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。

IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS 
Diarrhea
Diarrhea has resulted in dehydration with or without renal impairment; some of these cases were fatal. In the pivotal study, diarrhea occurred in 96% of patients treated with GILOTRIF (n=229), of which 15% was Grade 3 in severity and occurred within the first 6 weeks. Renal impairment as a consequence of diarrhea occurred in 6.1% of patients treated with GILOTRIF, out of which 3 (1.3%) were Grade 3.
For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction. 
Bullous and Exfoliative Skin Disorders
Grade 3 cutaneous reactions characterized by bullous, blistering, and exfoliating lesions occurred in 6 (0.15%) of the 3865 patients who received GILOTRIF across clinical trials. In the pivotal study, the overall incidence of cutaneous reactions consisting of rash, erythema, and acneiform rash was 90%, and the incidence of Grade 3 cutaneous reactions was 16%.  In addition, the incidence of Grade 1-3 palmar-plantar erythrodysesthesia syndrome was 7%. Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating lesions.  For patients who develop prolonged Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF until the adverse reaction resolves to Grade 1 or less, and resume GILOTRIF with appropriate dose reduction.
Interstitial Lung Disease (ILD)
ILD or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in 1.5% of the 3865 patients who received GILOTRIF across clinical trials; of these, 0.4% were fatal. The incidence of ILD appeared to be higher in patients of Asian ethnicity (2.1%) as compared to non-Asians (1.2%).  In the pivotal study, the incidence of Grade ≥3 ILD was 1.3% and resulted in death in 1% of GILOTRIF-treated patients.
Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.
Hepatic Toxicity
In 3865 patients who received GILOTRIF across clinical trials, 10.1% had liver test abnormalities, of which 7 (0.18%) were fatal.  In the pivotal study, liver test abnormalities of any grade occurred in 17.5% of the patients treated with GILOTRIF.
Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. In patients who develop severe hepatic impairment while taking GILOTRIF, treatment should be discontinued.
Keratitis
Keratitis, characterized as acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye occurred in 0.8% of patients treated with GILOTRIF among 3865 patients across clinical trials. Keratitis was reported in 5 (2.2%) patients in the pivotal study, with Grade 3 in 1 (0.4%).  Withhold GILOTRIF during evaluation of patients with suspected keratitis, and if diagnosis of ulcerative keratitis is confirmed, treatment with GILOTRIF should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
Embryofetal Toxicity
GILOTRIF is Pregnancy Category D. Based on its mechanism of action, GILOTRIF can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus
Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking GILOTRIF.
ADVERSE REACTIONS
The most common adverse reactions (≥20%) in the GILOTRIF-treated patients (n=229) in the pivotal study were diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus.
Serious adverse reactions were reported in 29% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were diarrhea (6.6%); vomiting (4.8%); and dyspnea, fatigue, and hypokalemia (1.7% each). Fatal adverse reactions in GILOTRIF-treated patients included pulmonary toxicity/ILD-like adverse reactions (1.3%), sepsis (0.43%), and pneumonia (0.43%).
More GILOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to chemotherapy-treated patients (0.9%; n=1).
DRUG INTERACTIONS
Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
Concomitant taking of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
Concomitant taking of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib.
USE IN SPECIFIC POPULATIONS 
Nursing Mothers
It is not known whether afatinib is present in human milk.  Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from GILOTRIF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Renal Impairment
GILOTRIF has not been studied in patients with severely impaired renal function. Closely monitor patients with moderate (CLcr 30-59 mL/min) to severe (CLcr <30 mL/min) renal impairment and adjust GILOTRIF dose if not tolerated.
Hepatic Impairment
GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.
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