Perjeta
Manufacturer:
Genentech, Inc.

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

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

2012年6月8日，罗氏（Roche）旗下基因泰克（Genentech）宣布，新的乳腺癌药物Perjeta已获FDA批准，用于HER-2阳性乳腺癌患者的治疗。HER-2阳性乳腺癌约占所有乳腺癌的四分之一，目前无法治愈。罗氏希望该药成为HER2阳性乳腺癌的标准治疗药物。

分析家们预测，该药有望成为罗氏另一个重磅抗癌药物。

今年早些时期，FDA给予该药优先审查地位，这意味着该机构认为，Perjeta可能代表着对当前疗法的一个重大进步。在临床试验中，与现有标准护理相比，Perjeta使癌症的恶化推迟了额外6个月。

去年，Genentech遭受了一次打击：FDA撤消了阿瓦斯汀（Avastin）治疗乳腺癌的批准，称该药的有效性不值得该药的风险。当时，FDA顾问及其他专家称，Genentech需要开展更多的试验，看看究竟哪一部分乳腺癌患者能够从治疗中获益。

罗氏称，Perjeta（通常称为帕妥珠单抗，pertuzumab），仅适用于HER-2阳性的乳腺癌患者。

Thomson Reuters分析师平均预期，到2016年，pertuzumab的销售额将达到6.08亿美元。不过，也有分析师称，该药的销售将超越10亿美元。

后续的重磅药物（FOLLOW-ON BLOCKBUSTERS）

与其他生物技术药物生产商一样，罗氏也正在寻求扩大其昂贵品牌药的寿命。Perjeta是该策略的一部分，因为它是罗氏销量排第三的突破性乳腺癌药物--赫赛汀（Herceptin）的后续版本。

赫赛汀（也被称为tratuzumab），在2011年的全球销售额达59亿美元，一个疗程的费用在3.2万美元左右。

赫赛汀于1998年首次获批，它与pertuzumab都是旨在阻断HER2功能的抗体。HER2是一种由癌相关基因产生的蛋白。Pertuzumab结合HER2的不同部位，这使得这2种药物的组合更加有效。

在临床试验中，接受赫赛汀+化疗的患者组，癌症无进展生存期为12.4个月，而接受Perjeta+赫赛汀+化疗的患者组，癌症无进展生存期达到了18.5个月。

目前，基因泰克公司也正在测试将Perjeta用于早期和晚期HER2阳性乳腺癌及晚期HER2胃癌的治疗。

Jefferies的分析师认为，如果Perjeta获得这些额外的批准，其销售峰值将达到85亿美元，根据上周的一份研究报告。

另外，基因泰克目前也在开发一种"装备抗体（armed antibody）"--TDM-1，用于HER2阳性乳腺癌的治疗。TDM-1是由赫赛汀与衍生自一种强大的化疗药物组成

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:
7/9/2012