The U.S. Food and Drug Administration today granted approval to Lenvima (lenvatinib) to treat patients with progressive, differentiated thyroid cancer (DTC) whose disease progressed despite receiving radioactive iodine therapy (radioactive iodine refractory disease).

The most common type of thyroid cancer, DTC is a cancerous growth of the thyroid gland which is located in the neck and helps regulate the body’s metabolism. The National Cancer Institute estimates that 62,980 Americans were diagnosed with thyroid cancer and 1,890 died from the disease in 2014. Lenvima is a kinase inhibitor, which works by blocking certain proteins from helping cancer cells grow and divide.   

“The development of new therapies to assist patients with refractory disease is of high importance to the FDA,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug eva luation and Research. “Today’s approval gives patients and healthcare professionals a new therapy to help slow the progression of DTC.” 

Lenvima was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that, if approved, would provide significant improvement in safety or effectiveness in the treatment of a serious condition. The drug also received orphan product designation because it is intended to treat a rare disease. Lenvima is being approved approximately two months ahead of the prescription drug user fee goal date of April 14, 2015, the date when the agency was scheduled to complete its review of the application.

Lenvima’s efficacy was demonstrated in 392 participants with progressive, radioactive iodine-refractory DTC who were randomly assigned to receive either Lenvima or a placebo.  Study results showed Lenvima-treated participants lived a median of 18.3 months without their disease progressing (progression-free survival), compared to a median of 3.6 months for participants who received a placebo. Additionally, 65 percent of participants treated with Lenvima saw a reduction in tumor size, compared to the two percent of participants who received a placebo. A majority of participants randomly assigned to receive the placebo were treated with Lenvima upon disease progression.

The most common side effects of Lenvima were high blood pressure (hypertension), fatigue, diarrhea, joint and muscle pain (arthralgia/myalgia), decreased appetite, decreased weight, nausea, inflammation of the lining of the mouth (stomatitis), headache, vomiting, excess protein in the urine (proteinuria), swelling and pain in the palms, hands and/or the soles of the feet (palmar-plantar erythrodysesthesia syndrome), abdominal pain and changes in voice volume or quality (dysphonia).

Lenvima may cause serious side effects, including cardiac failure, blood clot formation (arterial thromboembolic events), liver damage (hepatotoxicity), kidney damage (renal failure and impairment), an opening in the wall of the stomach or intestines (gastrointestinal perforation) or an abnormal connection between two parts of the stomach or intestines (fistula formation), changes in the heart’s electrical activity (QT Interval Prolongation), low levels of calcium in the blood (hypocalcemia), the simultaneous occurrence of headache, confusion, seizures and visual changes (Reversible Posterior Leukoencephalopathy Syndrome), serious bleeding (hemorrhage), risks to an unborn child if a patient becomes pregnant during treatment, and impairing suppression of the production of thyroid-stimulating hormone.

Lenvima is marketed by Woodcliff Lake, New Jersey-based Eisai Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, promotes and protects the public health by, among other things, assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
LENVIMA(lenvatinib)胶囊，为口服使用
美国初次批准：2015
适应证和用途
LENVIMA是一种激酶抑制剂适用为有局部地复发或转移，进展性，放射性碘-难治性分化型甲状腺癌患者的治疗(1)。
剂量和给药方法
⑴ 推荐剂量：24 mg口服，每天一次(2.1).
⑵ 在有严重肾或肝受损患者，剂量是14 mg每天一次(2.1).
剂型和规格
胶囊：4 mg和10 mg(3).
禁忌证
无。(4).
警告和注意事项
⑴ 高血压：用LENVIMA治疗前控制血压。对尽管优化高血压治疗的3级高血压不给LENVIMA。对危及生命高血压终止药物(5.1)。
⑵ 心力衰竭：监视心脏代偿失调的临床症状和体征。对3级不给LENVIMA心功能不全。对4级心功能不全终止药物(5.2)。
⑶ 动脉血栓栓塞事件：一次动脉血栓栓塞事件后终止LENVIMA(5.3)。
⑷ 肝毒性: LENVIMA开始前和治疗自始至终定期地监视肝功能检验. 对3级或更大肝受损不给LENVIMA。对肝衰竭终止治疗(5.4)。
⑸ 蛋白尿：用LENVIMA开始治疗前，和自始至终定期地，监视蛋白尿。对24小时尿蛋白≥2 克不给LENVIMA。对肾病综合征终止用药(5.5)。
⑹ 肾衰竭和肾受损： 对3或4级肾衰竭/受损不给LENVIMA (5.6)。
⑺ 胃肠道穿孔和瘘管形成：发生胃肠道穿孔或危及生命瘘管患者中终止LENVIMA (5.7)。
⑻ QT间期延长：在所有患者中监视和纠正电解质异常。对发生3级或更大QT间期延长不给LENVIMA (5.8)。
⑼ 低钙血症：监视血钙水平至少每月和需要时给予替代钙(5.9)。
⑽ 可逆性后部白质脑病综合征(RPLS)： 对RPLS不给LENVIMA直至完全解决(5.10)。
⑾ 出血事件：对3级出血不给LENVIMA。对4级出血终止治疗(5.11)。
⑿ 甲状腺刺激激素抑制的受损：每月监视TSH水平和有DTC患者需要时调整甲状腺取代药物 (5.12)。
⒀ 胚胎胎儿毒性：可能致胎儿危害。忠告对胎儿潜在风险和使用有效避孕(5.13，8.1，8.3)。
不良反应
对LENVIMA最常见不良反应(发生率大于或等于30%)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，掌，跖红肿综合征，腹痛，和发音困难(6)。
报告怀疑不良反应，联系Eisai公司电话1-877-873-4724或FDA电话1-800-FDA-1088或www.fda.gov/medwatch.
特殊人群中使用
哺乳：终止哺乳喂养(8.2)。 

View the label approved on 02/13/2015 (PDF)¹¹ for LENVIMA, NDA no. 206947  

研究中RR-DTC患者以2：1的比例被随机分成两个组（分组前以年龄≤65岁和＞65岁、地域、既往接受过VEGFR靶向治疗为基础进行分层），治疗组予LEN，对照组予安慰剂，两组均使用24mg/天，28天为一周期。一旦对照组患者疾病进展，可立即使用LEN治疗。

研究主要终点是无进展生存期（progression-free survival ，PFS)，次要终点包括总缓解率（ORR，即CR+PR）、总生存期（OS）和安全性。

研患者究共纳入392例（51%为男性，平均年龄63.0岁），最终结果显示，治疗组的PFS明显高于对照组（18.3个月 vs 3.6个月），风险比为0.21，其中，既往未接受过VEGFR靶向治疗的患者（195例）比接受过（66例）的PFS更长（18.7个月vs15.1个月）。

另外，治疗组的完全缓解率、部分缓解率和中位暴露时间分别为1.5%（4例）、63.2%（165例）和13.8个月；而对照组分别为0、1.5%（2例）和3.9个月。治疗组的中位响应时间为2个月。

在不良事件发生率方面，使用LEN治疗的5个最常见不良反应分别为：高血压（68%）、腹泻（59%）、食欲下降（50%）、体重减轻（46%）和恶心（41%）。其中≥3级的为高血压（42%）、蛋白尿（10%）、体重减轻（10%）、腹泻（8%）和食欲下降（5%）。78.5%的患者因为不良反应减少了使用剂量，14.2%的患者停止了LEN治疗。

研究表明，Lenvatinib能显著改善放射性碘131抵抗的分化型甲状腺癌的PFS，且其不良反应在可控制范围内