2015年12月11日，美国FDA今天批准Genentech公司研发的抗肿瘤靶向新药Alecensa（alectinib 中文药名：盐酸阿雷替尼）用于治疗晚期（转移性）ALK-阳性非小细胞肺癌（NSCLC），患者病情已经恶化，或谁不能再容忍目前的治疗，称为Xalkori（crizotinib），该药为Pfizer生产的。 肺癌是癌症死亡的主力军，在美国2015年估计新增221,200病例，158,040会导致死亡。非小细胞肺癌是肺癌的最常见类型。ALK（间变性淋巴瘤激酶）基因突变可以发生在几个不同类型的癌症细胞，包括肺癌细胞。ALK基因突变目前占据5%左右的非小细胞肺癌患者的。在转移性癌中，这种疾病蔓延到身体的新部位。针对ALK阳性非小细胞肺癌的患者，大脑是疾病传播的常见的地方。 FDA的药物评价和研究中心血液学和肿瘤学办公室主任Richard Pazdur, M.D.，说：‘今天的批准为一些已有的治疗没有任何起效，如一旦他们的疾病不再对Xalkori有任何反应那组病人提供一种新疗法’。‘除了对肺肿瘤的主要影响外，Alecensa临床试验提供了对肿瘤已经扩散到大脑起到一定效应，这是非常重要的效果，对于临床医生来说’。 Alecensa是一种口服的药物，阻止ALK蛋白的活性，某种意义上可以阻止非小细胞肺癌细胞的生长和传播。 在两对临床试验中参与者均是对Xalkori治疗转移性ALK阳性非小细胞肺癌，不再起作用，此时患者服用Alecensa的疗效及安全性的研究。研究参与者收到Alecensa每日两次，测量其药物对肺肿瘤的影响。 在第一对临床试验中，38%的参与者非小细胞肺癌肿瘤经历部分收缩的，这种效果持续了7.5 个月（平均）。在第二对研究中，44%的参与者非小细胞肺癌肿瘤经历部分收缩的，这种效果持续了11.2 个月（平均）。试验还审查了Alecensa?的影响个人的脑转移瘤，这在该病群体中是一个普遍现象。这两项试验中61%的参加者脑转移瘤经历完全或部分的减少，这种效果持续了9.1 个月（平均）。 Alecensa的最常见的副作用是疲劳，便秘，肿胀（水肿）和肌肉疼痛（肌痛）。Alecensa可能会导致严重的副作用，包括肝脏的问题，严重或危及生命的肺炎症、 心跳过缓和严重的肌肉问题。接受Alecensa治疗的患者暴露于阳光下，可能会导致晒伤。 Alecensa利用加速批准的途径获得批准，同时FDA还授予突破性疗法和优先审查权。 Indication and Important Safety Information Indication ALECENSA is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Important Safety Information Warnings and Precautions Hepatotoxicity •Elevations of AST >5X the upper limit of normal (ULN) occurred in 3.6% of patients, and elevations of ALT >5X the ULN occurred in 4.8% of patients. Elevations of bilirubin >3X the ULN occurred in 2.8% of patients. The majority (73% of the patients with hepatic transaminase elevations and 49% of the patients with bilirubin elevations) of these events occurred during the first 2 months of treatment. Four patients discontinued ALECENSA for Grade 3-4 AST and/or ALT elevations, and three patients discontinued ALECENSA for Grade 3 bilirubin elevations. Two patients with Grade 3-4 AST/ALT elevations had documented drug-induced liver injury by liver biopsy •Monitor liver function tests including ALT, AST, and total bilirubin every 2 weeks during the first 2 months of treatment, then periodically during treatment, with more frequent testing in patients who develop transaminase and bilirubin elevations. Based on the severity of the adverse drug reaction, withhold ALECENSA and resume at a reduced dose, or permanently discontinue ALECENSA Interstitial Lung Disease (ILD)/Pneumonitis •Severe ILD (Grade 3) occurred in one (0.4%) of 253 patients exposed to ALECENSA in clinical trials •Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, and fever) •Immediately withhold ALECENSA treatment in patients diagnosed with ILD/pneumonitis and permanently discontinue ALECENSA if no other potential causes of ILD/pneumonitis have been identified Bradycardia •Symptomatic bradycardia can occur with ALECENSA. Cases of bradycardia (7.5%) have been reported in patients treated with ALECENSA. Twenty percent of 221 patients treated with ALECENSA for whom serial ECGs were available had heart rates of <50 beats per minute (bpm) •Monitor heart rate and blood pressure regularly. Dose modification is not required in cases of asymptomatic bradycardia. In cases of symptomatic bradycardia that is not life-threatening, withhold ALECENSA until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm and evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications. If attributable to a concomitant medication, resume ALECENSA at a reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm, with frequent monitoring as clinically indicated. Permanently discontinue ALECENSA in case of recurrence. Permanently discontinue ALECENSA in cases of life-threatening bradycardia if no contributing concomitant medication is identified Severe Myalgia and Creatine Phosphokinase (CPK) Elevation •Myalgia or musculoskeletal pain occurred in 29% of patients in clinical trials. The incidence of Grade 3 myalgia/musculoskeletal pain was 1.2%. Dose modifications for myalgia/musculoskeletal pain were required in 0.8% of patients •Elevations of CPK occurred in 43% of 218 patients with CPK laboratory data available in clinical trials. The incidence of Grade 3 elevations of CPK was 4.6%. Median time to Grade 3 CPK elevation was 14 days (interquartile range 13-14 days). Dose modifications for elevation of CPK occurred in 5.0% of patients •Advise patients to report any unexplained muscle pain, tenderness, or weakness. Assess CPK levels every 2 weeks for the first month of treatment and as clinically indicated in patients reporting symptoms. Based on the severity of the CPK elevation, withhold ALECENSA, then resume or reduce dose Embryo-Fetal Toxicity •Based on findings from animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to pregnant women. Administration of ALECENSA to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7X those observed in humans with ALECENSA 600 mg twice daily. Advise pregnant women of the potential risk to a fetus •Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for 1 week following the final dose Most Common Adverse Reactions •The most common adverse reactions (incidence ≥20%) were fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). Management of adverse reactions may require temporary interruption, dose reduction, or discontinuation of treatment with ALECENSA Use in Specific Populations Pregnancy •Based on animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to a pregnant woman. There are no available data on ALECENSA use in pregnant women •In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively Lactation •Because of the potential for serious adverse reactions in breast-fed infants from ALECENSA, advise a lactating woman not to breastfeed during treatment with ALECENSA and for 1 week after final dose Females and Males of Reproductive Potential •ALECENSA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for 1 week after the final dose •Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with ALECENSA and for 3 months following the final dose Patient Counseling Information Photosensitivity •Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure while taking ALECENSA and for at least 7 days after discontinuation and to use proper protection from the sun. Advise patients to use a broad spectrum ultraviolet A (UVA)/ultraviolet B (UVB) sunscreen and lip balm (SPF ≥50) to help protect against potential sunburn 1）：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=42c49deb-713b-427a-9670-08af08adcffb 2）：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=42c49deb-713b-427a-9670-08af08adcffb