Kadcyla（曲妥珠单抗-emtansine共轭药物）是一种新型抗体-药物共轭物，日前获得美国FDA的批准用于治疗HER2阳性转移性乳腺癌。转移往往被视为晚期疾病的标志，意味着肿瘤已扩散至身体的其他部位。HER2是一种促进正常细胞生长的蛋白质，在一系列癌症细胞株中高表达（所谓的HER2阳性），其中包括若干乳腺癌细胞。HER2蛋白促进HER2阳性乳腺癌细胞的生长和存活。
HER2是人表皮生长因子受体2的简称。Kadcyla可用于经抗HER2方案治疗后的患者，抗HER2治疗方案广泛应用于乳腺癌的化疗，相关药物包括曲妥珠单抗，及紫杉烷类等。
FDA药品评价与研究中心血液肿瘤学主任Richard Pazdur博士说：Kadcyla是曲妥珠单抗与另一种干扰肿瘤细胞生长的药物DM1相结合的共轭物。Kadcyla可将药物靶向肿瘤位点，进而使肿瘤灶消退，延缓疾病进展并延长生存期。它是第四种获批的HER2蛋白靶向药物。
Kadcyla在研究期间被称作T-DM1，它首先获得了FDA的优先审核资格，可以将整个审批流程缩短至6个月。这一流程适用于那些无现行有效疗法且表现出良好安全性和有效性的药物，或者对市场流通的药物作出重大改善。
FDA的专家对EMILIA研究中Kadcyla的安全性和有效性进行审查，该研究中纳入了991例患者并随机分为两组：Kadcyla组和拉帕替尼联合卡培他滨组（卡培他滨是另一种化疗药物）。患者持续治疗直到疾病进展或药物副作用难以承受。研究的综合主要终点为：无进展生存期（癌症开始再次发展的时间），总体生存期（患者存活时间）。试验结果显示： Kadcyla组患者的无进展生存时间为9.6个月，与之相比，拉帕替尼联合卡培他滨组患者的无进展生存期则为6.4个月。Kadcyla组患者的中位总生存期为30.9个月，拉帕替尼联合卡培他滨组患者的中位总生存期为25.1个月。
然而对于Kadcyla，FDA给出了罕见的“黑框警告”（Boxed Warning）。FDA称，必须警告医生和患者，Kadcyla可能导致心脏毒性、肝脏毒性、以及死亡。它还可能引起严重的甚至危及生命的胚胎发育缺陷。妊娠期女性患者慎用。Kadcyla临床研究报道的副作用包括关节疼痛、肌肉痛、血小板减少症（低血液血小板水平），肝酶水平升高、便秘、头痛、疲劳和恶心等。
国家癌症研究所的报告显示，乳腺癌是美国女性致死率第二高的癌症。2013年，据估算约有232,340名女性将诊断为乳腺癌，39,620例患者死于该疾病。世界健康组织称乳腺癌是全世界最常见的女性癌症。
将近五分之一的乳腺癌患者高表达HER2蛋白
Kadcyla由加利福尼亚州的Genentech公司（罗氏子公司）推向市场。Genentech也运作了曲妥珠单抗和帕妥珠单抗的上市，而拉帕替尼是GSK(GlaxoSmithkline)公司的产品。Genentech 公司全球产品研发部首席医药官Hal Barron称：“Kadcyla，这种抗体共轭药物代表着一种全新的HER2阳性转移性乳腺癌治疗途径，EMILIA研究中显示，它可延长患者生存期近6个月。目前我们的流水线上拥有超过25种抗体-药物共轭产品，我们期望未来它们中可以诞生用于治疗其他癌症的药物。”
Genentech公司说，Kadcyla在未来的两周内将在美国全国范围内推广。该公司计划启动患者爱心帮助项目，以帮助那些买不起Kadcyla的患者，以及没有医疗保险的患者。Genentech公司称在未来的30年时间内他们将致力于HER2信号通路的研究。“HER2靶向治疗代表着第一例成功的个体化治疗案例。”肿瘤药物市场的另一家大拿罗氏公司也在积极寻找其第三畅销药物赫塞汀（曲妥珠单抗）的替代药品，这款药物的专利保护将在2015年到期。
Kadcyla® (ado-trastuzumab emtansine)
Kadcyla® (ado-trastuzumab emtansine) is approved, as a single medicine, for the treatment of people with HER2-positive metastatic breast cancer (mBC) who have received prior treatment with Herceptin® (trastuzumab) and a taxane chemotherapy. People should either:
•Have already been treated for their metastatic cancer, or
•Have had their early-stage cancer come back during or within six months after they completed a course of treatment following surgery.
Important Safety Information
KADCYLA is not the same medicine as trastuzumab (Herceptin)
There are possible serious side effects of KADCYLA. The patient’s doctor may do tests before starting KADCYLA and before each dose to monitor for these side effects. KADCYLA treatment may be stopped or the dose may be lowered if the patient experiences any of these side effects. Patients must contact their doctor right away if they experience any of these symptoms.
Liver Problems
•KADCYLA may cause severe liver problems that can be life-threatening. Symptoms of liver problems may include vomiting, eating disorder (anorexia), nausea, stomach pain, yellowing of the skin (jaundice), dark urine, or itching
Heart Problems
•KADCYLA may cause heart problems, including those without symptoms (such as reduced heart function) and those with symptoms (such as congestive heart failure). Symptoms may include swelling of the ankles or legs, shortness of breath, cough, rapid weight gain of greater than 5lbs in less than 24 hours, dizziness or loss of consciousness, or irregular heart beat
Pregnancy
•Receiving KADCYLA during pregnancy can result in the death of an unborn baby and birth defects. Birth control should be used while patients receive KADCYLA and for 6 months after their last dose of KADCYLA
•If patients are exposed to KADCYLA during pregnancy, they must contact their healthcare provider right away; they are also encouraged to enroll in the MotHER Pregnancy Registry by contacting 1 (800) 690-6720
•If patients are mothers who are breastfeeding, they should talk with their doctor about either stopping breastfeeding or stopping KADCYLA
Additional possible serious side effects of KADCYLA
Lung Problems
•KADCYLA may cause lung problems, including inflammation of the lung tissue, which can be life- threatening. Signs of lung problems may include trouble breathing, cough, tiredness, and fluid in the lungs
Infusion-Related Reactions
•Symptoms of an infusion-related reaction may include one or more of the following: the skin getting hot or red (flushing), chills, fever, trouble breathing, low blood pressure, wheezing, tightening of the muscles in the chest around the airways, or a fast heartbeat. The patient’s doctor will monitor the patient for infusion related reactions
Low Platelet Count
•Low platelet count may happen during treatment with KADCYLA. Platelets are cells in the blood that help the blood clot
Nerve Damage
•Symptoms may include numbness and tingling, burning or sharp pain, sensitivity to touch, lack of coordination, or muscle weakness or loss of muscle function
Skin Reactions Around the Infusion Site
•KADCYLA may leak from the vein or needle and cause reactions such as redness, tenderness, skin irritation, or pain or swelling at the infusion site. If this happens, it is more likely to happen within 24 hours of the infusion
HER2 testing and KADCYLA
Patients must have a HER2 test to determine if their cancer is HER2-positive before taking KADCYLA as benefit has only been shown in patients whose tumors are HER2-positive.
Most common side effects of KADCYLA
The most common side effects seen in people taking KADCYLA were:
•Tiredness
•Nausea
•Pain that affects the bones, muscles, ligaments, and tendons
•Low platelet count
•Headache
•Liver problems
•Constipation
KADCYLA Rx
Pharmacological Class:
HER2-targeted antibody-drug conjugate.
Active Ingredient(s):
Ado-trastuzumab emtansine 100mg, 160mg; per vial; powder; for IV infusion after reconstitution.
Company
Genentech, Inc.
Indication(s):
Treatment in patients with HER2-positive (+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy.
Pharmacology:
Ado-trastuzumab emtansine is an HER2-targeted antibody-drug conjugate. The antibody is the humanized anti-HER2 IgG1, trastuzumab. The small molecule cytotoxin, DM1, is a microtubule inhibitor. Upon binding to subdomain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death.
Clinical Trials:
The efficacy of Kadcyla was evaluated in a randomized open-label trial of 991 patients with HER2 (+), unresectable locally advanced or MBC. Prior taxane and trastuzumab-based therapy was required before trial enrollment. Patients were randomized (1:1) to receive lapatinib plus capecitabine or Kadcyla and were treated until progression of disease, withdrawal consent, or unacceptable toxicity.
The co-primary efficacy endpoints of the study were progression-free survival (PFS) based on tumor response assessments by an independent review committee (IRC) and overall survival (OS).
The trial demonstrated a statistically significant improvement in IRC-assessed PFS in the Kadcyla group compared to the lapatinib + capecitabine group [HR=0.65; 95% CI:0.55, 0.77, P<0.0001], and an increase in median PFS of 3.2 months (median PFS of 9.6 months in the Kadcyla group vs. 6.4 months in the lapatinib + capecitabine group). At the time of the second interim OS analysis, 331 events had occurred. The co-primary endpoint of OS was met; OS was significantly improved in patients receiving Kadcyla (HR =0.68, 95% CI: 0.55, 0.85, P = 0.0006). The median duration of survival was 30.9 months in the Kadcyla arm vs. 25.1 months in the lapatinib + capecitabine arm.
Legal Classification:
Rx
Adults:
Give by IV infusion only over 90 minutes 3.6mg/kg max every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Subsequent infusions may be given over 30 minutes if previously tolerated. Monitor closely for possible SC infiltration during infusion. Dose modifications: see full labeling.
Children:
Not established.
Warnings/Precautions:
Do not substitute for or with trastuzumab. Hepatotoxicity; monitor serum transaminases and bilirubin prior to starting and to each dose; reduce dose or discontinue if occurs. Risk of left ventricular dysfunction. Assess LVEF prior to initiation and every 3 months during treatment; interrupt and discontinue as appropriate. Risk of embryo-fetal toxicity. Permanently discontinue if interstitial lung disease or pneumonitis occurs. Monitor for signs/symptoms of extravasation, infusion-related or hypersensitivity reactions; if significant, slow or interrupt infusion; discontinue if life-threatening. Monitor platelets at baseline and prior to each dose; if platelets <50,000/mm3, delay dose until recovery to ≥75,000/mm3; if platelets <25,000/mm3, delay until recovery to ≥75,000/mm3 and reduce dose. If thrombocytopenia occurs <100,000/mm3 and concomitant anticoagulants, monitor closely. Monitor for neurotoxicity; withhold temporarily if Grade 3 or 4 peripheral neuropathy occurs. Test for HER2 protein overexpression or gene amplification using FDA-approved tests by labs with demonstrated proficiency. Pregnancy (Category D); use adequate contraception during and at least 6 months after last dose. Nursing mothers: not recommended.
Interaction(s)
Avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, atazanavir, indinavir, ritonavir, nefazodone, nelfinavir, saquinavir, telithromycin); if unavoidable, consider delaying therapy (see full labeling).
Adverse Reaction(s)
Fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache; increased transaminases, constipation.
How Supplied:
Single-use vial—1
LAST UPDATED:
5/10/2013