in vivo at steady state. Administration of regorafenib with a 5-day break prior to administration of irinotecan resulted in an increase of approximately 44% in AUC of SN-38, a substrate of UGT1A1 and an active metabolite of irinotecan. An increase in AUC of irinotecan of approximately 28% was also observed. This indicates that co-administration of regorafenib may increase systemic exposure to UGT1A1 and UGT1A9 substrates. Breast cancer resistance protein (BCRP) and P-glycoprotein substrates Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of rosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in Cmax. This indicates that co-administration of regorafenib may increase the plasma concentrations of other concomitant BCRP substrates (e.g. methotrexate, fluvastatin, atorvastatin). Therefore, it is recommended to monitor patients closely for signs and symptoms of increased exposure to BCRP substrates. Clinical data indicate that regorafenib has no effect on digoxin pharmacokinetics, therefore can be given concomitantly with p-glycoprotein substrates, such as digoxin, without a clinically meaningful drug interaction. Inhibitors of P-glycoprotein and BCRP/Inducers of P-glycoprotein and BCRP In vitro studies indicate that the active metabolites M-2 and M-5 are substrates for P-glycoprotein and BCRP. Inhibitors and inducers of BCRP and P-glycoprotein may interfere with the exposure of M-2 and M-5. The clinical significance of these findings is unknown (see also section 5.2). CYP isoform-selective substrates In vitro data indicate that regorafenib is a competitive inhibitor of the cytochromes CYP2C8 (Ki value of 0.6 micromolar), CYP2C9 (Ki value of 4.7 micromolar), CYP2B6 (Ki value of 5.2 micromolar) at concentrations which are achieved in vivo at steady state (peak plasma concentration of 8.1 micromolar). The in vitro inhibitory potency towards CYP3A4 (Ki value of 11.1 micromolar) and CYP2C19 (Ki value of 16.4 micromolar) was less pronounced. A clinical probe substrate study was performed to evaluate the effect of 14 days of dosing with 160 mg regorafenib on the pharmacokinetics of probe substrates of CYP2C8 (rosiglitazone) CYP2C9 (S-warfarin), CYP 2C19 (omeprazole) and CYP3A4 (midazolam). Pharmacokinetic data indicate that regorafenib may be given concomitantly with substrates of CYP2C8, CYP2C9, CYP3A4, and CYP2C19 without a clinically meaningful drug interaction (see also section 4.4). Antibiotics The concentration-time profile indicates that regorafenib and its metabolites may undergo enterohepatic circulation (see section 5.2). Co-administration with neomycin, a poorly absorbed antimicrobial agent used for eradicating the gastrointestinal microflora (which may interfere with the enterohepatic circulation of regorafenib) had no effect on the regorafenib exposure, but there was an approximately 80% decrease in the exposure of the active metabolites M-2 and M-5 which showed in vitro and in vivo comparable pharmacological activity as regorafenib.The clinical significance of this neomycin interaction is unknown, but may result in a decreased efficacy of regorafenib. Pharmacokinetic interactions of other antibiotics have not been studied. Bile salt-sequestering agents Regorafenib, M-2 and M-5 are likely to undergo enterohepatic circulation (see section 5.2). Bile salt-sequestering agents such as cholestyramine and cholestagel may interact with regorafenib by forming insoluble complexes which may impact absorption (or reabsorption), thus resulting in potentially decreased exposure. The clinical significance of these potential interactions is unknown, but may result in a decreased efficacy of regorafenib. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/Contraception in males and females Women of childbearing potential must be informed that regorafenib may cause foetal harm. Women of childbearing potential and men should ensure effective contraception during treatment and up to 8 weeks after completion of therapy. Pregnancy There are no data on the use of regorafenib in pregnant women. Based on its mechanism of action regorafenib is suspected to cause foetal harm when administered during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Stivarga should not be used during pregnancy unless clearly necessary and after careful consideration of the benefits for the mother and the risk to the foetus. Breast-feeding It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib or its metabolites are excreted in milk. A risk to the breast-fed child cannot be excluded. Regorafenib could harm infant growth and development (see section 5.3). Breast-feeding must be discontinued during treatment with Stivarga. Fertility There are no data on the effect of Stivarga on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility (see section 5.3). 4.7 Effects on ability to drive and use machines No studies on the effects of Stivarga on the ability to drive or use machines have been performed. If patients experience symptoms affecting their ability to concentrate and react during treatment with Stivarga, it is recommended that they do not drive or use machines until the effect subsides. 4.8 Undesirable effects Summary of the safety profile The overall safety profile of Stivarga is based on data from more than 1,200 treated patients in clinical trials including placebo-controlled phase III data for 500 patients with metastatic colorectal cancer (CRC) and 132 patients with gastrointestinal stromal tumours (GIST). The safety profile of regorafenib in these studies was consistent with the safety results of a phase III B study conducted in 2872 patients with metastatic colorectal cancer whose disease had progressed after treatment with standard therapies. The most serious adverse drug reactions in patients receiving Stivarga are severe liver injury, haemorrhage and gastrointestinal perforation. The most frequently observed adverse drug reactions (≥30%) in patients receiving Stivarga are asthenia/fatigue, hand foot skin reaction, diarrhoea, decreased appetite and food intake, hypertension, dysphonia and infection. Tabulated list of adverse reactions The adverse drug reactions reported in clinical trials in patients treated with Stivarga are shown in Table 3. They are classified according to System Organ Class and the most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions. Adverse drug reactions are grouped according to their frequencies. Frequency groups are defined by the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); and rare (≥1/10,000 to <1/1,000). Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Table 3: Adverse drug reactions (ADRs) reported in clinical trials in patients treated with Stivarga System Organ Class (MedDRA) Very common Common Uncommon Rare Infections and infestations Infection Neoplasms benign, malignant and unspecified (including cysts and polyps) Keratoacanthoma/Squamous cell carcinoma of the skin Blood and lymphatic system disorders Thrombocytopenia Anaemia Leucopenia Immune system disorders Hypersensitivity reaction Endocrine disorders Hypothyroidism Metabolism and nutrition disorders Decreased appetite and food intake Hypokalaemia Hypophosphataemia Hypocalcaemia Hyponatraemia Hypomagnesaemia Hyperuricaemia Nervous system disorders Headache Tremor Posterior reversible encephalopathy syndrome (PRES Cardiac disorders Myocardial infarction Myocardial ischaemia Vascular disorders Haemorrhage Hypertension Hypertensive crisis Respiratory, thoracic and mediastinal disorders Dysphonia Gastrointestinal disorders Diarrhoea Stomatitis Vomiting Nausea Taste disorders Dry mouth Gastro-oesophageal reflux Gastroenteritis Gastrointestinal perforation* Gastrointestinal fistula Hepatobiliary disorders Hyperbilirubinaemia Increase in transaminases Severe liver injury*# Skin and subcutaneous tissue disorders Hand-foot skin reaction** Rash Alopecia Dry skin Exfoliative rash Nail disorder Erythema multiforme Stevens-Johnson syndrome Toxic epidermal necrolysis Musculoskeletal and connective tissue disorders Musculoskeletal stiffness Renal and urinary disorders Proteinuria General disorders and administration site conditions Asthenia/fatigue Pain Fever Mucosal inflammation Investigations Weight loss Increase in amylase Increase in lipase Abnormal International normalised ratio fatal cases have been reported palmar-plantar erythrodysesthesia syndrome in MedDRA terminology according to drug-induced liver injury (DILI) criteria of the international DILI expert working group Description of selected adverse reactions In most cases of severe liver injury, liver dysfunction had an onset within the first 2 months of therapy, and was characterized by a hepatocellular pattern of injury with transaminase elevations >20xULN, followed by bilirubin increase. In clinical trials, a higher incidence of severe liver injury with fatal outcome was observed in Japanese patients (~1.5%) treated with Stivarga compared with non-Japanese patients (<0.1%). In the two placebo-controlled phase III trials, the overall incidence of hemorrhage was 19.3% in patients treated with Stivarga. Most cases of bleeding events in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 16.9%), most notably epistaxis (7.6%). Fatal events in patients treated with Stivarga were uncommon (0.6%), and involved the respiratory, gastrointestinal and genitourinary tracts. In the two placebo-controlled phase III trials, infections were more often observed in patients treated with Stivarga as compared to patients receiving placebo (all grades: 31.0% vs. 14.4%). Most infections in patients treated with Stivarga were mild to moderate in severity (Grades 1 and 2: 22.9%), and included urinary tract infections (6.8%), nasopharyngitis (4.2%) as well as mucocutaneous and systemic fungal infections (2.4%). No difference in fatal outcomes associated with infection between treatment groups was observed (0.6%, Stivarga arm vs. 0.6%, placebo arm) In the placebo-controlled metastatic CRC phase III trial, the overall incidence of hand-foot skin reaction was 45.2% in patients treated with Stivarga as compared to 7.1% in patients receiving placebo. In the placebo-controlled GIST phase III trial, the overall incidence of hand-foot skin reaction was 66.7% in patients treated with Stivarga as compared to 15.2% in patients receiving placebo. In both trials, most cases of hand-foot skin reaction in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 28.6%, CRC and 44.7%, GIST). The incidence of Grade 3 hand-foot skin reaction was 16.6% (CRC) and 22.0% (GIST). In both trials, the overall incidence of hand-foot skin reaction (78.4%, CRC and 88.2%, GIST) was higher in Stivarga-treated Asian patients compared to other ethnicities. The incidence of Grade 3 hand-foot skin reaction in Asians was 28.4% (CRC) and 23.5% (GIST) (see sections 4.2 and 4.4). In the placebo-controlled metastatic CRC phase III trial the overall incidence of hypertension was 30.4% in patients treated with Stivarga as compared to 7.9% in patients receiving placebo. In the placebo-controlled GIST phase III trial, the overall incidence of hypertension was 59.1% in patients treated with Stivarga as compared to 27.3% in patients receiving placebo. In both trials, most cases of hypertension in patients treated with Stivarga appeared during the first cycle of treatment and were mild to moderate in severity (Grades 1 and 2: 22.8%, CRC and 31.1%, GIST). The incidence of Grade 3 hypertension was 7.6% (CRC) and 27.3% (GIST). One case of Grade 4 hypertension was reported in the GIST trial. In the placebo-controlled phase III trial in patients with metastatic CRC, the overall incidence of treatment emergent proteinuria was 7.4% in patients treated with Stivarga as compared to 2.4% in patients receiving placebo . Of these events, 40.5% in the Stivarga arm and 66.7% in the placebo arm have been reported as not recovered / not resolved. In the placebo-controlled GIST phase III trial, the overall incidence of proteinuria was 6.8% in patients treated with Stivarga compared to 1.5% in patients receiving placebo. Across all clinical trials, cardiac disorder events (all grades) have been more often (20.5% vs. 10.4%) reported in Stivarga-treated patients aged 75 years or older (N=78) as compared to Stivarga-treated patients below 75 years (N=995). Laboratory test abnormalities Treatment-emergent laboratory abnormalities observed in the placebo-controlled phase III trials are shown in Table 4, Table 4a and Table 5 (see also section 4.4). Table 4: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trial in patients with metastatic CRC (CORRECT)
Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 International normalized ratio No Grade 4 denoted in CTCAE, Version 3.0 Compared to the global phase III CRC trial (CORRECT) with predominantly (~80%) Caucasian patients enrolled, a higher incidence of liver enzyme increases was observed in Stivarga-treated patients in the Asian phase III CRC trial (CONCUR) with predominantly (> 90%) East Asian patients enrolled. Table 4a: Treatment emergent liver enzyme test abnormalities reported in placebo-controlled phase III trial in Asian patients with metastatic CRC (CONCUR)
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 Table 5: Treatment-emergent laboratory test abnormalities reported in placebo-controlled phase III trial (double-blind phase) in patients with GIST (GRID)
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 International normalized ratio - No Grade 4 denoted in CTCAE, Version 4.0 In the two placebo-controlled phase III trials, tests on thyroid stimulating hormone (TSH) showed post baseline >ULN in 26.1% of patients treated with Stivarga and in 15.1% of patients receiving placebo. TSH post baseline >4 times ULN was reported in 6.9% of patients treated with Stivarga and in 0.7% of patients receiving placebo. Concentration of free triiodothyronine (FT3) post baseline below lower limit of normal (<LLN) was reported in 25.6% of patients treated with Stivarga and in 20.9% of patients receiving placebo. Concentration of free thyroxin (FT4) post baseline <LLN was reported in 8.0% of patients treated with Stivarga and 6.6% of patients receiving placebo. Overall approximately 7% of patients treated with Stivarga developed hypothyroidism requiring hormonal replacement treatment. 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose The highest dose of Stivarga studied clinically was 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhoea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no specific antidote for Stivarga overdose. In the event of suspected overdose, Stivarga should be discontinued immediately, with best supportive care initiated by a medical professional, and the patient should be observed until clinical stabilisation. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitor; ATC Code: L01XE21 Mechanism of action and pharmacodynamic effects Regorafenib is an oral tumour deactivation agent that potently blocks multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), and the tumour microenvironment (PDGFR, FGFR). In particular, regorafenib inhibits mutated KIT, a major oncogenic driver in gastrointestinal stromal tumors, and thereby blocks tumor cell proliferation. In preclinical studies regorafenib has demonstrated potent antitumour activity in a broad spectrum of tumour models including colorectal and gastrointestinal stromal tumour models which is mediated by its anti-angiogenic and anti-proliferative effects. In addition, regorafenib has shown anti-metastatic effects in vivo. Major human metabolites (M-2 and M-5) exhibited similar efficacies compared to regorafenib in in vitro and in vivo models. Clinical efficacy and safety Metastatic colorectal cancer (CRC) The clinical efficacy and safety of Stivarga have been evaluated in an international, multi-centre, randomised, double-blind, placebo-controlled phase III study (CORRECT) in patients with metastatic colorectal cancer who have progressed after failure of standard therapy. The primary efficacy endpoint was Overall Survival (OS). Secondary endpoints were Progression-Free Survival (PFS), objective tumour response rate and disease control rate. In total, 760 patients were randomised 2:1 to receive 160 mg regorafenib (4 tablets Stivarga each containing 40 mg regorafenib) orally once daily (N=505) plus Best Supportive Care (BSC) or matching placebo (N=255) plus BSC for 3 weeks on therapy followed by 1 week off therapy. The mean daily regorafenib dose received was 147 mg. Patients continued therapy until disease progression or unacceptable toxicity. A pre-planned interim analysis for efficacy was performed when 432 deaths had occurred. The study was un-blinded after this planned interim analysis of OS had crossed the pre-specified efficacy boundary. Of the 760 randomised patients, the median age was 61 years, 61% were male, 78% were Caucasian, and all patients had baseline ECOG Performance Status (PS) of 0 or 1. PS ≥2 was reported during Stivarga treatment in 11.4% of patients. The median treatment duration and daily dose, as well as the rate of dose modification and dose reduction were similar to those observed in patients with a reported PS ≥ 2 receiving placebo (8.3%). The majority of patients with PS ≥2 discontinued treatment for progressive disease. The primary site of disease was colon (65%), rectum (29%), or both (6%). A KRAS mutation was reported in 57% of patients at study entry. Most patients (52%) received 3 or fewer previous lines of treatment for metastatic disease. Therapies included treatment with fluoropyrimidine-based chemotherapy, an anti-VEGF therapy, and, if the patient was KRAS wild type, an anti-EGFR therapy. The addition of Stivarga to BSC resulted in significantly longer survival as compared to placebo plus BSC with a hazard ratio of 0.774 (p=0.005178 stratified log rank test) and a median OS of 6.4 months vs. 5.0 months [95% CI 0.636, 0.942] (see Table 6 and Figure 1). PFS was significantly longer in patients receiving Stivarga plus BSC (hazard ratio: 0.494, p<0.000001, see Table 6). The response rate (complete response or partial response) was 1% and 0.4% for Stivarga and placebo treated patients, respectively (p=0.188432, 1-sided). The disease control rate (complete response or partial response or stable disease) was significantly higher in patients treated with Stivarga (41.0% vs. 14.9%, p<0.000001, 1 sided). Table 6: Efficacy results from the CORRECT study
Hazard ratio < 1 favours Stivarga based on investigator's assessment of tumour response Figure 1: Kaplan-Meier curve of overall survival
Hazard ratio < 1 favors Stivarga NR: not reached Figure 2: Kaplan-Meier curves of Progression-Free Survival
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