FDA批准mTOR抑制剂依维莫司治疗乳腺癌

7月20日美国食品药品管理局(FDA)宣布，已批准依维莫司的适应证扩大至治疗激素受体阳性、HER2阴性晚期乳腺癌绝经后女性患者。

依维莫司(Afinitor)为哺乳动物雷帕霉素靶蛋白(mTOR)抑制剂，此次获准可与依西美坦(Aromasin)联合用于来曲唑(Femara)或阿那曲唑(Arimidex)治疗后复发或出现疾病进展的上述女性患者。该药物是首个被批准用于激素受体阳性乳腺癌的mTOR抑制剂，作为雌激素受体和(或)孕激素受体阳性乳腺癌辅助治疗药物他莫昔芬替代品的依西美坦、来曲唑和阿那曲唑均属于芳香化酶抑制剂。

该项批准是基于随机、双盲、安慰剂对照Ⅲ期BOLERO-2试验的结果，该试验纳入了724例上述新适应证的绝经后女性患者。结果显示，接受依维莫司(10 mg/d)+依西美坦(25 mg/d)治疗者的中位无进展生存期(主要终点指标)为7.8个月，而依西美坦(25 mg/d)+安慰剂组为3.2个月，前者中位无进展生存期延长1倍多，差异非常显著。联合治疗组客观应答率为12.6%，而对照组为1.7%；依维莫司治疗组3例完全应答(0.6%)，58例部分应答(12%)，而安慰剂组无1例完全应答，4例部分应答(1.7%)。根据药品说明书有关信息，总生存率结果“在中期分析时还不成熟，未见与治疗相关的显著差异”。

FDA称，依维莫司治疗组患者的最常见不良反应包括口炎、感染、皮疹、疲乏、腹泻和食欲减退。不良事件多见于≥65岁的老年患者，应对该类患者密切监测。

依维莫司于2009年首次被批准用于其他药物治疗无效的晚期肾细胞癌患者的治疗，此后又获准用于进展性晚期原发性胰腺神经内分泌瘤成人患者、肾血管平滑肌脂肪瘤伴有无需立即手术的结节性硬化症(TSC)患者以及需要治疗但不适合手术切除的与TSC有关的室管膜下巨细胞星形细胞瘤成人和儿童患者。

德州大学M.D.安德森癌症中心乳腺肿瘤内科部主任Gabriel Hortobagyi博士在依维莫司生产商诺华公司发布的声明中称：“该项批准重新定义了晚期激素阳性乳腺癌处置方案，为医生和患者提供了关键的新选择。”该公司还指出，有关依维莫司治疗HER2阳性乳腺癌的两项Ⅲ试验正在进行中。

爱思唯尔  版权所有

By: ELIZABETH MECHCATIE, Internal Medicine News Digital Network
The approval of everolimus has been expanded to include a group of postmenopausal women with advanced hormone receptor–positive, HER2-negative breast cancer, the Food and Drug Administration announced on July 20.

A mammalian target of rapamycin (mTOR) inhibitor marketed as Afinitor, everolimus is indicated in combination with exemestane (Aromasin) for this group of women when they have had recurrence or progression of disease after treatment with letrozole (Femara) or anastrozole (Arimidex).

The drug becomes the first mTOR inhibitor approved for advanced hormone receptor–positive breast cancer. Exemestane, letrozole, and anastrazole are aromatase inhibitors, a class of drugs that has become an alternative to tamoxifen for adjuvant treatment of women with estrogen receptor– and/or progesterone receptor–positive breast cancer.

The new approval is based on the phase III BOLERO-2 trial, a randomized, double-blind, placebo-controlled study of 724 postmenopausal women who matched the population in the new indication.

Median progression-free survival, the primary end point, more than doubled among those treated with everolimus (the approved tablet dose of 10 mg per day) plus exemestane (25 mg per day). The median reached 7.8 months in this group, vs. 3.2 months among those treated with exemestane (25 mg per day) and placebo, a difference that was highly significant statistically.

The objective response rate was 12.6% among those on the combination, compared with 1.7% in the control group. There were 3 complete responses (0.6%) and 58 partial responses (12%) in women who received everolimus, compared with no complete responses and 4 partial responses (1.7%) among those given placebo.

Overall survival results "were not mature at the time of the interim analysis, and no statistically significant treatment-related difference in OS was noted," according to the prescribing information.

The most common adverse effects reported in patients treated with everolimus included stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. Adverse events are more common among patients aged 65 years and older, who should be monitored closely, according to the FDA statement announcing the approval.

Everolimus was first approved in 2009 as a treatment for advanced renal cell carcinoma that has progressed after treatment with other cancer therapies. This was followed by approvals for adults with progressive advanced neuroendocrine tumors of pancreatic origin, patients with renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery, and adults and children with subependymal giant cell astrocytoma associated with TSC who require treatment but are not candidates for curative surgery.

"This approval redefines the treatment and management of advanced hormone receptor–positive breast cancer, offering a critical new option for physicians and patients," Dr. Gabriel Hortobagyi, chair of Breast Medical Oncology, at the University of Texas M.D. Anderson Cancer Center, said in a statement released by Novartis Pharmaceuticals Corp., which markets everolimus. The company noted that two ongoing phase III trials are studying everolimus in HER2-positive breast cancer.