新型靶向药Brigatinib（商品名 Alunbrig 中文暂定：布吉他滨）片被FDA加速批准用于治疗局部晚期和转移性肺癌
结果显示，Brigatinib 90毫克的总体有效率为48%，180毫克的总体有效率为53%。两种计量的平均有效时间都为13.8个月。Brigatinib 90毫克对脑部转移的有效率为42%，180毫克的有效率为67%。在对脑部转移有效的患者中，78%的经90毫克治疗的患者和68%的经180毫克治疗的患者有效时间至少在4个月以上。
贮存在控制室温20°C至25°C (68°F至77°F)；外出允许15°C至30°C (59°F至86°F)间(见USP)。
Alunbrig will be available as 30mg strength tablets in 21- and 180-count bottles and as 90mg strength tablets in 7- and 30-count bottles.
ALUNBRIG (Brigatinib) Approved For The Treatment Of ALK+ Metastatic Non-Small Cell Lung Cancer.
Approval Date: April 28, 2017 Company: Takeda Pharmaceutical Company: Limited
ALUNBRIG™ (brigatinib) tablets, for oral use
Initial U.S. Approval: 2017
Mechanism of Action
Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.
At clinically achievable concentrations (≤ 500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo anti-tumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.
INDICATIONS AND USAGE
ALUNBRIG is a kinase inhibitor 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.
DOSAGE AND ADMINISTRATION
90 mg orally once daily for the first 7 days; if tolerated, increase to 180 mg orally once daily. May be taken with or without food.
DOSAGE FORMS AND STRENGTHS
Tablets: 30 mg and 90 mg
WARNINGS AND PRECAUTIONS
Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 9.1% of patients at the recommended dose. Monitor for new or worsening respiratory symptoms, particularly during the first week of treatment. Withhold ALUNBRIG for new or worsening respiratory symptoms and promptly evaluate for ILD/pneumonitis. Upon recovery, either dose reduce or permanently discontinue ALUNBRIG.
Hypertension: Monitor blood pressure after 2 weeks and then at least monthly during treatment. For severe hypertension, withhold ALUNBRIG, then dose reduce or permanently discontinue.
Bradycardia: Monitor heart rate and blood pressure regularly during treatment. If symptomatic, withhold ALUNBRIG, then dose reduce or permanently discontinue.
Visual Disturbance: Advise patients to report visual symptoms. Withhold ALUNBRIG and obtain ophthalmologic evaluation, then dose reduce or permanently discontinue ALUNBRIG.
Creatine Phosphokinase (CPK) Elevation: Monitor CPK levels regularly during treatment. Based on the severity, withhold ALUNBRIG, then resume or reduce dose.
Pancreatic Enzyme Elevation: Monitor lipase and amylase levels regularly during treatment. Based on the severity, withhold ALUNBRIG, then resume or reduce dose.
Hyperglycemia: Assess fasting serum glucose prior to starting ALUNBRIG and regularly during treatment. If not adequately controlled with optimal medical management, withhold ALUNBRIG, then consider dose reduction or permanently discontinue, based on severity.
Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use a non-hormonal method of effective contraception.
The most common adverse reactions (≥25%) with ALUNBRIG were nausea, diarrhea, fatigue, cough, and headache.
To report SUSPECTED ADVERSE REACTIONS, contact ARIAD Pharmaceuticals, Inc. at 1-844-217-6468 or www.alunbrig.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.
CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong CYP3A inducers.
CYP3A Substrates: Hormonal contraceptives may be ineffective due to decreased exposure.
USE IN SPECIFIC POPULATIONS
Lactation: Advise not to breastfeed.
HOW SUPPLIED/STORAGE AND HANDLING
30 mg tablets: round, white to off-white film-coated tablet with "U3" debossed on one side and plain on the other side; available in:
Bottles of 21 tablets NDC 76189-113-21
Bottles of 180 tablets NDC 76189-113-18
90 mg tablets: oval, white to off-white film-coated tablet with "U7" debossed on one side and plain on the other side; available in:
Bottles of 7 tablets NDC 76189-119-07
Bottles of 30 tablets NDC 76189-119-30
Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F) (see USP).