FDA批准2种药物联合治疗晚期黑色素瘤

葛兰素史克公司1月9日宣布，美国食品药品管理局(FDA)已加速批准两种靶向口服药物trametinib和dabrafenib联合用于BRAF V600E或V600K突变型不可切除性或转移性黑色素瘤的治疗。

该公司称，FDA批准的一种检测方法可用于上述突变检测。

2013年5月，FDA分别批准trametinib(商品名Mekinist)和dabrafenib(商品名Tafinlar)用于上述突变型不可切除性或转移性黑色素瘤，同时还批准了这两种突变的检测方法。这两种药物均为激酶抑制剂。

GSK声明指出，该批准令是基于在Ⅰ/Ⅱ期研究中呈现出的应答率和中位应答持续时间。该项研究比较了108例患者接受联合治疗(150 mg dabrafenib，2次/日+2 mg trametinib，1次/日)和单纯dabrafenib治疗结果。结果显示，联合治疗和单纯dabrafenib治疗患者总应答率分别为76%和54%，中位应答持续时间分别为10.5个月和5.6个月。

与联合治疗相关的最常见不良事件包括发热(71%)、寒颤(58%)、疲乏(52%)、皮疹(45%)、恶心(44%)、呕吐(40%)以及腹泻(36%)。最常见3级或4级不良事件为肾衰、发热、背痛以及出血。

据GSK称，与治疗相关的严重不良反应(包括某些潜在致命性反应)为新发原发性皮肤癌、BRAF野生型黑色素瘤肿瘤诱发以及出血事件。

FDA加速批准程序是基于临床证据表明，药物对能够预示患者临床获益的替代终点有效。作为加速批准的条件，要求制造商提供更多证实患者获益的临床证据，一旦后续研究不能证实获益，FDA可撤销批准。

GSK称，完全批准将取决于正在开展的Ⅲ期研究结果。

更新后的trametinib说明书指出，联合治疗“改善疾病相关症状或总生存率尚未得到证实”。

查阅Mekinist处方信息可点击us.gsk.com/products/assets/us_mekinist.pdf，查阅Tafinlar处方信息(尚未更新有关联合治疗获批的内容)可点击us.gsk.com/products/assets/us_tafinlar.pdf。

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By: ELIZABETH MECHCATIE, Internal Medicine News Digital Network

A combination of two targeted, orally administered drug therapies – trametinib and dabrafenib – has been approved by the Food and Drug Administration for treating patients with unresectable melanoma or metastatic melanoma with BRAF V600E or V600K mutations, manufacturer GlaxoSmithKline announced on Jan. 9.

An FDA-approved test is used to detect the mutations, according to the company statement.

Trametinib, marketed as Mekinist, and dabrafenib, marketed as Tafinlar, were each approved in May 2013 as separate treatments for metastatic or unresectable melanomas that express the mutations – along with a companion test to detect the mutations. Both are kinase inhibitors.

The GSK statement noted that the accelerated approval of the combination therapy is based on the response rate and median duration of response results in a phase I/II study of 108 patients, which compared the combination (150 mg of dabrafenib twice a day and 2 mg of trametinib once a day) to treatment with dabrafenib alone. The overall response rates, as assessed by the investigators, were 76% among those on the combination and 54% for those on dabrafenib alone. The median duration of response was 10.5 months among those on the combination, vs. 5.6 months among those on dabrafenib alone.

The most common adverse events associated with the combination treatment included fever in 71% of patients, chills in 58%, fatigue in 52%, rash in 45%, nausea in 44%, vomiting in 40%, and diarrhea in 36%. Renal failure, pyrexia, back pain, and hemorrhage were among the most common grade-3 or -4 adverse events among those on the combination.

Serious adverse effects associated with treatment, including some potentially fatal effects, are new primary cutaneous skin cancers, tumor promotion in wild-type BRAF melanoma, and hemorrhagic events, according to GSK.

The FDA approval occurred through an accelerated process based on clinical evidence that the treatment has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.

Full approval is dependent on the results of an ongoing phase III study, GSK said.

The updated trametinib label states that "improvement in disease-related symptoms or overall survival has not been demonstrated" for the combination treatment.

The prescribing information for Mekinist is available at us.gsk.com/products/assets/us_mekinist.pdf.The prescribing information for Tafinlar (which does not yet include the updated information on the combination therapy approval) is available at us.gsk.com/products/assets/us_tafinlar.pdf.