——放射性碘难治性分化型甲状腺癌新药lenvatinib,显著延长进展生存期
2015年2月13日,美国食品和药品监管局(FDA)批准Lenvima (lenvatinib)治疗有进展性，分化型甲状腺癌(DTC)患者尽管接受放射活性碘治疗(放射活性碘难治疾病)其疾病进展。
最常见类型甲状腺癌，DTC是位于颈部的甲状腺的癌性生长和有助于调节机体代谢。美国国家癌症研究所估计2014年62,980名美国人被诊断患甲状腺癌和1,890例死于此病。Lenvima是一种激酶抑制剂，通过阻断某些蛋白免受癌细胞生长和分裂而作用。
”FDA的药品评价和研究中心血液学和肿瘤产品室主任Richard Pazdur，M.D.说：“新治疗的开发发展帮助有难治性疾病患者对FDA是高度重要性，”“今天批准给予患者和卫生保健专业人员一种新治疗有助于减慢DTC的进展。
Lenvima是在FDA的优先审评程序下审评，程序对如被批准将提供在治疗某种严重情况治疗安全性或有效性显著改善药物提供加快审评。药物还接到孤儿产品指定因为它意向治疗一种罕见疾病。Lenvima正在被比处方药物用户收费目标日期2015年4月14日(即监管局计划完成申请审评的日期)提前约2个月被批准。
在392例有进展性，放射活性碘-难治性DTC参加者被随机赋予接受或Lenvima或某种安慰剂中显示Lenvima的疗效。研究结果显示被Lenvima治疗参加者无疾病进展地生存中位18.3个月(无进展生存)，与之比较接受安慰剂参加者中位3.6个月。此外，用Lenvima治疗参加者65%见到肿瘤大小减小，与之比较，接受安慰剂参加者为2%。随机赋予接受安慰剂参加者的多数在疾病进展时用Lenvima治疗。
Lenvima的最常见副作用是高血压，疲乏，腹泻，关节痛/肌肉痛，食欲减退，体重减轻，恶心，口炎，头痛，呕吐，蛋白尿，肿胀和掌，跖红肿综合征，腹痛和发音困难。
Lenvima可能致严重副作用，包括心衰，动脉血栓栓塞事件，肝毒性，肾衰和受损，胃肠道穿)或胃或小肠的两部分间异常连接(瘘管形成)，心电活动变化(QT间期延长)，低钙血症，头痛，混乱，癫痫发作同时发生和视觉变化(可逆性后部白质脑病综合征)，严重出血(出血)，如治疗期间患者成为妊娠对未出生儿童风险，和甲状腺-刺激激素生成的受损性抑制。
Lenvima由总部在新泽西卫才[Eisai]公司上市
LENVIMA(lenvatinib)
Lenvima
Generic Name: lenvatinib
Date of Approval: February 13, 2015
Company: Eisai Co., Ltd.
Treatment for: Thyroid Cancer

LENVIMA™ (lenvatinib) is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).
Important Safety Information
Warnings and Precautions
Hypertension was reported in 73% of LENVIMA-treated patients (of which 44% were ≥ Grade 3) and 16% of patients in the placebo group. Control blood pressure prior to treatment and monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly during treatment. Withhold LENVIMA for Grade 3 hypertension; resume at a reduced dose when hypertension is controlled at ≤ Grade 2. Discontinue LENVIMA for life-threatening hypertension.
Cardiac dysfunction was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction.
Arterial thromboembolic events were reported in 5% of LENVIMA-treated patients; events of Grade 3 or greater were 3%. Discontinue LENVIMA following an arterial thrombotic event. LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.
4% of LENVIMA-treated patients experienced an increase in ALT and 5% experienced an increase in AST that was Grade 3 or greater. Monitor liver function before initiation and during treatment with LENVIMA. Withhold LENVIMA for the development of ≥ Grade 3 liver impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure.
Proteinuria was reported in 34% of LENVIMA-treated patients (of which 11% were Grade 3). Monitor for proteinuria before initiation of, and periodically during treatment. Obtain a 24 hour urine protein if urine dipstick proteinuria ≥2+ is detected. Withhold LENVIMA for ≥ 2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.
Events of renal impairment were reported in 14% of LENVIMA-treated patients Renal failure or impairment ≥ Grade 3 was 3% in LENVIMA-treated patients. Withhold LENVIMA for development of Grade 3 or 4 renal failure / impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment.
Events of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.
QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of ≥ Grade 3 QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline.
Hypocalcemia ≥ Grade 3 was reported in 9 % of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia.
Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 3 patients across clinical studies in which 1108 patients received LENVIMA. Confirm the diagnosis of RPLS with MRI. Withhold LENMIVA for RPLS until fully resolved. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms.
Hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. The incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. There was one case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.
LENVIMA impairs exogenous thyroid suppression. Elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. Monitor TSH levels monthly and adjust thyroid replacement medication as needed.
LENVIMA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.
Advise women not to breastfeed during treatment with LENVIMA.
Adverse Reactions
The most common adverse reactions observed in LENVIMA-treated patients vs. placebo treated patients respectively were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decreased (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%).