FDA批准Kadcyla用于晚期乳腺癌治疗

美国食品药品管理局(FDA)2月22日宣布，HER-2靶向抗体-药物共轭物Ado-trastuzumab emtansine已获准用于治疗HER-2阳性、晚期转移性乳腺癌女性患者。

根据药品说明书，基因泰克公司以商品名Kadcyla上市的该药品，是由HER-2靶向抗体曲妥珠单抗和微管抑制剂DM1结合而成，作为单一制剂用于“治疗此前已接受曲妥珠单抗和紫杉烷类药物单独或联合治疗的HER-2阳性、转移性乳腺癌患者。”患者或为已接受药物治疗的转移患者，或在接受6个月完整辅助治疗期间疾病复发。该药通过静脉输注给药，每3周1次。

FDA药物评价与研究中心血液与肿瘤产品办公室主任Richard Pazdur博士在声明中指出：“Kadcyla是由曲妥珠单抗与一种干扰癌症细胞生长的名为DM1 的药物结合而成。Kadcyla输送后者至癌症病灶，可缩小肿瘤，减缓疾病进展，延长生存时间。”

Kadcyla是FDA批准的第4个HER2蛋白靶向乳腺癌治疗药物。其他3个获准用于HER2阳性乳腺癌患者的药物是曲妥珠单抗(赫赛汀，1998年)、拉帕替尼(泰克博，2007年)和帕妥珠单抗(Perjeta，2012年)。

该项批准令是基于一项纳入991例此前已接受曲妥珠单抗和紫杉烷类化疗的HER2阳性、局部晚期乳腺癌患者或转移性乳腺癌患者的随机、开放性Ⅲ期研究。根据FDA和基因泰克公司的有关声明，Kadcyla治疗患者中位无进展生存期为9.6个月，而拉帕替尼+卡培他滨治疗患者为6.4个月；Kadcyla治疗患者中位总生存期为30.9个月，而拉帕替尼+卡培他滨治疗患者为25.1个月。总生存期和无进展生存期均为该项研究的主要终点指标。

与治疗有关的最常见副作用(受累患者比例>25%)为乏力、恶心、肌肉骨骼疼痛、血小板减少、头痛、转氨酶升高以及便秘。

这药物在6个月内获得快速批准，而一般评审时间为12个月。快速批准用于可能为目前缺少满意替代治疗的疾病提供更为安全和有效治疗的药物，或与上市药物相比具有显著改善的药物。Ado-trastuzumab emtansine在临床试验期间被称为T-DM1。

根据罗氏集团旗下基因泰克公司的声明，Kadcyla将在获批后2周内上市。目前欧洲药品管理局(EMA)也正在对该适应证进行评审。

对于与Kadcyla有关的严重不良事件，应致电800-332-1088或通过www.fda.gov/medwatch报告至FDA MedWatch系统。药品说明书详见www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf。

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By: ELIZABETH MECHCATIE, Internal Medicine News Digital Network

Ado-trastuzumabemtansine, a HER-2 targeted antibody-drug conjugate, has been approved by the Food and Drug Administration for treatment of women with HER2-positive, late-stage metastatic breast cancer, the agency announced Feb. 22.

Marketed as Kadcyla by Genentech, the treatment is a combination of an HER2-targeted antibody, trastuzumab, and DM1, a microtubule inhibitor, and is indicated as a single agent "for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination," according to the prescribing information. Patients should have either received previous therapy for metastatic disease, or had disease recurrence during or within 6 months of completing adjuvant therapy, according to the indication. The treatment is administered in an intravenous infusion every 3 weeks.

"Kadcyla is trastuzumab connected to a drug called DM1 that interferes with cancer cell growth," Dr. Richard Pazdur, director of the office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research, said in a statement. "Kadcyla delivers the drug to the cancer site to shrink the tumor, slow disease progression, and prolong survival," he added.

Kadcyla is the fourth FDA-approved breast cancer treatment that targets the HER2 protein. The other three drugs approved for treating HER2-positive breast cancer are trastuzumab (Herceptin), approved in 1998; lapatinib (Tykerb), approved in 2007; and pertuzumab (Perjeta), approved in 2012.

Approval of Kadcyla was based on a randomized, open label, phase III study of 991 patients with HER2-positive, locally-advanced breast cancer or metastatic breast cancer who had previously been treated with trastuzumab and a taxane chemotherapy. The median progression-free survival was 9.6 months among those treated with Kadcyla, compared with 6.4 months in patients treated with lapatinib plus capecitabine. The median overall survival was 30.9 months among those treated with Kadcyla, compared with 25.1 months among those treated with lapatinib and capecitabine, according to statements from the FDA and Genentech. Overall survival and progression-free survival were the study’s primary endpoints.

The most common side effects associated with treatment (affecting more than 25% of patients) were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation.

This accelerated approval was completed in 6 months instead of the usual 12-month review period, which is used for drugs that may provide safer and effective treatment when there is no satisfactory alternative treatment or when the treatment provides significant improvements over available treatments. Ado-trastuzumabemtansine has been referred to as T-DM1 during clinical trials.

Kadcyla will be available within 2 weeks of approval, according to the statement from Genentech, a member of the Roche group. The agent is currently under review by the European Medicines Agency for the same indication.

Serious adverse events associated with Kadcyla should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch. The prescribing information is available at www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf.