新药pertuzumab（商品名 PERJETA）已被美国FDA批准上市，一个新抗-HER2治疗，治疗HER2-阳性后期(转移)乳癌患者。 Perjeta意向为既往未曾接受抗-HER2治疗或化疗治疗的转移乳癌患者，Perjeta是与曲妥单抗，另一种抗-HER2治疗，和多西他奇，一类型化疗联用。 HER2是涉及正常细胞生长的一种蛋白。发现在某些类型癌细胞(HER2-阳性)上量增高，包括有些乳癌。在这些HER2-阳性乳癌，HER2蛋白量增高促进癌细胞生长和活存。 Perjeta是一种人源化单克隆抗体，通过生物技术方法制造。静脉给药和被认为通过靶向HER-蛋白上与曲妥单抗[trastuzumab]不同部分起作用，导致HER2-阳性乳癌细胞生长和活存进一步减低。因为存在生产问题可能潜在地影响药物长期供应，Genentech，Perjeta的制造商，已承诺采取步骤及时方式解决这些生产问题。 FDA的药物评价和研究中心主任Janet Woodcock, M.D.说：“对转移乳癌需要另外治疗，今天我们做出决定批准此药而不延迟患者的可供利用性与未来供应相关的未解决生产问题”“Genentech当前正在发展一个计划以减轻患者短缺Perjeta的任何潜在影响。” 乳癌是妇女中癌-相关死亡第二位领先原因。今年估计有226,870例妇女将被诊断有乳癌，和39,510例将死于该病，约20%乳癌有HER2蛋白量增高。 FDA的药物评价和研究中心血液学和肿瘤产品办公室主任Richard Pazdur, M.D.说“自从曲妥单抗第一个被批准以来, 继续研究已允许我们更好了解HER2在乳癌中的作用，”“这项研究提供结合两个靶向药物结合的背景–曲妥单抗和Perjeta 与多西他奇[docetaxel]减慢乳癌疾病进展。” 涉及808例HER2-阳性转移乳癌患者的一项单一临床试验评价了Perjeta的安全性和有效性，患者治疗前测试以确定HER2蛋白是否增加。患者被随机赋予接受Perjeta，曲妥单抗和多西他奇或曲妥单抗和多西他奇与一个安慰剂。 研究被设计测定患者无癌症进展或次年的时间长度，无进展活存(PFS)。含Perjeta联合治疗有中位PFS为18.5个月，而含安慰剂联用治疗有中位PFS为12.4月 需要提醒患者的是，该药物为处方药，需要有临床肿瘤科医生诊断和开具处方，同时也需要注意用量及其监测并发症等。 批准日期：2012年6月8日；公司：Genentech PERJETA（帕妥珠单抗[pertuzumab]）注射液 用于静脉注射 美国初步批准：2012年 警告： 左心室功能异常和胚胎毒性见完整的预警信息。 左心室功能障碍：PERJETA可导致亚临床和临床心脏衰竭表现为LVEF和CHF降低。在治疗前和治疗期间评估心脏功能。停止PERJETA治疗，确认左心室功能的临床显着降低。 胚胎 - 胎儿毒性：暴露于PERJETA可导致胚胎胎儿死亡和出生缺陷。向患者提供这些风险和有效避孕的需要。 最近的主要变化 警告和注意事项：03/2016 作用机制 帕妥珠单抗靶向人表皮生长因子受体2蛋白（HER2）的胞外二聚化结构域（Subdomain II），从而阻断HER2与其他HER家族成员（包括EGFR，HER3和HER4）的配体依赖性异二聚化。 结果，贝伐珠单抗通过两种主要信号通路，丝裂原活化蛋白（MAP）激酶和磷酸肌醇3-激酶（PI3K）抑制配体启动的细胞内信号转导。 这些信号通路的抑制分别可导致细胞生长停滞和细胞凋亡。 此外，佩替珠单抗介导抗体依赖性细胞介导的细胞毒性（ADCC）。 尽管pertuzumab单独抑制人肿瘤细胞的增殖，但是pertuzumab和曲妥珠单抗的组合增加了HER2过表达异种移植模型中的抗肿瘤活性。 适用范围及用途 PERJETA是一种HER2/neu受体拮抗剂，适用于： 与曲妥珠单抗和多西紫杉醇组合用于治疗HER2阳性转移性乳腺癌（MBC）患者，尚未接受先前的HER2治疗或化学疗法用于转移性疾病。 与曲妥珠单抗和多西他赛组合使用作为HER2阳性，局部晚期，炎症或早期乳腺癌（直径大于2厘米或淋巴结阳性）患者的新辅助治疗，作为早期乳腺癌的完整治疗方案的一部分。该指征是基于病理学完整反应率的改善的证明。没有数据可以显示无事件生存或总体生存的改善。 使用限制： PERJETA作为含阿霉素的方案的一部分的安全性尚未确定。 PERJETA早期乳腺癌治疗超过6个周期的安全性尚未确定。 剂量和管理 仅用于静脉滴注不要作为静脉推注或推注使用。 初始PERJETA剂量为840mg，静脉输注60分钟，随后每3周施用420mg静脉输注30-60分钟。 MBC：每3周静脉滴注给予PERJETA，曲妥珠单抗和多西紫杉醇。 新辅助：在术前每3周静脉输注3至6个周期，对PERJETA，曲妥珠单抗和多西紫杉醇进行治疗。 剂量形式和强度 420mg/14mL一次性小瓶。 禁忌症 PERGETA禁用于对pertuzumab或其任何赋形剂已知超敏反应的患者。 警告和注意事项 左心室功能障碍：监测LVEF并酌情停药。 输液相关反应：监测体征和症状。如果发生显着的输注相关反应，缓慢或中断输注并进行适当的医疗治疗。 超敏反应/过敏反应：监测体征和症状。如果发生严重的超敏反应/过敏反应，立即停止输注，并进行适当的药物治疗。 HER2检测：使用经FDA批准的实验室检测，具有良好的熟练程度。 不良反应 转移性乳腺癌 PERJETA与曲妥珠单抗和多西紫杉醇组合最常见的不良反应（>30％）为腹泻，脱发，中性粒细胞减少，恶心，疲劳，皮疹和周围神经病变。 新辅助治疗乳腺癌 PERJETA与曲妥珠单抗和多西紫杉醇组合最常见的不良反应（>30％）为脱发，腹泻，恶心和中性粒细胞减少。 在3次循环后，PERJETA联合曲妥珠单抗和多西紫杉醇的最常见不良反应（>30％）为疲劳，脱发，腹泻，恶心，呕吐和中性粒细胞减少。 PERJETA与多西他赛，卡铂和曲妥珠单抗（TCH）联用的最常见的不良反应（>30％）为疲劳，脱发，腹泻，恶心，呕吐，中性粒细胞减少，血小板减少症和贫血。 在特定人口中使用 女性和男性的生殖潜力：在PERJETA开始之前验证女性的怀孕状态。 包装规格/存储和处理 提供 PERJETA作为420mg/14mL（30mg/mL）一次性小瓶提供，含有无防腐剂的溶液。 NDC 50242-145-01。 将小瓶存放在2°C至8°C（36°F至46°F）的冰箱中，直到使用时间为止。 将小瓶放在外箱中以防止光照。 不要冻结 不要。 完整说明书附件 https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=17f85d17-ab71-4f5b-9fe3-0b8c822f69ff PERJETA: FDA-approved for 2 indications in HER2+breast cancer IndicationPERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated for: •Treatment of metastatic breast cancer in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease •Use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival Limitations of Use: •The safety of PERJETA as part of a doxorubicin-containing regimen has not been established •The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established Important Safety InformationBoxed WARNINGS: Left Ventricular Dysfunction and Embryo-Fetal Toxicity •PERJETA administration can result in subclinical and clinical cardiac failure manifesting as decreased LVEF and CHF. Evaluate cardiac function prior to and during treatment. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function •Exposure to PERJETA can result in embryo-fetal death and birth defects. Advise patients of these risks and the need for effective contraception Based on its mechanism of action and findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. PERJETA is a HER2/neu receptor antagonist. Cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death have been reported with use of another HER2/neu receptor antagonist (trastuzumab) during pregnancy. In an animal reproduction study, administration of pertuzumab to pregnant cynomolgus monkeys during the period of organogenesis resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death at exposures 2.5 to 20 times the exposure in humans at the recommended dose, based on Cmax Verify the pregnancy status of females of reproductive potential prior to the initiation of PERJETA. Advise pregnant women and females of reproductive potential that exposure to PERJETA in combination with trastuzumab during pregnancy or within 7 months prior to conception can result in fetal harm, including embryo-fetal death or birth defects. Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of PERJETA in combination with trastuzumab There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PERJETA during pregnancy. Encourage women who receive PERJETA in combination with trastuzumab during pregnancy or within 7 months prior to conception, to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 or visiting http://www.motherpregnancyregistry.com/ If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with trastuzumab, health care providers and patients should immediately report PERJETA exposure to Genentech at 1-888-835-2555 Additional Important Safety Information PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. Left Ventricular Dysfunction (LVD) •In Study 1, for patients with MBC, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group. Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and in 1.8% of patients in the placebo-treated group •Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF •In Study 2, for patients treated in the neoadjuvant setting, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab and docetaxel–treated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline >10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and in no patients in the other 3 arms. LVEF recovered to ≥50% in all patients •In Study 3, for patients treated in the neoadjuvant setting, in the overall treatment period, LVEF decline >10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, in 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and in 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, in 1.3% of patients treated with PERJETA in combination with TCH, and in none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥50% in all but one patient •Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting and every 6 weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within your institution’s normal limits •If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if the LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks Infusion-Related Reactions •PERJETA has been associated with infusion reactions •In Study 1, on the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting •In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE v3.0) Grades 1-2 •Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions Hypersensitivity Reactions/Anaphylaxis •In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCI-CTCAE (version 3). Overall, 4 patients in the PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis •In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the PERJETA and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH-treated group (13.2%), of which 2.6% were NCI-CTCAE (version 3) Grades 3-4 •Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients HER2 Testing •Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC •Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized Most Common Adverse Reactions Metastatic Breast Cancer •The most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue Neoadjuvant Treatment of Breast Cancer •The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel were alopecia, diarrhea, nausea, and neutropenia. The most common NCI-CTCAE v3.0 Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea •The most common adverse reactions (>30%) with PERJETA in combination with trastuzumab and docetaxel when given for 3 cycles following 3 cycles of FEC were fatigue, alopecia, diarrhea, nausea, vomiting, and neutropenia. The most common NCI-CTCAE (version 3) Grades 3-4 adverse reactions (>2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting •The most common adverse reactions (>30%) with PERJETA in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles were fatigue, alopecia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia, and anemia. The most common NCI-CTCAE (version 3) Grades 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity 乳腺癌药物Perjeta（pertuzumab）获瑞士批准上市 2012年8月15日乳腺癌药物帕妥珠单抗（Perjeta，通用名：pertuzumab）已获瑞士药品监管机构Swissmedic批准，可与赫赛汀（Herceptin）及多西紫杉醇（docetaxel）联合用于治疗此前未经化疗的类表皮生长因子受体2（HER2）阳性型转移性或局部复发而不能手术切除的乳腺癌患者。 Perjeta此次获准基于其III期临床研究CLEOPATRA。研究表明，Perjeta与Herceptin及化疗的联合疗法能使患者的无进展生存期（PFS）比Herceptin结合化疗的单独疗法延长六个月。 据悉，自Herceptin上市十多年以来，Perjeta是恶性乳腺癌治疗领域的最大进步。对HER2阳性转移性乳腺癌患者而言，Perjeta+Herceptin+化疗是目前唯一一种在无进展生存期方面显著优于Herceptin+化疗的治疗方案。与Herceptin一样，Perjeta也是种靶向HER2受体的个性化药物，但由于二者的靶点不同，他们很可能以互补的作用方式发挥药效。 据悉，Perjeta已于今年6月8日获FDA批准用于治疗HER2阳性型转移性乳腺癌，且罗氏已向EMA提交该药的上市许可申请（MAA），联合Herceptin及多西紫杉醇化疗用于此前未经预处理的HER2阳性型转移性或局部复发而不能手术切除的乳腺癌患者。