商品名：Gilotrif 
通用名：Afatinib 
中文名：阿法替尼
审批分类：优先审评
药企：
Boehringer Ingelheim
适应症：
EGFR Del19或L858R突变型非小细胞肺癌（一线药物）。
剂型规格：
本品为片剂，有20mg、30mg、40mg三种规格。推荐剂量为40mg，每天口服一次。
活性成分：
阿法替尼马来酸盐，结构式如下：

作用机理：
阿法替尼能共价结合到EGFR (ErbB1)、HER2 (ErbB2)、HER4 (ErbB4)，不可逆抑制这些激酶自磷酸化，下调ErbB信号。
临床试验：
一项多中心、随机、开放标签试验中，345例患者按2:1分成Gilotrif组和常规化疗（培美曲唑+顺铂）组，中位无进展生存期分别为11.1个月、6.9个月，总生存期分别为28.1个月、28.2个月。对264例患者的肿瘤样品进行了回顾分析，对于Del19突变型，中位无进展生存期分别为13.7个月、5.6个月；对于L858R突变型，中位无进展生存期分别为10.8个月、8.1个月；对于其他类型，中位无进展生存期分别为2.8个月、9.9个月。
不良反应：
腹泻（96%）、皮肤反应（90%）、间质性肺病（1.5%）、肝毒性（10.1%）、角膜炎（0.8%）、胚胎-胎儿毒性。

相关专利：
WO0250043A1（化合物）；WO03094921A2（抗癌用途）；WO03066060A2（抗炎用途）；US2005085495A1（工艺）；WO2005037824A2（工艺）；WO2007085638A1（工艺）；US2011207932A1（工艺）；WO2011084796A2（氘代）；WO2012121764A1（晶型）；WO2013052157A1（晶型）。
补充说明：
阿法替尼是继吉非替尼、厄洛替尼、拉帕替尼（EGFR/HER2双靶点）、埃克替尼（中国）后第五个EGFR抑制剂，由于该药能抑制HER2，目前还在进行治疗乳腺癌的临床试验。

EGFR基因突变的非小细胞肺癌又一新药afatinib获准
7月12日，肿瘤学家的得到了一件对付肺癌的新武器—美国FDA批准了勃林格殷格翰的afatinib（阿法替尼），这是一种非小细胞肺癌的靶向治疗药，将以商品名Gilotrif销售，一种用以识别最可能对该药应答的晚期非小细胞肺癌人群的诊断测试也一起获准。
在去年的美国临床肿瘤学会年会上，afatinib备受关注，勃林格殷格翰公司遂积极推进其开发计划。
在一系列临床试验中对Gilotrif的安全性和有效性进行了评估，总共涉及345名有EGFR突变的弥散性非小细胞肺癌患者。最常见的副作用是皮肤破裂、干燥、发痒，口腔炎症，感染指甲附近感染，体重下降，食欲不振。
接受Gilotrif治疗的患者的无进展生存期为11.1个月，而目前的标准治疗仅6.9。更令人印象深刻的是，两个EGFR发生突变的患者存活13.6个月，没有见到他们的癌症恶化。
随同该药一起获准的诊断试剂therascreen由英国Qiagen公司生产，用于识别肺癌细胞表达EGFR的患者。afatinib是一种酪氨酸激酶抑制剂，不可逆地抑制人类表皮生长因子受体2（Her2的）和表皮生长因子受体（EGFR）激酶。它最可能在肿瘤表达EGFR基因19外显子缺失或21外显子L858R替代基因突变的患者身上奏效。FDA一直鼓励开发针对这类患者的药物。
FDA的药物评价和研究中心血液学和肿瘤学产品办公室主任Richard Pazdur博士指出：“它的获准进一步说明了对一种疾病分子途径的了解可以导致开发有针对性的治疗药巨大潜力。Gilotrif是今年获准的用于未作治疗的有EGFR 19外显子缺失或21外显子 L858R突变的转移性非小细胞肺癌患者的第二个新药。”
今年5月，Astellas的Tarceva（erlotinib, 厄洛替尼片）作为扩大的适应症获得FDA批准。
攻克肺癌是新药开发者面临的一项艰难任务，肺癌患者的生存预后往往相当糟糕。但在不太遥远的将来还会有其它药物陆续跟进——诺华公司的新一代ALK抑制剂LDK378和百事美施贵宝公司的免疫治疗药nivolumab两者都已被FDA认定为突破性治疗药，获得审批的方面的特殊待遇。
Gilotrif的获准对勃林格殷格翰公司意义重大，该公司研究开发管道中有一系列候选的抗癌药。nintedanib一种血管生成抑制剂，能限制项肿瘤提供养料的血管生长。其肿瘤无恶化生存时间为3.4个月，而相比之下只接受多西他赛（docetaxel）的肺癌患者为2.7个月。中位总体生存时间，次要的终点指标nintedanib组为10.1个月，多西他赛组9.1个月，有腺癌组织学证据的患者有2.3个月的优势。  

Afatinib Tablets Now Available for Use in Treatment of NSCLC
Afatinib (Gilotrif) tablets were approved by the FDA on July 15, 2013, as a first-line oral treatment for non– small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.1 The oral tablets became commercially available in the United States September 2.

Using an FDA-approved test kit, clinicians can make an informed decision on whether to initiate afatinib based on EGFR mutations in cancer cells. The FDA approved afatinib concurrently with the therascreen EGFR RGQ PCR Kit, a companion diagnostic that helps determine if a patient’s lung cancer cells express the EGFR mutations. Although the effectiveness of afatinib has been validated in patients with NSCLC with exon 19 deletions and exon 21 (L858R) substitution mutations, efficacy and safety have not been proven with other types of EGFR mutations.2

Pharmacology and Pharmacokinetics
Afatinib, a tyrosine kinase inhibitor, reduces ErbB signaling by binding to the kinase domains of EGFR, HER2, and HER4. ErbB receptors are involved in the growth and proliferation of cancer cells.2

Maximum concentrations of afatinib occur 2 to 5 hours after administration. With an elimination half-life of 37 hours, steady-state plasma levels are reached within 8 days. In pharmacokinetic studies, high-fat meals and p-glycoprotein (p-gp) inhibitors increased peak concentrations of afatinib and total exposure to it. Afatinib is minimally metabolized by liver enzymes, with 88% of each dose recovered unchanged, primarily in feces.2

Patients with mild-to-moderate renal impairment experienced higher trough concentrations of afatinib than patients with normal renal function. Hepatic impairment did not affect exposure. No dose adjustment is required in hepatic or renal impairment, but patients with severe renal impairment (creatinine clearance <30 mL/min) and patients with Child-Pugh class C hepatic dysfunction have not received afatinib in clinical studies.2

Dosage and Administration
A single, daily, oral dose of afatinib should be taken on an empty stomach ≥1 hour before or ≥2 hours after a meal, preferably at the same time each day. If a patient misses the usual administration time, the missed dose may be taken at a later time, but only if the patient separates daily doses by at least 12 hours. The usual daily dose of afatinib is 40 mg, although dose reductions may be necessary when restarting therapy after adverse events or to manage drug interactions.2

Clinical Trials
Patients with metastatic, nonsquamous NSCLC, enrolled in the phase III LUX-Lung 3 trial, received afatinib (230 patients) or a combination of pemetrexed and cisplatin (115 patients). Patients taking afatinib experienced a median progression-free survival of 11.1 months versus 6.9 months for patients taking pemetrexed/cisplatin (P = .001). The difference in survival was more pronounced in patients with tumors harboring exon 19 deletions and L858R EGFR mutations. Patients with those specific mutations who received afatinib experienced a median progression-free survival of 13.6 months compared with 6.9 months in the chemotherapy arm.3

Diarrhea occurred in 96% of patients treated with afatinib, of which 15% was grade 3. For patients who develop prolonged grade 2 diarrhea lasting ≥48 hours, or equal to grade 3, afatinib should be withheld until diarrhea resolves to ≤ grade 1 and resumed with appropriate dose reduction.2

In addition to diarrhea, the most common grade 3 drug-related adverse events observed in the afatinib treatment arm were rash (16%) and inflammation of the nail bed (paronychia) (11%). The most common drug-related grade 3 adverse events observed in the pemetrexed/cisplatin arm were neutropenia (15%), fatigue (13%), and leucopenia (8%). There was a low discontinuation rate associated with treatment-related adverse events in the trial (8% discontinuation rate for afatinib; 12% for chemotherapy).1
Warnings and Precautions
P-gp inhibitors such as ritonavir, cyclosporine, ketoconazole, itraconazole, erythromycin, verapamil, tacrolimus, and amiodarone may increase exposure to afatinib. Likewise, p-gp inducers such as rifampin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort may reduce exposure to afatinib. Concomitant use of a p-gp inhibitor requires a 10-mg afatinib dose reduction. If the p-gp inhibitor is discontinued, the usual dose of afatinib may be restored after 2 to 3 days without the p-gp inhibitor.2 Afatinib is a pregnancy category D medication. Animal studies show an increased risk of fetal death, reduced fetal weight, and skeletal, vascular, and dermal abnormalities.