靶向抗癌药Stivarga获美国FDA批准为二线治疗肝细胞癌（HCC），成为近10年来首个肝癌新药
近日，美国食品和药物管理局（FDA）批准了其Stivarga（regorafenib，瑞戈非尼）片剂，用于既往使用过Nexavar（索拉非尼）治疗的肝细胞癌（HCC）患者的二线治疗。Stivarga是第一个也是唯一一个显著改善二线HCC患者总体生存的疗法。此次FDA的批准扩大了拜耳在肝癌领域的领先地位，在HCC的治疗方案中可在Nexavar治疗后病情进展的患者中直接使用Stivarga。
Stivarga是一种口服多激酶抑制剂，影响正常细胞功能和病理过程，如肿瘤发生，肿瘤血管生成，转移和肿瘤免疫。
批准日期：2017年4月28日  公司：Bayer
STIVARGA®（瑞戈非尼[regorafenib]）片剂，用于口服使用
美国初步批准：2012年
警告：
致命毒性请参阅完整的BOXED警告的完整说明信息。
•临床试验中发生严重有时致命的肝毒性。
•在治疗前和治疗期间监测肝功能。
•根据严重程度和持续性，中毒，然后减少或停止STIVARGA的肝毒性，表现为肝功能检查升高或肝细胞坏死。
最近的主要变化
适应症和用法，结直肠癌：6/2016
适应症和用法，肝细胞癌：4/2017
剂量和给药，剂量修改：4/2017
警告和注意事项：4/2017
作用机制
Regorafenib是一种涉及正常细胞功能和肿瘤发生，肿瘤血管生成，转移和肿瘤免疫等病理过程的多种膜结合和细胞内激酶的小分子抑制剂。在体外生物化学或细胞测定中，regorafenib或其主要人类活性代谢物M-2和M-5抑制RET，VEGFR1，VEGFR2，VEGFR3，KIT，PDGFR-α，PDGFR-β，FGFR1，FGFR2，TIE2， DDR2，TrkA，Eph2A，RAF-1，BRAF，BRAF V600E，SAPK2，PTK5，Abl和CSF1R在临床上达到的regorafenib浓度。在体内模型中，regorafenib在大鼠肿瘤模型中表现出抗血管生成活性，并且在几种小鼠异种移植模型中抑制肿瘤生长，包括一些用于人结肠直肠癌，胃肠道基质和肝细胞癌的肿瘤生长。雷卡非尼也显示了在小鼠异种移植模型和人结肠直肠癌的两个小鼠原位模型中的抗转移活性。
适用范围及用途
STIVARGA是用于治疗患者的激酶抑制剂：
•以前用氟嘧啶，奥沙利铂和伊立替康为基础的化学疗法治疗转移性结直肠癌（CRC），抗VEGF治疗，以及RAS野生型抗EGFR治疗。
•以前曾接受甲磺酸伊马替尼和苹果酸苹果酸盐治疗的局部晚期，不可切除或转移性胃肠道间质瘤（GIST）。
•以前用索拉非尼治疗的肝细胞癌（HCC）
剂量和管理
•推荐剂量：口服160 mg，每28天一次的头21天每日一次。
•吃低脂饭后服用STIVARGA。
剂量形式和强度
片剂：40毫克
禁忌症
没有。
警告和注意事项
•肝毒性：监测肝功能检查。根据严重程度和持续时间，减少或停止STIVARGA。
•感染：在恶化或严重感染的患者中禁止STIVARGA。
•出血：永久性停止STIVARGA，用于严重或危及生命的出血。
•胃肠穿孔或瘘管：停止STIVARGA。
•皮肤毒性：根据皮肤毒性的严重性和持续性，禁止并减少或停止STIVARGA。
•高血压：暂时或永久性地阻止STIVARGA严重或不受控制的高血压。
•心脏缺血和梗塞：阻止STIVARGA用于新的或急性心肌缺血/梗死，并且仅在解决急性缺血事件后恢复。
•可逆性后脑白质病综合征（RPLS）：停止STIVARGA。
•创伤愈合并发症：手术前停止STIVARGA。伤口开裂患者停药。
•胚胎 - 胎儿毒性：可引起胎儿的危害。建议对胎儿有潜在危险的妇女，并在治疗期间和最终剂量后2个月内使用有效的避孕措施。建议男性在最终剂量后2个月内使用有效的避孕药。
不良反应
最常见的不良反应（≥20％）是疼痛（包括胃肠和腹痛），HFSR，乏力/疲劳，腹泻，食欲降低/食物摄取，高血压，感染，发音障碍，高胆红素血症，发热，粘膜炎，体重减轻，皮疹和恶心。
要报告可疑的不良反应，请联系Bayer HealthCare Pharmaceuticals Inc.，电话：1-888-842-2937或FDA，1-800-FDA-1088或WWW.FDA.GOV/MEDWATCH。
药物相互作用
•强CYP3A4诱导物：避免强CYP3A4诱导物。
•强CYP3A4抑制剂：避免强烈的CYP3A4抑制剂。
•BCRP底物：密切观察患者暴露于BCRP底物的症状。
在特定人口中使用
护理母亲：停止药物或哺乳，考虑到药物对母亲的重要性。
如何提供/存储和处理
提供
片剂以包装三瓶的包装的形式提供，每瓶含28片，每片包装共84片（NDC 50419-171-03）。
储存和处理
将STIVARGA储存在25°C（77°F）; 允许偏离15至30°C（59至86°F）[见USP受控室温]。
将片剂储存在原始瓶子中，不要取出干燥剂。 首先打开瓶子后，保持瓶子的密封。
打开瓶子7周后丢弃任何未使用的药片。 按照当地要求处理未使用的药片。
注：本品美国、瑞士、德国、日本、英语等国家均有销售，采购者以在线咨询为准！

FDA Approves Stivarga (Regorafenib) for Liver Cancer
The US Food and Drug Administration (FDA) has expanded the approved use of the targeted therapy drug Stivarga (regorafenib) to treat liver cancer. Stivarga had already been approved to treat colorectal cancer and gastrointestinal stromal tumors. This is the first FDA approval for a liver cancer drug in nearly a decade. It’s for people whose liver cancer has stopped responding to the targeted drug Nexavar (sorafenib).
Stivarga works by blocking proteins on or near the surface of a cell that help cancer cells grow, as well as proteins that help form new blood vessels to feed growing tumors.
The FDA based its approval on a clinical trial of 573 people with liver cancer whose tumors grew after they were treated with Nexavar. Those who received Stivarga lived for an average 10.6 months compared to 7.8 months for those who did not.
In addition, those who received Stivarga went about 1 ½ months longer without their cancer getting worse than those who did not.
The FDA evaluated Stivarga under its priority review program, in which the FDA tries to make a decision within 6 months instead of the usual 10 months. The drug was also granted orphan product designation, which provides incentives to the drug’s developers because it is intended to treat a rare disease.
The most common side effects of this drug include weakness and fatigue, pain and redness in the hands and feet, rash, diarrhea, loss of appetite, nausea, weight loss, high blood pressure, mouth sores, infection, voice changes, stomach pain, and fever.
Rare, but serious, side effects can include liver damage, severe bleeding, blistering and peeling of skin, very high blood pressure, heart attack, perforated intestines, and swelling in the brain.
Women who are pregnant or breastfeeding should not take Stivarga because it may cause harm to a developing fetus or a newborn baby. Both women and men who are taking Stivarga should use birth control during and for 2 months after taking the final dose.
Stivarga (Regorafenib Tablets)
Indications
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.
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.
STIVARGA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
Important Safety Information
Warning: Hepatotoxicity
•Severe and sometimes fatal hepatotoxicity has occurred in clinical trials.
•Monitor hepatic function prior to and during treatment.
•Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.
Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients across all 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 metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and in 0.4% of patients in the placebo arm. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the STIVARGA arm. In hepatocellular carcinoma (HCC), there was no increase in the incidence of fatal hepatic failure as compared to placebo.
Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 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 upper limit of normal (ULN) or baseline values. 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.
Infections: STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo-controlled trials. The incidence of grade 3 or greater infections in STIVARGA treated patients was 9%. The most common infections were urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with STIVARGA (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% vs 0.2%). Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection.
Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA vs 9.5% with placebo in randomized, placebo-controlled trials. The incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA was 3.0%. The incidence of fatal hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin.
Gastrointestinal Perforation or Fistula: Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of STIVARGA administered as a single agent; this included eight fatal events. Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and in 0.2% of patients in the placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula.
Dermatological Toxicity: In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients with STIVARGA arm and 25.5% of patients in the placebo arm including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia syndrome (PPES) and severe rash, requiring dose modification.
In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated patients (53% vs 8%) than in the placebo-treated patients. Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% vs <1%), Grade 3 rash (3% vs <1%), serious adverse reactions of erythema multiforme (<0.1% vs 0%), and Stevens-Johnson syndrome (<0.1% vs 0%) were higher in STIVARGA-treated patients. Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3:18%). Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of STIVARGA administered as a single agent. Withhold STIVARGA, reduce the dose, or permanently discontinue depending on the severity and persistence of dermatologic toxicity.
Hypertension: Hypertensive crisis occurred in 0.2% in STIVARGA-treated patients and in none of the patients in placebo arm across all randomized, placebo-controlled trials. STIVARGA caused an increased incidence of hypertension (30% vs 8% in mCRC, 59% vs 27% in GIST, and 31% vs 6% in HCC). The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in randomized, placebo controlled trials). Do not initiate STIVARGA until 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.
Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% with STIVARGA vs 0.2% with placebo) in randomized placebo-controlled trials. Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristics finding on MRI, occurred in one of 4800 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.
Wound Healing Complications: Treatment with STIVARGA should be stopped at least 2 weeks prior to scheduled surgery. Resuming treatment after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence.
Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose.
Nursing Mothers: 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.
Most Frequently Observed Adverse Drug Reactions in mCRC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), pain (59% vs 48%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).
Most Frequently Observed Adverse Drug Reactions in GIST (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in GIST, respectively, were: HFSR/PPE (67% vs 12%), pain (60% vs 55%), hypertension (59% vs 27%), asthenia/fatigue (52% vs 39%), diarrhea (47% vs 9%), mucositis (40% vs 8%), dysphonia (39% vs 9%), infection (32% vs 5%), decreased appetite and food intake (31% vs 21%), and rash (30% vs 3%).
Most Frequently Observed Adverse Drug Reactions in HCC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in HCC, respectively, were: pain (55% vs 44%), HFSR/PPE (51% vs 7%), asthenia/fatigue (42% vs 33%), diarrhea (41% vs 15%), hypertension (31% vs 6%), infection (31% vs 18%), decreased appetite and food intake (31% vs 15%).
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=824f19c9-0546-4a8a-8d8f-c4055c04f7c7