抗癌新药STIVARGA(REGORAFENIB)TABLET ORAL获美国批准上市 ——比目标日期提前一个月完成优先审评 2012年9月27日美国食品药品监督管理局批准Stivarga(regorafenib)治疗经治疗后进展和播散至机体其他部位(转移)结肠直肠癌患者。 Stivargas是一种多-激酶抑制剂阻断几个促进癌生长的酶。药物是在FDA的优先审评程序下进行，该程序为在治疗中提供重要进展或当无适当存在治疗提供治疗的药物提供加快6个月的审评。 Stivarga正是在产品的处方药物用户收费目标日期2012年10月27日提前1个月被批准 ，监管局计划在该日期完成药物申请审评。 FDA的药物研究和评价中心的血液学和肿瘤室主任Richard Pazdur，M.D说：“Stivarga是最新的结肠直肠癌治疗显示延长患者生命能力和过去两个月为结肠直肠癌患者第二个被批准药物”。 根据美国疾病控制和预防中心，结肠直肠癌是美国男性和女性中第三位最常见癌症和第三位领先致死癌症。美国国立卫生研究院估计在2012年143,460美国人将被诊断结肠直肠癌，和51,690人将死于此病。 在760例既往治疗过转移结肠直肠癌患者单个临床研究评价Stivarga 的安全性和有效性。患者被随机赋予接受Stivarga或安慰剂除了最佳支持治疗(BSC)，其中包括有助于处理副作用和癌的症状治疗。患者接受治疗直至其癌进展或副作用成为不能接受为止。 研究结果显示用Stivarga加BSC治疗患者生活中位数为6.4个月与之比较用安慰剂加BSC治疗患者中位数5个月。结果还显示用Stivarga加BSC治疗患者经历肿瘤生长延缓(无进展活存)中位时间2个月相比较接受安慰剂加BSC患者中位时间1.7个月。 Stivarga 正被批准有一个黑框警告警告患者和卫生保健专业人员用Stivarga治疗患者在临床研究期间发生严重和致命性肝毒性。用Stivarga治疗患者报道最常见副作用包括软弱或疲乏，食欲不振，手足综合征(也称为掌足红肿)，腹泻，口腔溃疡(口腔粘膜炎)，体重减轻，感染，高血压，和音量或质量变化(发音困难)， 2012年8月，美国FDA批准Zaltrap(ziv-aflibercept)与FOLFIRI(叶酸，氟尿嘧啶[fluorouracil]和伊立替康)化疗方案联合使用治疗转移结肠直肠癌成年。 Stivarga is marketed由位于韦恩，新泽西州的Bayer HealthCare Pharmaceuticals上市， Zaltrap is marketed by位于布里奇沃特，新泽西州 Bridgewater，基于sanofi-aventis公司上市。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use STIVARGA safely and effectively. See full prescribing information for STIVARGA. STIVARGA ® (regorafenib) tablets, for oral use Initial U.S. Approval: 2012 WARNING: HEPATOTOXICITYSee full prescribing information for complete boxed warning. • Severe and sometimes fatal hepatotoxicity has occurred in clinical trials. (5.1) • Monitor hepatic function prior to and during treatment. (5.1) • Interrupt and then reduce or discontinue Stivarga for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence. (2.2) RECENT MAJOR CHANGES Indications and Usage, Colorectal Cancer ( 1.1) 6/2016  Warnings and Precautions, Hepatotoxicity ( 5.1) 6/2016  Warnings and Precautions, Dermatologic Toxicity ( 5.3) 6/2016 INDICATIONS AND USAGE Stivarga is a kinase inhibitor indicated for the treatment of patients with: • Metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS-wild type, an anti-EGFR therapy. ( 1.1) • Locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. ( 1.2) DOSAGE AND ADMINISTRATION • Recommended dose: 160 mg orally, once daily for the first 21 days of each 28-day cycle. ( 2.1) • Take Stivarga with a low-fat meal. ( 2.1, 12.3) DOSAGE FORMS AND STRENGTHS Tablets: 40 mg (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS • Hepatotoxicity: Monitor liver function tests and dose reduce or discontinue based on severity and duration. • Hemorrhage: Permanently discontinue Stivarga for severe or life-threatening hemorrhage. ( 5.2) • Dermatologic toxicity: Interrupt and then reduce or discontinue Stivarga depending on severity and persistence of dermatologic toxicity. ( 5.3) • Hypertension: Temporarily or permanently discontinue Stivarga for severe or uncontrolled hypertension. ( 5.4) • Cardiac ischemia and infarction: Withhold Stivarga for new or acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events. ( 5.5) • Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue Stivarga. ( 5.6) • Gastrointestinal perforation or fistula: Discontinue Stivarga. ( 5.7) • Wound healing complications: Stop Stivarga before surgery. Discontinue in patients with wound dehiscence. ( 5.8) • Embryo-fetal toxicity: Can cause fetal harm. Advise women of potential risk to a fetus and to use effective contraception during treatment and for 2 months after the final dose. Advise males to use effective contraception for 2 months after the final dose. ( 5.9, 8.1, 8.3) ADVERSE REACTIONS The most common adverse reactions (≥20%) are asthenia/fatigue, hand-foot skin reaction (HFSR), diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain, decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea. (6) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Strong CYP3A4 inducers: Avoid strong CYP3A4 inducers. ( 7.1) • Strong CYP3A4 inhibitors: Avoid strong CYP3A4 inhibitors. ( 7.2) USE IN SPECIFIC POPULATIONS Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of the drug to the mother. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 6/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Colorectal Cancer Stivarga® is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy. 1.2 Gastrointestinal Stromal Tumors Stivarga is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended dose is 160 mg Stivarga (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity. Take Stivarga at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat [see Clinical Pharmacology (12.3)]. Do not take two doses of Stivarga on the same day to make up for a missed dose from the previous day. 2.2 Dose Modifications Interrupt Stivarga for the following: • Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia (PPE)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR • Symptomatic Grade 2 hypertension • Any Grade 3 or 4 adverse reaction. Reduce the dose of Stivarga to 120 mg: • For the first occurrence of Grade 2 HFSR of any duration • After recovery of any Grade 3 or 4 adverse reaction • For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity Reduce the dose of Stivarga to 80 mg: • For re-occurrence of Grade 2 HFSR at the 120 mg dose • After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity) Discontinue Stivarga permanently for the following: • Failure to tolerate 80 mg dose • Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN) • Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN • Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg • For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks  3 DOSAGE FORMS AND STRENGTHS Stivarga is a 40 mg, light pink, oval-shaped, film-coated tablet, debossed with ‘BAYER’ on one side and ‘40’ on the other side. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Severe drug-induced liver injury with fatal outcome occurred in Stivarga-treated patients in clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm. In Study 2, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm [see Adverse Reactions (6.1)]. Obtain liver function tests (ALT, AST, and bilirubin) before initiation of Stivarga and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline. Temporarily hold and then reduce or permanently discontinue Stivarga depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)]. 5.2 Hemorrhage Stivarga caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% in Stivarga-treated patients compared to 8% and 3% in placebo-treated patients in Studies 1 and 2. Fatal hemorrhage occurred in 4 of 632 (0.6%) of Stivarga-treated patients in Studies 1 and 2 and involved the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue Stivarga in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)]. 5.3 Dermatologic Toxicity Stivarga increased the incidence of adverse reactions involving the skin and subcutaneous tissues (72% versus 24% in Study 1 and 78% versus 24% in Study 2), including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE), and severe rash requiring dose modification. The overall incidence of HFSR was higher in Stivarga-treated patients, (45% versus 7% in Study 1 and 67% versus 12% in Study 2) than in the placebo-treated patients. Most cases of HFSR in Stivarga-treated patients appeared during the first cycle of treatment (69% and 71% of patients who developed HFSR in Study 1 and Study 2, respectively). The incidence of Grade 3 HFSR (17% versus 0% in Study 1 and 22% versus 0% in Study 2), Grade 3 rash (6% versus <1% in Study 1 and 7% versus 0% in Study 2), serious adverse reactions of erythema multiforme (0.2% vs. 0% in Study 1) and Stevens-Johnson Syndrome (0.2% vs. 0% in Study 1) was higher in Stivarga-treated patients [see Adverse Reactions (6.1)]. In both studies, a higher incidence of HFSR was observed in Asian patients treated with Stivarga (all grades: 78.4% in Study 1 and 88.2% in Study 2 and Grade 3: 28.4% in Study 1 and 23.5% in Study 2) [see Use in Specific Populations (8.8)]. Toxic epidermal necrolysis occurred in 0.17% of 1200 Stivarga-treated patients across all clinical trials. Withhold Stivarga, reduce the dose, or permanently discontinue Stivarga depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for symptomatic relief. 5.4 Hypertension Stivarga caused an increased incidence of hypertension (30% versus 8% in Study 1 and 59% versus 27% in Study 2) [see Adverse Reactions (6.1)]. Hypertensive crisis occurred in 0.25% of 1200 Stivarga-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (72% in Study 1 and Study 2). Do not initiate Stivarga unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold Stivarga for severe or uncontrolled hypertension [see Dosage and Administration (2.2)]. 5.5 Cardiac Ischemia and Infarction Stivarga increased the incidence of myocardial ischemia and infarction in Study 1 (1.2% versus 0.4%) [see Adverse Reactions (6.1)]. Withhold Stivarga in patients who develop new or acute onset cardiac ischemia or infarction. Resume Stivarga only after resolution of acute cardiac ischemic events, if the potential benefits outweigh the risks of further cardiac ischemia. 5.6 Reversible Posterior Leukoencephalopathy Syndrome Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 1200 Stivarga-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion or altered mental function. Discontinue Stivarga in patients who develop RPLS. 5.7 Gastrointestinal Perforation or Fistula Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with Stivarga across all clinical trials; this included four fatal events. In Study 2, 2.1% (4/188) of Stivarga-treated patients who were treated during the blinded or open-label portion of the study developed gastrointestinal fistula or perforation; of these, two cases of gastrointestinal perforation were fatal. Permanently discontinue Stivarga in patients who develop gastrointestinal perforation or fistula. 5.8 Wound Healing Complications No formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as regorafenib can impair wound healing, discontinue treatment with regorafenib at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on clinical judgment of adequate wound healing. Discontinue regorafenib in patients with wound dehiscence. 5.9 Embryo-Fetal Toxicity Based on animal studies and its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no available data on Stivarga use in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Stivarga and for 2 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Stivarga and for 2 months after the final dose [see Use in Specific Populations (8.1), (8.3)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Hepatotoxicity [see Warnings and Precautions (5.1)] • Hemorrhage [see Warnings and Precautions ( 5.2 )] • Dermatological Toxicity [see Warnings and Precautions ( 5.3 )] • Hypertension [see Warnings and Precautions (5.4)] • Cardiac Ischemia and Infarction [see Warnings and Precautions ( 5.5 )] • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions ( 5.6 )] • Gastrointestinal Perforation or Fistula [see Warnings and Precautions ( 5.7 )] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice. The most frequently observed adverse drug reactions (≥20%) in patients receiving Stivarga are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain, decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea. The most serious adverse reactions in patients receiving Stivarga are hepatotoxicity, hemorrhage, and gastrointestinal perforation. 6.1 Clinical Trials Experience Colorectal Cancer The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer received Stivarga as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 7.3 (range 0.3, 47.0) weeks for patients receiving Stivarga. Due to adverse reactions, 61% of the patients receiving Stivarga required a dose interruption and 38% of the patients had their dose reduced. Adverse reactions that resulted in treatment discontinuation occurred in 8.2% of Stivarga-treated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of Stivarga. Table 1 compares the incidence of adverse reactions (≥10%) in patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 1). Table 1: Adverse drug reactions reported in ≥10% of patients treated with Stivarga in Study 1 and reported more commonly than in patients receiving placebo Adverse Reactions Stivarga (N=500) Placebo (N=253) Grade Grade All % ≥ 3 % All % ≥ 3 % General disorders and administration site conditions Asthenia/fatigue Pain Fever 64 29 28 15 3 2 46 21 15 9 2 0 Metabolism and nutrition disorders Decreased appetite and food intake 47 5 28 4 Skin and subcutaneous tissue disorders HFSR/PPE Rash † 45 26 17 6 7 4 0 <1 Gastrointestinal disorders Diarrhea Mucositis 43 33 8 4 17 5 2 0 Investigations Weight loss 32 <1 10 0 Infections and infestations Infection 31 9 17 6 Vascular disorders Hypertension Hemorrhage ‡ 30 21 8 2 8 8 <1 <1 Respiratory, thoracic and mediastinal disorders Dysphonia 30 0 6 0 Nervous system disorders Headache 10 <1 7 0 Adverse reactions graded according to National Cancer Institute Common Toxicity for Adverse Events version 3.0 (NCI CTCAE v3.0). The term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash. Fatal outcomes observed. Laboratory abnormalities observed in Study 1 are shown in Table 2. Table 2: Laboratory test abnormalities reported in Study 1 Laboratory Parameter Stivarga (N=500 ) Placebo (N=253 ) Grade Grade All % 3 % 4 % All % 3 % 4 %   Blood and lymphatic system disorders Anemia 79 5 1 66 3 0 Thrombocytopenia 41 2 <1 17 <1 0 Neutropenia 3 1 0 0 0 0 Lymphopenia 54 9 0 34 3 0 Metabolism and nutrition disorders Hypocalcemia 59 1 <1 18 1 0 Hypokalemia 26 4 0 8 <1 0 Hyponatremia 30 7 1 22 4 0 Hypophosphatemia 57 31 1 11 4 0 Hepatobiliary disorders Hyperbilirubinemia 45 10 3 17 5 3 Increased AST 65 5 1 46 4 1 Increased ALT 45 5 1 30 3 <1 Renal and urinary disorders Proteinuria 60 <1 0 34 <1 0 Investigations Increased INR ‡ 24 4 N/A 17 2 N/A Increased Lipase 46 9 2 19 3 2 Increased Amylase 26 2 <1 17 2 <1 % based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo). Common Terminology Criteria for Adverse Events (CTCAE), v3.0. International normalized ratio: No Grade 4 denoted in CTCAE, v3.0. Gastrointestinal Stromal Tumors The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 2) in which 132 patients (median age 60 years; 64% men) with previously-treated GIST received Stivarga as a single agent at a dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 66 patients (median age 61 years; 64% men) received placebo. The median duration of therapy was 22.9 (range 0.1, 50.9) weeks for patients receiving Stivarga. Dose interruptions for adverse events were required in 58% of patients receiving Stivarga and 50% of patients had their dose reduced. Adverse reactions that resulted in treatment discontinuation were reported in 2.3% of Stivarga-treated patients compared to 1.5% of patients who received placebo. Table 3 compares the incidence of adverse reactions (≥10%) in GIST patients receiving Stivarga and reported more commonly than in patients receiving placebo (Study 2). Table 3: Adverse reactions reported in ≥10% patients treated with Stivarga in Study 2 and reported more commonly than in patients receiving placebo* Adverse Reactions Stivarga (N=132) Placebo (N=66) Grade Grade All % ≥ 3 % All % ≥ 3 % Skin and subcutaneous tissue disorders HFSR/PPE Rash † Alopecia 67 30 24 22 7 2 12 3 2 2 0 0 General disorders and administration site conditions Asthenia/Fatigue Fever 52 21 4 0 39 11 2 2 Vascular disorders Hypertension Hemorrhage 59 11 28 4 27 3 5 0 Gastrointestinal disorders Diarrhea Mucositis Nausea Vomiting 47 40 20 17 8 2 2 <1 9 8 12 8 0 2 2 0 Respiratory, thoracic and mediastinal disorders Dysphonia 39 0 9 0 Infections and infestations Infection 32 5 5 0 Metabolism and nutrition disorders Decreased appetite and food intake Hypothyroidism ‡ 31 18 <1 0 21 6 3 0 Nervous system disorders Headache 16 0 9 0 Investigations Weight loss 14 0 8 0 Musculoskeletal and connective tissue disorders Musculoskeletal stiffness 14 0 3 0 Adverse reactions graded according to NCI CTCAE v4.0. The term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rash and pruritic rash. Hypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline. Laboratory abnormalities observed in Study 2 are shown in Table 4. Table 4: Laboratory test abnormalities reported in Study 2 Laboratory Parameter Stivarga (N=132*) Placebo (N=66 *) Grade Grade All % 3 % 4 % All % 3 % 4 % Blood and lymphatic system disorders Thrombocytopenia Neutropenia Lymphopenia 13 16 30 1 2 8 0 0 0 2 12 24 0 3 3 2 0 0 Metabolism and nutrition disorders Hypocalcemia Hypokalemia Hypophosphatemia 17 21 55 2 3 20 0 0 2 5 3 3 0 0 2 0 0 0 Hepatobiliary disorders Hyperbilirubinemia Increased AST Increased ALT 33 58 39 3 3 4 1 1 1 12 47 39 2 3 2 0 0 0 Renal and urinary disorders Proteinuria 33 3 -  30 3 -  Investigations Increased lipase 14 0 1 5 0 0 Percent based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or 66 (placebo). NCI CTCAE v4.0. No Grade 4 denoted in NCI CTCAE v4.0. 6.2 Postmarketing Experience The following adverse reaction has been identified during postapproval use of Stivarga. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: • hypersensitivity reaction 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inducers on Regorafenib Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Stivarga decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of Stivarga with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) [see Clinical Pharmacology (12.3)]. 7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib o-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Stivarga increased the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of Stivarga with strong CYP3A4 inhibitors (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole) [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal studies and its mechanism of action, Stivarga can cause fetal harm when administered to a pregnant woman. There are no available data on Stivarga use in pregnant women. Administration of regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations [see Data]. Advise pregnant women of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%, respectively. Data Animal Data In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC). In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. Daily administration of regorafenib to pregnant rats during organogenesis resulted in fetal findings of delayed ossification at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) and dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis. In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies, as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies. 8.2 Lactation Risk Summary There are no data on the presence of regorafenib or its metabolites in human milk, the effects of regorafenib on the breastfed infant, or on milk production. In rats, regorafenib and its metabolites are excreted in milk. Because of the potential for serious adverse reactions in breastfed infants from Stivarga, do not breastfeed during treatment with Stivarga and for 2 weeks after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females Use effective contraception during treatment and for 2 months after completion of therapy. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 months following the final dose of Stivarga [see Nonclinical Toxicology (13.1)]. Infertility 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 Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and efficacy of Stivarga in pediatric patients less than 18 years of age have not been established. Animal Data In 28-day repeat-dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings occurred at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat-dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate. 8.5 Geriatric Use Of the 632 Stivarga-treated patients enrolled in Studies 1 and 2, 37% were 65 years of age and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients. 8.6 Hepatic Impairment No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions (5.1)]. Stivarga is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C), since it has not been studied in this population. 8.7 Renal Impairment No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days [see Clinical Pharmacology (12.3)]. No dose adjustment is recommended for patients with mild renal impairment. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). Stivarga has not been studied in patients with severe renal impairment or end-stage renal disease. 8.8 Race Based on pooled data from three placebo-controlled trials (Studies 1 and 2, and a study conducted in East Asia), a higher incidence of HFSR and liver function test abnormalities occurred in Asian patients treated with Stivarga as compared with Whites [see Warnings and Precautions (5.1, 5.3)]. No starting dose adjustment is necessary based on race. 10 OVERDOSAGE The highest dose of Stivarga studied clinically is 220 mg per day. The most frequently observed adverse drug reactions at this dose were dermatological events, dysphonia, diarrhea, mucosal inflammation, dry mouth, decreased appetite, hypertension, and fatigue. There is no known antidote for Stivarga overdose. In the event of suspected overdose, interrupt Stivarga, institute supportive care, and observe until clinical stabilization. 11 DESCRIPTION Stivarga (regorafenib) has the chemical name 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate. Regorafenib has the following structural formula: Regorafenib is a monohydrate and it has a molecular formula C21H15ClF4N4O3 • H2O and a molecular weight of 500.83. Regorafenib is practically insoluble in water, slightly soluble in acetonitrile, methanol, ethanol, and ethyl acetate and sparingly soluble in acetone. Stivarga tablets for oral administration are formulated as light pink, oval-shaped tablets debossed with "BAYER" on one side and "40" on the other. Each tablet contains 40 mg of regorafenib in the anhydrous state, which corresponds to 41.49 mg of regorafenib monohydrate, and the following inactive ingredients: cellulose microcrystalline, croscarmellose sodium, magnesium stearate, povidone, and colloidal silicon dioxide. The film-coating contains the following inactive ingredients: ferric oxide red, ferric oxide yellow, lecithin (soy), polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of multiple doses of Stivarga (160 mg once daily for 21 days) on the QTc interval was evaluated in an open-label, single-arm study in 25 patients with advanced solid tumors. No large changes in the mean QTc interval (i.e., > 20 msec) were detected in the study. 12.3 Pharmacokinetics Absorption Following a single 160 mg dose of Stivarga in patients with advanced solid tumors, regorafenib reaches a geometric mean peak plasma level (Cmax) of 2.5 µg/mL at a median time of 4 hours and a geometric mean area under the plasma concentration vs. time curve (AUC) of 70.4 µg*h/mL. The AUC of regorafenib at steady-state increases less than dose proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean Cmax of 3.9 µg/mL and a geometric mean AUC of 58.3 µg*h/mL. The coefficient of variation of AUC and Cmax is between 35% and 44%. The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%. In a food-effect study, 24 healthy men received a single 160 mg dose of Stivarga on three separate occasions: under a fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%, respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions. Stivarga was administered with a low-fat meal in Studies 1 and 2 [see Dosage and Administration (2.1), Clinical Studies (14)]. Distribution Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins. Elimination Following a single 160 mg oral dose of Stivarga, the geometric mean (minimum to maximum) elimination half-lives for regorafenib and the M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer mean (minimum to maximum) elimination half-life of 51 hours (32 to 70 hours). Metabolism Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl). Both metabolites have similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively). Excretion Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg. Specific Populations Age, sex, race and weight had no clinically meaningful effect on the pharmacokinetics of regorafenib. Hepatic Impairment The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 14 patients with hepatocellular carcinoma (HCC) and mild hepatic impairment (Child-Pugh A); 4 patients with HCC and moderate hepatic impairment (Child-Pugh B); and 10 patients with solid tumors and normal hepatic function after the administration of a single 100 mg dose of Stivarga. No clinically important differences in the mean exposure of regorafenib, M-2, or M-5 were observed in patients with mild or moderate hepatic impairment compared to the patients with normal hepatic function. The pharmacokinetics of regorafenib has not been studied in patients with severe hepatic impairment (Child-Pugh C). Renal Impairment The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 10 patients with mild renal impairment (CLcr 60-89 mL/min) and 18 patients with normal renal function following the administration of Stivarga at a dose of 160 mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in patients with mild renal impairment compared to patients with normal renal function. Limited pharmacokinetic data were available from patients with moderate renal impairment (CLcr 30-59 mL/min). The pharmacokinetics of regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease. Drug Interaction Studies Effect of Regorafenib on Cytochrome P450 Substrates: In vitro studies suggested that regorafenib is an inhibitor of CYP2C8, CYP2C9, CYP2B6, CYP3A4 and CYP2C19; M-2 is an inhibitor of CYP2C9, CYP2C8, CYP3A4 and CYP2D6, and M-5 is an inhibitor of CYP2C8. In vitrostudies suggested that regorafenib is not an inducer of CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity. Patients with advanced solid tumors received single oral doses of CYP substrates, 2 mg of midazolam (CYP3A4), 40 mg of omeprazole (CYP2C19) and 10 mg of warfarin (CYP2C9) or 4 mg of rosiglitazone (CYP2C8) one week before and two weeks after Stivarga at a dose of 160 mg once daily. No clinically meaningful effect was observed in the mean AUC of rosiglitazone (N=12) or the mean omeprazole (N=11) plasma concentrations measured 6 hours after dosing or the mean AUC of midazolam (N=15). The mean AUC of warfarin (N=8) increased by 25% [see Warnings and Precautions (5.2)]. Effect of CYP3A4 Strong Inducers on Regorafenib: Twenty-two healthy men received a single 160 mg dose of Stivarga alone and then 7 days after starting rifampin. Rifampin, a strong CYP3A4 inducer, was administered at a dose of 600 mg daily for 9 days. The mean AUC of regorafenib decreased by 50% and mean AUC of M-5 increased by 264%. No change in the mean AUC of M-2 was observed [see Drug Interactions (7.1)]. Effect of CYP3A4 Strong Inhibitors on Regorafenib: Eighteen healthy men received a single 160 mg dose of Stivarga alone and then 5 days after starting ketoconazole. Ketoconazole, a strong CYP3A4 inhibitor, was administered at a dose of 400 mg daily for 18 days. The mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93% [see Drug Interactions (7.2)]. Effect of Neomycin on Regorafenib: Twenty-seven healthy men received a single 160 mg dose of Stivarga and then 5 days after starting neomycin. Neomycin, a non-absorbable antibiotic, was administered at a dose of 1 gram three times daily for 5 days. No clinically meaningful effect on the mean AUC of regorafenib was observed; however, the mean AUC of M-2 decreased by 76% and the mean AUC of M-5 decreased by 86%. The decreased exposure of M-2 and M-5 may result in a decreased efficacy of Stivarga. The effects of other antibiotics on the exposure of regorafenib and its active metabolites have not been studied. Effect of Regorafenib on UGT1A1 Substrates: In vitro studies showed that regorafenib, M-2, and M-5 competitively inhibit UGT1A9 and UGT1A1 at therapeutically relevant concentrations. Eleven patients received irinotecan-containing combination chemotherapy with Stivarga at a dose of 160 mg. The mean AUC of irinotecan increased by 28% and the mean AUC of SN-38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of Stivarga. In vitro screening of transporters: In vitro data suggested that regorafenib, M-2, and M-5 are inhibitors of breast cancer resistance protein (BCRP) and that regorafenib and M-2 are inhibitors of multidrug resistance protein 1 (MDR1). 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity inin vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells. Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans. 13.2 Animal Toxicology and/or Pharmacology In a chronic 26-week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the recommended dose, this finding was present in half of the examined animals. 14 CLINICAL STUDIES 14.1 Colorectal Cancer The clinical efficacy and safety of Stivarga were evaluated in an international, multicenter, randomized (2:1), double-blind, placebo-controlled trial (Study 1) in 760 patients with previously-treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS); additional efficacy outcome measures included progression-free survival (PFS) and objective tumor response rate. Patients were randomized to receive 160 mg regorafenib orally once daily (N=505) plus best supportive care (BSC) or placebo (N=255) plus BSC for the first 21 days of each 28-day cycle. Stivarga was administered with a low-fat breakfast that contains less than 30% fat [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. Treatment continued until disease progression or unacceptable toxicity. Baseline demongraphics were: median age 61 years, 61% men, 78% White, and all patients had an ECOG performance status of 0 or 1. The primary sites of disease were colon (65%), rectum (29%), or both (6%). History of KRAS evaluation was reported for 729 (96%) patients; 430 (59%) of these patients were reported to have KRAS mutation. The median number of prior lines of therapy for metastatic disease was 3. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and with bevacizumab. All but one patient with KRAS mutation-negative tumors received panitumumab or cetuximab. The addition of Stivarga to BSC resulted in a statistically significant improvement in survival compared to placebo plus BSC (see Table 5 and Figure 1). Table 5 Efficacy Results from Study 1 Stivarga (N=505) Placebo (N=255) Overall Survival Number of Deaths (%) 275 (55%) 157 (62%) Median Overall Survival (months) 6.4 5.0 95% CI * (5.8, 7.3) (4.4, 5.8) HR (95% CI) 0.77 (0.64, 0.94) Stratified log-rank test p-value  0.0102 Progression-Free Survival Number of Deaths or Progressions (%) 417 (83%) 231 (91%) Median Progression-Free Survival (months) 2.0 1.7 95% CI (1.9, 2.3) (1.7, 1.8) HR (95% CI) 0.49 (0.42, 0.58) Stratified log-rank test p-value † <0.0001 Overall Response Rate Overall Response, N (%) 5 (1%) 1 (0.4%) 95% CI 0.3%, 2.3% 0%, 2.2% CI=confidence interval Stratified by geographic region and time from diagnosis of metastatic disease. Crossed the O’Brien-Fleming boundary (two-sided p-value < 0.018) at second interim analysis. Figure 1: Kaplan-Meier Curves of Overall Survival 14.2 Gastrointestinal Stromal Tumors The efficacy and safety of Stivarga were evaluated in an international, multicenter, randomized (2:1), double-blind, placebo-controlled trial (Study 2) in 199 patients with unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST), who had been previously treated with imatinib mesylate and sunitinib malate. Randomization was stratified by line of therapy (third vs. four or more) and geographic region (Asia vs. rest of the world). The major efficacy outcome measure of Study 2 was progression-free survival (PFS) based on disease assessment by independent radiological review using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodule within a pre-existing tumor mass was progression. The key secondary outcome measure was overall survival. Patients were randomized to receive 160 mg regorafenib orally once daily (N=133) plus best supportive care (BSC) or placebo (N=66) plus BSC for the first 21 days of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. In Study 2, the median age of patients was 60 years, 64% were men, 68% were White, and all patients had baseline ECOG performance status of 0 (55%) or 1 (45%). At the time of disease progression as assessed by central review, the study blind was broken and all patients were offered the opportunity to take Stivarga at the investigator’s discretion. Fifty-six (85%) patients randomized to placebo and 41 (31%) patients randomized to Stivarga received open-label Stivarga. A statistically significant improvement in PFS was demonstrated among patients treated with Stivarga compared to placebo (see Table 6 and Figure 2). There was no statistically significant difference in overall survival at the time of the planned interim analysis based on 29% of the total events for the final analysis. Table 6 Efficacy Results for Study 2 Stivarga (N=133) Placebo (N=66) Progression-free Survival Number of deaths or progressions (%) 82 (62%) 63 (96%) Median Progression-Free Survival (months) 4.8 0.9 95% CI (3.9, 5.7) (0.9, 1.1) HR (95% CI) 0.27 (0.19, 0.39) Stratified log-rank test p-value <0.0001 Overall Survival Number of Deaths (%) 29 (22%) 17 (26%) Median Overall Survival (months) NR NR HR (95% CI) 0.77 (0.42, 1.41) Stratified log-rank test p-value 0.2 Stratified by line of treatment and geographical region. NR: Not reached. Figure 2: Kaplan-Meier Curves of Progression-Free Survival for Study 2 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tablets are supplied in packages containing three bottles, with each bottle containing 28 tablets, for a total of 84 tablets per package (NDC 50419-171-03). 16.2 Storage and Handling Store Stivarga at 25°C (77°F); excursions are permitted from 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening. Discard any unused tablets 7 weeks after opening the bottle.Dispose of unused tablets in accordance with local requirements. 拜耳与美国NSABP合作调查Stivarga辅助治疗早期阶段（IIIB和IIIC）结直肠癌 2016年6月6日，德国制药巨头拜耳（Bayer）近日宣布，与美国乳腺与肠道外科辅助治疗研究组（NSABP）合作启动一项新的III期临床研究（ARGO），调查Stivarga（regorafenib）作为一种额外的辅助疗法，用于结直肠癌的治疗。ARGO研究将调查regorafenib作为一种单一制剂，用于完成标准辅助化疗的IIIB和IIIC阶段结直肠癌的辅助治疗。该阶段的结直肠癌，肿瘤已开始侵入结肠壁，但尚未扩散到其他组织。 当前，尽管接受辅助化疗，但IIIB和IIIC阶段结直肠癌患者病情进展为转移性疾病（即疾病从结肠扩散至其他组织）的风险仍高达约40%。鉴于临床前研究中regorafenib表现出的抗转移作用，以及该药治疗转移性结直肠癌的疗效，拜耳预计，regorafenib也有望能帮助较早期阶段（IIIB和IIIC）的结直肠癌患者。 ARGO研究是一项随机、双盲、安慰剂对照III期研究，将在美国招募约1100例III阶段结直肠癌患者，研究中，患者将以1:1的比例随机接受120mg regorafenib或安慰剂治疗，计划治疗持续时间为2年。该研究将由NSABP开展，拜耳提供咨询及资金支持。如果获得积极数据，拜耳将利用这些数据提交Strivarga治疗早期阶段（IIIB和IIIC阶段）结直肠癌的上市申请。 今年5月，Stivarga治疗肝细胞癌III期RESORCE临床研究获得成功，数据显示，Stivarga能够显著延长不可手术及既往接受过拜耳已上市靶向抗癌药多吉美（品牌名：Nexavar ，通用名：索拉菲尼，sorafenib）治疗但病情继续恶化的肝细胞癌患者的总生存期。目前，肝细胞癌仍然缺乏有效的治疗手段，Stivarga有望成为继多吉美之后第二个系统性治疗肝细胞癌的靶向药物。 Stivarga是一种口服多激酶抑制剂，在临床前研究中，regorafenib能够抑制数个促血管生成VEGF受体酪氨酸激酶，这些激酶在肿瘤的血管生成中发挥着重要作用。该药还可以抑制癌和肿瘤微环境中的多种激酶，包括VEGFR 1-3, KIT, RET, PDGFR及FGFR。Stivarga由拜耳开发，由拜耳和Onyx制药联合推广。 目前，Strivarga已获全球90个国家批准（包括美国、欧盟、日本）治疗转移性结直肠癌（mCRC），同时获全球70多个国家批准治疗转移性胃肠道间质瘤（GIST）。 https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=824f19c9-0546-4a8a-8d8f-c4055c04f7c7