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Vectibix(panitumumab)
药品介绍：
结直肠癌治疗药Vectibix(panitumumab、帕尼单抗)是第一个完全人源化单克隆抗体，其靶向作用于表皮生长因子受体（EGFR）。2005年7月，Panitumumab获得FDA快速通道审批资格。2005年底，安进公司及其合作伙伴Abgenix公司共同向FDA提交了该品生物制剂许可申请，用于治疗化疗失败后转移性结直肠癌。
Panitumumab是IgG2单克隆抗体，与EGFR具有高亲和性。Panitumumab运用Abgenix公司的XenoMouse技术研究而成，为完全人源化的单克隆抗体，没有任何鼠蛋白。
人体免疫系统可以识别嵌合抗体中的鼠蛋白，从而引起免疫应答，表现为输液反应、变态反应和过敏反应。而完全人源化单克隆抗体可以在提供有效治疗的同时减少此类免疫应答。
EGFR在正常情况下可帮助调节人体内细胞的生长，但其也会刺激癌细胞生长。EGFR存在于癌细胞的表面，当体内出现蛋白质与EGFR相结合时，EGFR会被激活，如表皮生长因子（EGF）或转化生长因子a（TGF-alpha）。结合改变了EGFR的形态，刺激肿瘤细胞的生长。Panitumumab与EGFR相结合，可阻止其与EGF或TGF-alpha结合，从而阻断癌细胞生长。
【关于该药】
Vectibix是单株抗体，抗体是身体自身的防御机转，以对抗外来异物，像是感染或癌细胞；单株抗体是在实验室中所制作的，以将外来异物的极特定比例作为标靶。
Vectibix和称作生长因子受体基因（Epidermal Growth Factor Receptor, EGFR）的蛋白质相结合，根据FDA的统计，EGFR可于70%的大肠直肠癌患者身上找到。
Vectibix并非第一个针对大肠直肠癌的单株抗体，另外一种单株抗体Erbitux也是针对大肠直肠癌的EGFR作用。
第三种单株抗体Avastin也是用来治疗大肠直肠癌，它被认为是针对不同的生长因子（血管内皮神经营养因子vascular endothelial growth factor, VEGF）来作用。
Erbitux于2004年2月12日由FDA所核准，FDA于两周后核准Avastin。
【药物试验】
FDA之所以核准Vectibix，是以临床实验的结果为基础，该实验的研究对象为欧洲的463名罹患移转性大肠直肠癌患者。
这463名患者已经接受过化疗，其中有三种化疗药物，之后，这463名患者全都接受「最佳的支持照护」。
有半数的患者也在实验开始时就接受Vectibix的治疗，剩下的一半则被允许在肿瘤恶化的状况下使用Vectibix。
平均而言，患者在因癌症而病逝或病况恶化前96天服用Vectibix，相较于最初仅接受最佳支持照护的患者则是60天前服用。
在为期48周的研究中，整体存活率对两组而言都是相似的。
J. Randolph
Hecht医师向WebMD表示，几乎每一位患者都在48周期间病况都有进展，这里的有「进展」，指的是其肿瘤「恶化」了。
Hecht医师指出，不过，在第8周时的第一次观察，最佳支持照护组中有70%的人病况恶化，Vectibix组中仅51%的人病况恶化，其间约20%的差异会持续一阵子，到了32周时，就没有什么太大的差异了。
Hecht医师主导美国对Vectibix的研究，但他并未参与欧洲的实验；Hecht医师为洛杉矶加州大学肠胃肿瘤计划主任。
此外，服用Vectibix的患者中有8%的肿瘤缩小，在某些病例中，那些肿瘤缩小到比治疗前尺寸的一半还要来得小。
Hecht医师表示，在每一个不同的时间点作观察，可看到Vectibix组的肿瘤恶化状况，会比在最佳支持照护组的状况好很多；他表示，那是另一个观察角度。
【副作用】
Vectibix的研究中，最严重的负作用包括肺纤维化（肺脏的纤维组织之形成）、由感染所并发的严重皮肤疹、药物注射反应（infusion
reactions）、腹痛、恶心、呕吐和便秘。
与药物相关最常见的副作用，包括皮肤疹、疲惫、腹痛、恶心和腹泻。
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Vectibix+化学疗法显著延长结肠癌患者生存期 |
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Amgen公司上周二表示，结肠癌患者在初始治疗阶段就采用使用其产品Vectibix+化学疗法之后，病情无恶化生存期得到显著延长，效果远好于单用化学疗法。
其中，体内未发生KRAS基因突变的患者对这种疗法更加适用。目前，这种药物仅获准用于那些虽然采用过化学疗法但癌细胞仍发生扩散的结肠癌患者。
而检测Vectibix治疗体内发生KRAS基因突变患者的临床实验刚刚开始。前期实验结果已证实，KRAS基因正常（野生型）的患者对Vectibix及其同类药物应答率较好，这种药物均通过阻断表皮生长因子而起作用，但KRAS基因发生突变的患者对这类药物则无应答。在所有的肠癌患者中，大约有35%的人发生KRAS基因突变。
Amgen公司研发部负责人罗格称：“不仅携带野生型KRAS基因的患者使用Vectibix治疗之后效果显著，发生KRAS基因突变的患者在标准化学疗法中添加该药之后也可以在一定程度上增强疗效。”
Vectibix与抗癌药Erbitux属同类产品，后者由ImClone Systems制药公司研发，目前由百时美-施贵宝和礼来两家公司联合销售。Vectibix上市后，在与Erbitux的竞争中不太顺利，去年销售额仅为1.53亿美元，而后者去年销售额则达到10亿美元。
在实验过程中，Vectibix的常见副作用包括皮肤毒性、低血镁和腹泻。Amgen计划在即将举行的医疗会议上公布具体的临床实验结果。 |
Indication:
Vectibix® (panitumumab) is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastaticcolorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.
Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal cancer with these mutations.
Important Safety Information including Boxed WARNINGS:
Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy.
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WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS
Dermatologic Toxicity:Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. Withhold Vectibix® for dermatologic toxicities that are grade 3 orhigher or are considered intolerable. If toxicity does not improve to < grade 2 within 1 month, permanentlydiscontinueVectibix®.
The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema,rash,skinexfoliation, paronychia, dry skin, and skin fissures. Subsequent to the developmentofseveredermatologictoxicities,infectiouscomplications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported.
Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Severe infusion reactions included
anaphylactic reactions, bronchospasm, and hypotension. Although not reported with Vectibix®, fatal infusion reactions have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®.
| Increased Toxicity with Combination ChemotherapyVectibix® is not indicated for use in combination with chemotherapy.
In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastaticcolorectalcancer, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs. 72%) adverse reactions. All patients received bevacizumab; 86% received an oxaliplatin fluoropyrimidine-based regimen and 14% received an irinotecan fluoropyrimidine-based regimen. NCI-CTC grade 3-4 adverse drug reactions occurring at a higher rate in Vectibix®-treated patients included rash/dermatitis/acneiform (26% vs. 1%), diarrhea (23% vs. 12%), dehydration (16% vs. 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs. 4%), stomatitis/mucositis (4% vs. <1%) and hypomagnesemia (4% vs. 0%). NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs. 4%) and included fatal events in 3 (<1%) Vectibix®-treatedpatients.
In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-armstudyof24patientsreceivingVectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.
Pulmonary Fibrosis
Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic pulmonary fibrosis and resulted in death. The second patient had symptoms of pulmonary fibrosis, which was confirmed by CT. Additionally, a third patientdiedwithbilateralpulmonaryinfiltrates of uncertain etiology with hypoxia. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies.
Therefore, the estimated risk in a general population that may include such patients is uncertain. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.
Electrolyte Depletion/Monitoring
In the randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia
occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completionofVectibix® therapy. Institute appropriate treatment, eg, oral or IV electrolyte repletion, as needed.
Photosensitivity
Exposure to sunlight can exacerbate dermatologic toxicity. It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving Vectibix®.
Dermatologic, Mucosal, and Ocular ToxicityOcular toxicities occurred in 15% of patients and included, but were not limited to: conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation.
The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders were observed in 9% of patients. .
Pregnancy Category C
Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix®
therapy.
Adverse Reactions
The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix® are pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.
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