近日，FDA批准Lorbrena（Lorlatinib）为第三代间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（TKI）—用于治疗接受克唑替尼和至少一种其它ALK抑制剂治疗之后疾病发生恶化，或接受阿来替尼（Alectinib）或色瑞替尼（Ceritinib）作为第一个ALK抑制剂治疗但疾病恶化的ALK阳性转移性NSCLC患者。Lorlatinib是辉瑞研发的一种靶向ALK/ROS1的双靶点抑制剂。 
批准日期：2018年11月2日  公司：辉瑞
LORBRENA(罗拉替尼[lorlatinib])片，口服
美国初步批准:2018年
作用机制
Lorlatinib是一种激酶抑制剂，对ALK和ROS1以及TYK1、FER、FPS、TRKA、TRKB、TRKC、FAK、FAK2和ACK具有体外活性。Lorlatinib对多种ALK酶的体外活性显示，包括在crizotinib和其他ALK抑制剂疾病进展时在肿瘤中检测到的一些突变。
在小鼠皮下植入含有ALK变异体1或碱基突变的EML4融合物的小鼠体内，包括在疾病进展时在肿瘤中检测到的G1202R和I1171T突变。Lorlatinib还演示了eml4-alk驱动肿瘤细胞系植入颅内小鼠抗肿瘤活性及延长生存期。lorlatinib体内模型整体抗肿瘤活性与ALK磷酸化的剂量相关，且与之相关。
适应症和用法
LORBRENA是一种激酶抑制剂，用于治疗癌症进展的间变性淋巴瘤激酶(ALK)阳性转移非小细胞肺癌(NSCLC)患者crizotinib和至少一种ALK转移性疾病抑制剂;或阿立替尼作为第一个ALK抑制剂治疗转移性疾病;或ceritinib作为第一个ALK抑制剂治疗转移性疾病。
根据肿瘤应答率和应答持续时间加快审批。持续批准这一指示可能取决于在临床试验中对临床效益的验证和描述。
剂量和管理
建议用量为每天口服100mg。
剂型及强度
片剂:25mg或100mg。
禁忌症
与强CYP3A诱导剂一起使用。
警告和预防措施
使用强CYP3A有严重肝毒性的危险
诱导剂:在开始使用LORBRENA之前，停用强CYP3A诱导剂，用于3个强CYP3A诱导剂的血浆半衰期。
中枢神经系统(中枢神经系统)效应:中枢神经系统效应包括癫痫、幻觉和认知功能的变化、情绪(包括自杀意念)、言语、精神状态和睡眠。保留和恢复根据严重程度，以相同剂量或减少剂量或永久间断使用。
高脂血症:引起或增加降脂剂的剂量。
根据严重程度，保留和恢复LORBRENA相同或减少剂量。
房室传导阻滞:根据严重程度以相同或减少剂量保留和恢复洛布列纳。
间质性肺病/气管炎:怀疑患有ILD/肺炎患者立即停用LORBRENA。对于任何严重的与治疗相关的呼吸道感染/肺炎，永久停止使用洛布列纳。
胚胎-胎儿毒性:可导致胎儿伤害。告知女性生殖的潜力，潜在的风险对胎儿。建议有生育潜力的男性和女性使用有效的非激素避孕方法。
不良反应
最常见的不良反应(发生率≥20%)水肿,peripheralneuropathy,认知效果、呼吸困难、疲劳,体重增加,关节痛,moodeffects,腹泻。
要报告可疑的不良反应，请联系辉瑞公司，电话1-800-438-1985或www.pfizer.com或FDA，电话1-800-FDA-1088或www.fda.gov/medwatch。
药物的相互作用
CYP3A诱导剂:禁用强的CYP3A诱导剂。避免与适当的CYP3A诱导剂同时使用。
CYP3A抑制剂:避免同时使用强CYP3A抑制剂;如果不能避免同时使用，减少LORBRENA剂量。
CYP3A底物:避免与CYP3A底物同时使用，其中最小浓度变化可能导致严重的治疗失败。
用于特定人群
哺乳期:建议不要哺乳。
如何提供/存储和处理
LORBRENA的可用优势和包配置:
  包装配置     强度(毫克)    NDC        
   30瓶：       25毫克    0069-0227-01
   30瓶：       100毫克   0069-0231-01
储存地点:20o至25oC (68o至77o F);允许在15o - 30o(华氏59度- 86度)之间飞行[见USP控制室温]。
完整说明资料附件：
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdf
Lorbrena Approved for Previously-Treated ALK-Positive Metastatic NSCLC
Pfizer announced that the Food and Drug Administration (FDA) has approved Lorbrena (lorlatinib) for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on: crizotinib and at least 1 other ALK inhibitor for metastatic disease; or alectinib as the first ALK inhibitor therapy for metastatic disease; or ceritinib as the first ALK inhibitor therapy for metastatic disease.
Lorbrena, a third generation ALK tyrosine kinase inhibitor (TKI), has been approved under the accelerated pathway based on tumor response rate and duration of response. Continued approval may be based on verification and description of clinical benefit in a confirmatory trial.
The FDA approval was supported by data from a non-randomized, dose-ranging and activity-estimating, multi-cohort, multicenter Phase 1/2 study that eva luated Lorbrena in patients with ALK-positive metastatic NSCLC who were previously treated with 1 or more ALK TKIs (N=215) .
Results showed an overall response rate (ORR) of 48% (95% CI, 42%, 55%) among treated patients (4% complete response; 44% partial response); 57% of patients had previous treatment with >1 ALK TKI. The median duration of response was 12.5 months (95% CI, 8.4, 23.7). In addition, an assessment of intracranial ORR showed a 60% response rate (95% CI, 49%, 70%) among patients with measurable intracranial lesions; 69% of patients had a history of brain metastases. The median duration of response in these patients was 19.5 months (95% CI, 12.4, not reached [NR]).
The most frequent adverse reactions reported with treatment included edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea.
“Lorbrena's approval is an important milestone for patients, having demonstrated marked activity in a study that included a broad range of individuals with ALK-positive non-small cell lung cancer. This includes patients who were heavily pretreated and facing limited options after receiving first- and second-generation ALK tyrosine kinase inhibitors," stated Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development.
Lorbrena will be available as 25mg and 100mg strength tablets in 30-count bottles.