FDA批准2种新型激酶抑制剂

圣路易斯(MD Consult)——2013年5月28日，美国食品药品管理局(FDA)和葛兰素史克(GlaxoSmithKline)宣布Tafinlar(dabrafenib)和Mekinist(trametinib)获准用于治疗不可切除的或转移性黑色素瘤。这两种药物均为激酶抑制剂。

Tafinlar适用于BRAF V600E突变成年患者的单药口服治疗，但不适用于野生型BRAF黑色素瘤患者。Mekinist适用于BRAF V600E或V600K突变成年患者的单药口服治疗，但不适用于之前已接受过BRAF抑制剂治疗的患者。上述突变必须采用FDA批准的方法进行检测，比如伴随诊断性分析方法bioMérieux's THxID BRAF检测法。

FDA批准dabrafenib是基于一项全球多中心试验的结果。该试验纳入了250例BRAF V600E突变阳性且之前未接受过治疗的不可切除的或转移性黑色素瘤成年患者。以3:1的比例将患者随机分配至dabrafenib组或达卡巴嗪组。疾病进展时达卡巴嗪组的28例患者交叉接受dabrafenib。试验结果表明，dabrafenib组患者的无进展生存期(PFS)较达卡巴嗪组患者显著延长，差异有统计学意义。Dabrafenib组患者的中位PFS为5.1个月，而达卡巴嗪组仅为2.7个月。Dabrafenib组的客观应答率为52%，而达卡巴嗪组仅为17%。

在这项试验中，dabrafenib组患者最常见的不良反应(任何级别)包括过度角化、头痛、发热、关节疼痛、乳头瘤、脱发、手足综合征(PPE)、皮疹、腰背疼痛、咳嗽、肌肉疼痛、便秘和鼻咽炎。

接受Tafinlar治疗者报告的最严重不良反应包括皮肤鳞状细胞癌风险增加、发热合并低血压、重度寒战、脱水、肾功能衰竭和血糖升高。

FDA批准trametinib是基于一项3期全球开放性试验的结果。该试验纳入了322例存在BRAF V600E 或V600K突变的不可切除的或转移性黑色素瘤成年患者。所有受试者之前最多接受过1种针对晚期或转移性疾病的化疗方案并且没有使用过BRAF或MEK抑制剂。以2:1的比例将患者随机分配至trametinib组或化疗组。试验结果表明，trametinib组患者的PFS较化疗组患者显著延长，差异有统计学意义。Trametinib组患者的中位PFS为4.8个月，而化疗组仅为1.5个月。疾病进展时化疗组的51例患者交叉接受trametinib治疗。

Trametinib组患者最常见的不良反应包括皮疹、腹泻、淋巴水肿、痤疮样皮炎、口腔炎、血压升高、腹痛、出血、皮肤干燥、瘙痒和甲沟炎。

接受Mekinist治疗者报告的最严重不良反应包括心衰、肺部炎症、皮肤感染和视力下降。

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ST LOUIS (MD Consult) - On May 28, 2013, the US Food and Drug Administration (FDA) and GlaxoSmithKline announced the approval of Tafinlar (dabrafenib) and Mekinist (trametinib) for the treatment of unresectable or metastatic melanoma. Both drugs are kinase inhibitors.

Tafinlar is indicated as a single-agent oral treatment in adult patients with BRAF V600E mutation, but not for patients with wild-type BRAF melanoma. Mekinist is indicated as a single-agent oral treatment in adult patients with BRAF V600E or V600K mutations. Mekinist is not indicated for the treatment of patients who have received a prior BRAF inhibitor therapy. These mutations must be detected by an FDA-approved test, such as the companion diagnostic assay, bioMérieux's THxID BRAF test.

The approval of dabrafenib was granted on the basis of results from 1 multicenter, international trial that included 250 randomly assigned previously untreated adult patients with BRAF V600E mutation-positive unresectable or metastatic melanoma. Patients were assigned to receive dabrafenib or dacarbazine in a 3:1 ratio, respectively. Twenty-eight patients crossed over from the dacarbazine arm at the time of disease progression to receive dabrafenib. The study demonstrated a statistically significant increase in progression-free survival (PFS) in patients treated with dabrafenib, compared with dacarbazine. The median PFS was 5.1 months with dabrafenib compared with 2.7 months with dacarbazine. The objective response rate with dabrafenib was 52% versus 17% with dacarbazine.

In this study, the most common adverse reactions of any grade in patients who received dabrafenib included hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia, rash, back pain, cough, myalgia, constipation, and nasopharyngitis.

The most serious adverse effects reported in patients receiving Tafinlar included an increased risk of cutaneous squamous cell carcinoma, fevers complicated by hypotension, severe rigors, dehydration, kidney failure, and hyperglycemia.

The approval of trametinib was granted on the basis of results from an open-label, international, phase 3 study that included 322 adult patients with unresectable or metastatic melanoma who had a BRAF V600E or V600K mutation. Participants had received no more than 1 prior chemotherapy regimen for advanced or metastatic disease and no prior BRAF or MEK inhibitor treatment. They were randomly assigned to receive trametinib or chemotherapy in a 2:1 ratio, respectively. The study demonstrated a statistically significant increase in PFS in patients treated with trametinib, compared with chemotherapy. The median PFS was 4.8 months for patients receiving trametinib compared with 1.5 months for patients receiving chemotherapy. Fifty-one patients crossed over from the chemotherapy arm at the time of disease progression to receive trametinib.

The most common adverse reactions in patients receiving trametinib included rash, diarrhea, lymphoedema, dermatitis acneiform, stomatitis, hypertension, abdominal pain, hemorrhage, dry skin, pruritis, and paronychia.

The most serious adverse effects reported in patients receiving Mekinist included heart failure, lung inflammation, skin infections, and vision loss.