Pharmacological Class:
Human epidermal growth factor receptor (HER2) dimerization inhibitor.

Active Ingredient(s):
Pertuzumab 420mg/14mL (30mg/mL); soln for IV infusion; preservative-free.

Company
Genentech, Inc.
Indication(s):
In combination with trastuzumab and docetaxel: to treat patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

Pharmacology:
Pertuzumab targets the extracellular dimerization domain of the HER2 protein and, thereby, blocks ligand-dependent heterodimerization of HER2 with others, including EGFR, HER3 and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signal pathways, mitogen-activated protein kinase and phosphoinositide 3-kinase. Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively. In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity.

Clinical Trials:
Perjeta was assessed in a randomized trial of 808 patients with HER2-positive metastatic breast cancer. Breast tumor specimens were required to show HER2 overexpression. Patients were randomized 1:1 to receive placebo + trastuzumab and docetaxel or Perjeta + trastuzumab and docetaxel. Perjeta was given by IV at an initial dose of 840mg, followed by 420mg every 3 weeks thereafter. Trastuzumab was given by IV at an initial dose of 8mg/kg, followed by 6mg/kg every 3 weeks thereafter. Patients were treated with Perjeta and trastuzumab until progression of disease, withdrawal of consent, or unacceptable toxicity. Docetaxel was given as an initial dose of 75mg/m2 by IV infusion every 3 weeks for at least 6 cycles. The docetaxel dose could be escalated to 100mg/m2 at the investigator’s discretion if the initial dose was well tolerated.

The primary endpoint of the randomized trial was progression-free survival (PFS) as assessed by an independent review facility (IRF). PFS was defined as the time from the date of randomization to the date of disease progression or death (from any cause) if the death occurred within 18 weeks of the last tumor assessment. Additional endpoints included overall survival (OS), PFS (investigator-assessed), objective response rate (ORR) and duration of response.

The randomized trial demonstrated a statistically significant improvement in IRF-assessed PFS in the Perjeta-treated group compared with the placebo-treated group [hazard ratio (HR) = 0.62 (95% CI: 0.51, 0.75), P< 0.0001] and an increase in median PFS of 6.1 months (median PFS of 18.5 months in the Perjeta group vs. 12.4 months in the placebo group). The results for investigator-assessed PFS were comparable to those observed for IRF-assessed PFS.

Legal Classification:
Rx

Adults:
In combination with trastuzumab and docetaxel: initially 840mg IV over 60 minutes, followed every 3 weeks thereafter by a dose of 420mg IV over 30–60 minutes. Dose modification (missed dose, LVEF, or infusion reactions): see literature.

Children:
Not established.

Warnings/Precautions:
Risk of embryo-fetal toxicity. Pretreatment LVEF value of ≤50%, history of CHF, decreases in LVEF to <50% during prior trastuzumab therapy, uncontrolled hypertension, recent MI, serious cardiac arrythmia requiring treatment or a cumulative prior anthracycline exposure to >360mg/m2 of doxorubicin or its equivalent: not studied. Assess LVEF at baseline and every 3 months during treatment; if LVEF is <40%, or is 40% to 45% with a ≥10% absolute decrease below the pretreatment value, withhold and repeat LVEF within 3 weeks; discontinue if LVEF has not improved. Monitor for signs/symptoms of infusion reactions; slow or interrupt infusion and treat if occurs; discontinue if severe. Test for HER2 protein overexpression using FDA-approved tests by labs with demonstrated proficiency. Pregnancy (Cat.D); use adequate contraception during and at least 6 months after therapy. Nursing mothers: not recommended.

Adverse Reaction(s)
Diarrhea, alopecia, neutropenia, nausea, fatigue, rash, peripheral neuropathy; decreases in LVEF; pregnant women: possible oligohydramnios (monitor).

How Supplied:
Single-use vial—1

LAST UPDATED:
10/31/2012
 PERJETA(pertuzumab)注射剂，为静脉使用
美国初次批准：2012
适应证和用途
PERJETA是一种HER2/neu受体拮抗剂适用于与曲妥单抗[trastuzumab]和多西他奇[docetaxel]联用为未曾接受既往抗-HER2治疗或化疗的HER2-阳性转移乳癌患者为转移疾病的治疗。
剂量和给药方法
（1）只为静脉输注。不要静脉推注或丸注给药。
（2）初始剂量为840mg历时60-分钟静脉输注。其后每3周420mg历时30至60分钟静脉输注。
剂型和规格
420mg/14mL单次用小瓶。
禁忌证
无。
警告和注意事项
（1）胚胎-胎儿毒性：但给予妊娠妇女可能发生胎儿危害。
（2）左心室功能不全：监视LVEF和如适当时撤消给药。
（3）输注相关反应, 超敏性反应/过敏反应：监视体征和症状。如发生重要输注-相关反应，减慢或中断输注和给予适当医药治疗。
（4）HER2测试：由证实精通熟练实验室用FDA批准的检验进行。
不良反应
用PERJETA与曲妥单抗和多西他奇联用最常见不良反应(> 30%)是腹泻，脱发，中性细胞减少，恶心，疲乏，皮疹,和周围神经病。
在特殊人群中使用
（1）哺乳母亲：终止哺乳或终止PERJETA，考虑药物对母亲的重要性。
（2）女性的生殖潜能：忠告女性关于预防妊娠和计划，鼓励患者参加MotHER妊娠注册电话1-800-690-6720联系。
2013年9月30日，美国食品和药品监督管理局(FDA)授权加速批准Perjeta(pertuzumab)作为有早期乳癌手术前患者完整治疗方案的一部分(新辅助情况)。Perjeta是被FDA批准第一个为乳癌的新辅助治疗药物。
Perjeta在2012年被批准为有晚期或后期(转移)HER2-阳性乳癌患者的治疗。HER2-阳性乳癌有增加量的HER2蛋白对癌细胞生长和活存有贡献。
Perjeta的新使用是意向为有HER2-阳性，局部晚期，炎症或早期乳癌(肿瘤直径大于2 cm或有阳性淋巴结)处于有癌症回复或播散(转移)或因疾病死亡高风险的患者。它将手术前与曲妥珠单抗[trastuzumab]和其他化疗联用和，取决于所用治疗方案，可能是手术后接着化疗。手术后，患者应继续接受曲妥珠单抗完成一年治疗。
FDA的药物评价和研究中心血液学和肿瘤室主任Richard Pazdur，M.D.说：“我们正在看到治疗范式显著转变至早期阶段乳癌，”“通过在疾病最早情况高危患者可得到有效治疗，我们可能延缓或阻止癌症复发。”
在2012年5月， FDA发出一个关于使用病理学完全缓解(pCR)指导原则草案，被定义为在乳腺和淋巴结中缺乏侵入性癌症，作为一个支持为新辅助治疗高风险，早期阶段乳癌加速批准药物的终点。在FDA的加速批准程序下，当进行验证性临床试验时患者被提供得到有前途药物治疗严重或危及生命情况。
Perjeta的新辅助治疗加速批准是根据一项研究设计测量pCR。在研究中，417例参加者被随机赋予四种新辅助治疗方案之一：曲妥珠单抗加多西他赛[docetaxel]，Perjeta加曲妥珠单抗和多西他赛，Perjeta加曲妥珠单抗或Perjeta加多西他赛。约39 % who接受Perjeta加曲妥珠单抗和多西他赛参加者实现pCR，与之比较接受曲妥珠单抗加多西他赛约 21 %。
正在有HER2-阳性乳癌有乳癌手术前和处在其癌症回复高风险参加者中进行对加速批准验证试验。多余4,800例参加者被纳入这个试验，将进一步提供对疗效，安全性和长期结果资料。预期结果在2016年。
接受Perjeta加曲妥珠单抗和多西他赛参加者报道最常见副作用是脱发，腹泻，恶心和感染斗争白细胞减低。其他明显副作用包括心脏功能减低，输注相关反应，超敏性反应和过敏反应。
FDA在监管局的优先审评程序下审评Perjeta的为新辅助治疗使用，对在治疗中可能提供一个的药物提供加快审评。
乳癌是妇女癌症相关死亡的第二大原因。根据美国癌症研究所估计2013年232,340妇女将被诊断有乳癌，和39,620将死于该病。几乎20%乳癌有HER2蛋白量增加。