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肺癌靶向药物

ID #1068

什么是二代易瑞沙

易瑞沙二代又叫凡德他尼英文名(vandetanib) ZD6474

   凡德他尼 (vandetanib)是一种合成的苯胺喹唑啉化合物,被称“二代易瑞沙”,为口服的小分子多靶点酪酸激酶抑制剂(TKI),可同时作用于肿瘤细胞EGFR、VEGFR和RET酪氨酸激酶,还可选择性的抑制其他的酪氨酸激酶,以及丝氨酸/苏氨酸激酶。Ⅰ期临床研究显示剂量限制性毒性为腹泻、高血压和皮疹。常见的毒副作用是腹泻、皮疹、恶心、呕吐以及无症状的QT间期延长。其毒副作用与剂量相关,在<300 mg/d时,病人耐受性良好,最大耐受剂量(MTD)为300 mg。Ⅱ期临床研究涉及的病种很多。目前我国正在进行凡德他尼治疗NSCLC的临床试验。
    1. 治疗晚期NSCLC(非小细胞肺癌)003号研究比较了凡德他尼 300 mg/d和吉非替尼250 mg/d对一线或二线化疗失败的168例晚期NSCLC病人的疗效,与吉非替尼相比,凡德他尼明显地增加了有效率和延长了疾病无进展生存时间,分别为8%和1%,11.9周和8.1周,(P=0.011)。在临床试验中如果病人病情进展或不能耐受毒性,允许其改变治疗方案。试验结果表明,用吉非替尼代替凡德他尼的病人疾病控制率为14%,而用凡德他尼代替吉非替尼的病人疾病控制率达到32%,预计中位总生存期由凡德他尼→吉非替尼为6.1个月,而由吉非替尼→凡德他尼为7.4个月。0007号研究正在进行中,目的是评价凡德他尼联合紫杉醇(200 mg/m2)+卡铂(AUC=6)一线治疗ⅢB-IV期NSCLC的疗效。初步试验结果显示,凡德他尼可同时联合传统的化疗药物治疗NSCLC,没有明显增加3~4度的不良反应。
    2. 治疗晚期乳腺癌46例,既往接受紫杉醇+蒽环类化疗失败的转移性乳癌患者,接受凡德他尼(100 mg或300 mg),44例可评价的患者中未见客观疗效,2组病人各有1例病情稳定(SD)≥24周,作者认为单药凡德他尼治疗复发耐药的乳腺癌疗效有限,但耐受性良好。
    3. 治疗晚期多发性骨髓瘤,18例化疗或造血干细胞移植治疗失败的多发性骨髓瘤患者,口服凡德他尼(100 mg)3~29.4周,球蛋白或尿M蛋白未见改善,毒副作用可耐受,常见的毒副作用包括恶心、呕吐、腹泻、皮疹、皮肤瘙痒、感觉障碍等,但未见明确的QT间期改变。
    4. 治疗甲状腺癌甲状腺髓样癌发病率低,具有遗传性,无论放射治疗、联合化疗抑或内分泌治疗效果不佳,预后差。0008号研究是一项进行中的、开放的Ⅱ期研究,评估凡德他尼治疗进展期遗传性甲状腺髓样癌的疗效和毒副作用。11例可评价的病人中(接受凡德他尼 300 mg/d,至少3个月),2例患者获得PR,9例患者获SD。另外,病人血浆肿瘤标志物降钙素和癌胚抗原分别较基线值下降了72%和25%。目前人们认为,凡德他尼治疗甲状腺髓样癌主要作用于肿瘤细胞靶点RET酪氨酸激酶,RET可促进肿瘤细胞生长和存活,40%的散发性和100%遗传性甲状腺髓样癌有RET基因的过表达。

    我的评价:吉非替尼易瑞沙),作为治疗晚期非小细胞肺癌,改变了肺癌患者命运,让患者看到康复希望,虽然,它可出现耐药,但是为患者争取了生存的时间。而易瑞沙耐药后,如何给患者治疗,一直是目前世界性难题。本人也治疗一例易瑞沙耐药患者,效果不错,延迟效果达到近6个月时间,虽然患者目前出现新的转移,但是,也在积累这方面治疗经验。作为所谓二代易瑞沙,凡德他尼,它的作用靶点更多,比易瑞沙单一(酪氨酸酶抑制剂)要可靠,从近期III临床观察,凡德他尼比吉非替尼效率更高。尤其,对服用吉非替尼无效,但服凡德他尼可能有效。关于,长期服易瑞沙耐药后,再服凡德他尼是否有效,目前没有这方面资料显示结果,也没有医学单位做这方面工作。从理论上讲,应该会有些效果,毕竟它作用了多个靶点。我分析,易瑞沙耐药不是全面耐药,癌细胞只是部分耐药,如果加上凡德他尼多靶点作用,可能对已对酪氨酸酶抑制剂耐药癌细胞,通过其他靶点将其杀死,比如通过肿瘤细胞EGFR、VEGFR,这是血管生成受体,这样子,凡德他尼可以抑制耐药部分的癌细胞,同时,继续加强它的选择性的抑制其他的酪氨酸激酶,这样会达到一定效果。当然,这是从理论上分析的,还要从临床实践中加以证实,如果这样的分析是正确的,这将会给在服易瑞沙患者带来福音。有的患者问,特罗凯可以代替易瑞沙,好象是对的,因为特罗凯药量是易瑞沙3倍给药量,最大耐受给药,药物的分子结构比吉非替尼工艺要高,但是特罗凯也只是作用一个靶点,所以,当易瑞沙耐药后,服特罗凯效用可能性不大,临床上可以证明。

    FDA已批准上市或进入快速通道的作用于信号转导的药物

    药物 商品名 适应证

    伊马替尼(imatinib) 格列卫(Glivec,Gleevec)   慢粒白血病、GIST

    吉非替尼(gefitinib)   易瑞沙(Iressa) NSCLC

    埃罗替尼(erlotinib)   Tarceva     NSCLC、胰腺癌

    索拉非尼(sorafenib)     Nexevar    肾癌、肝癌

    舒尼替尼(索坦)sunitinib   Sutent     肾癌、GIST

    范得他尼(vandetanib)       Zactima 甲状腺髓样癌

    目前仍在进行的Ⅱ期临床试验有单药范得他尼治疗甲状腺癌、单药范得他尼治疗化疗±放疗获得完全或部分缓解的小细胞肺癌;范得他尼联合泰素/卡铂一线治疗NSCLC 。启动或即将启动的Ⅲ期临床试验有多西紫杉醇±范得他尼二线治疗NSCLC;范得他尼对比埃罗替尼二线治疗NSCLC等。

==== 汉译英 ====

Iressa is also called the van der Thani second-generation English name (vandetanib) ZD6474

   Van Der Thani (vandetanib) is a synthetic Anilinoquinazoline compounds, has been called "second-generation IRESSA" for the oral administration of small molecule multi-target kinase inhibitors butyricum (TKI), can also act on tumor cells EGFR, VEGFR and RET tyrosine kinase, can selectively inhibit other tyrosine kinases, as well as serine / threonine kinase. Phase Ⅰ Clinical studies have shown that dose-limiting toxicity is diarrhea, high blood pressure and rash. Common side effects were diarrhea, rash, nausea, vomiting, and asymptomatic QT interval prolongation. Of its toxic side effects and dose-related, in the <300 mg / d, the patient was well-tolerated, maximum tolerated dose (MTD) as 300 mg. Phase Ⅱ clinical research, which involved a lot of diseases. Where is being conducted in Germany Thani NSCLC, clinical trials.
    1. The treatment of advanced NSCLC (non-small cell lung cancer) were studied and compared 003 van der Thani 300 mg / d, and gefitinib 250 mg / d on the first-line or second-line chemotherapy in 168 patients with advanced NSCLC the patient, and Kyrgyzstan compared to the non-imatinib, van der Thani significantly increased the efficiency and prolong the disease progression-free survival time, were 8% and 1%, 11.9 weeks and 8.1 weeks, (P = 0.011). In clinical trials, progress of the disease or if the patient can not tolerate the toxicity, allowing it to change the treatment regimen. Experimental results show that gefitinib to replace van der Thani patient disease control rate of 14%, while with the van der Thani instead of gefitinib in patients with disease control rate of 32%, estimated median overall survival period from the Van Der Thani → gefitinib was 6.1 months, but by gefitinib → van der Thani was 7.4 months. No. 0007 Study is underway to evaluate the van der Thani plus paclitaxel (200 mg/m2) + carboplatin (AUC = 6) first-line treatment of NSCLC Phase Ⅲ B-IV efficacy. Initial test results showed that at the same time Nico van der, he combined the traditional chemotherapy drugs NSCLC, there is no significant increase in 3 ~ 4 degrees adverse reactions.
    2. The treatment of advanced breast cancer, 46 patients received paclitaxel + past anthracycline chemotherapy in metastatic breast cancer patients failed to receive van der Thani (100 mg or 300 mg), 44 Li can be seen in patients with an objective evaluation of efficacy, 2 1 case each group of patients in stable condition (SD) ≥ 24 weeks, authors believe that single-agent treatment of recurrent van der Thani resistant breast cancer is limited, but well tolerated.
    3. The treatment of advanced multiple myeloma, 18 patients with chemotherapy or hematopoietic stem cell transplantation for treatment failure in patients with multiple myeloma, oral van der Thani (100 mg) 3 ~ 29.4 weeks, globulin or urine M protein, not improved, drugs, side effects can be tolerated, common side effects include nausea, vomiting, diarrhea, rash, pruritus, sensory disturbances, etc., but no clear change in QT interval.
    4. The treatment of thyroid cancer, medullary thyroid cancer incidence rate is low, with genetic, regardless of radiation therapy, chemotherapy or endocrine treatment results are poor, and poor prognosis. 0008 study is an ongoing, open phase Ⅱ study to assess the van der Thani patients with advanced hereditary medullary thyroid cancer, the efficacy and toxicity. 11 patients evaluable patients (van der Thani receiving 300 mg / d, at least 3 months), 2 patients had PR, 9 patients were SD. In addition, the patient serum tumor markers calcitonin and carcinoembryonic antigen were decreased compared with baseline values by 72% and 25%. At present It is believed that van der Thani treatment of medullary thyroid carcinoma a major role in the tumor cell target RET tyrosine kinase, RET can promote tumor cell growth and survival, 40% of sporadic and 100% of hereditary medullary thyroid carcinoma are RET gene over-expression.

    My rating: Gefitinib (Iressa), as a treatment for advanced non-small cell lung cancer, has changed the fate of patients with lung cancer, so patients can see hope for recovery, although it may appear resistant, but the fight for the survival for patients时间. Easily understood Ruisha resistance, how to patient care has always been a difficult problem at present. I also treat drug-resistant case of Iressa in patients with good results, delay effects to reach nearly 6 months, although the patients are a new transfer, but also accumulated treatment experience in this regard. As a so-called second-generation Iressa, van der Thani, and its role in target more than Iressa single (tyrosinase inhibitors) are reliable, from the recent III clinical observations, van der Thani than gefitinib Imatinib more efficient. In particular, the right to take gefitinib invalid, but the service van der Thani may be effective. With regard to long-term service Iressa resistance again after serving van der Thani is valid, there is no information in this respect the results, nor did medical units to do work in this area. In theory, it should be some effect, after all, it is the role of a number of targets. My analysis, Iressa resistance is not fully resistant to drug-resistant cancer cells only partially, if coupled with van der Thani multi-target effect, may have been on tyrosinase inhibitor-resistant cancer cells, through other target point of its kill, for example, by tumor cells, EGFR, VEGFR, which is angiogenic receptors, like this, where Germany Thani can inhibit drug-resistant part of the cancer cells, while continuing to strengthen its selective inhibition of other dairy histidine kinase, it will achieve some success. Of course, this is from a theoretical analysis, we will also be confirmed from clinical practice, if such analysis is correct, this will give the clothes to bring the Gospel in patients with Iressa. Some patients ask, Tarceva can replace Iressa, appears to be right, because Iressa Tarceva dose is administered three times the amount of the maximum tolerated dose of drug compared with the molecular structure of gefitinib Nepal craft must be high, but the role of Tarceva is only one target, so when Iressa drug resistance, the service is unlikely that the effectiveness of Tarceva in clinical practice can attest.

    FDA has approved the listing of or access to fast-track the role of drugs in the signal transduction


    Drug Trade Name Indication

    Gleevec (imatinib) Gleevec (Glivec, Gleevec) chronic myeloid leukemia, GIST

    Gefitinib (gefitinib) Iressa (Iressa) NSCLC

    Tarceva (erlotinib) Tarceva NSCLC, pancreatic cancer

    Sorafenib (sorafenib) Nexevar kidney, liver,

    Sunitinib sunitinib Sutent renal cell carcinoma, GIST

    Vander Thani (vandetanib) Zactima medullary thyroid carcinoma

    Are still carried out in Phase Ⅱ clinical trials with a single drug Vanderbilt Thani treatment of thyroid cancer, single-agent Vanderbilt Thani radiotherapy ± chemotherapy achieved complete or partial remission of small cell lung cancer; Van der Thani combined paclitaxel / carboplatin first-line treatment of NSCLC. Started or are about to start Phase Ⅲ clinical trials of a number of Docetaxel ± Van der Thani second-line treatment of NSCLC; Van der Thani contrast to erlotinib and other second-line treatment of NSCLC.

Tags: 易瑞沙二代

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更新日期: 2009-12-14 01:57
作者: : mcyclub
修订: 1.2

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