一項針對黑色素瘤中常見基因突變的實驗性藥物研究證實，藥物dabrafenib成功地縮小了發(fā)生腦轉(zhuǎn)移的黑色素瘤患者的腫瘤病灶,，有效率達(dá)90%,。這項國際臨床I期藥物試驗研究發(fā)表在5月18日的國際著名雜志《柳葉刀》（The Lancet）上。

BRAF基因編碼絲氨酸/蘇氨酸蛋白激酶B-Raf,與細(xì)胞生長調(diào)控密切相關(guān),。在黑色素瘤中,，BRAF常常突變引發(fā)細(xì)胞生長調(diào)控紊亂。Dabrafenib針對突變型BRAF--Val600 BRAF發(fā)揮作用,。

為了證實其安全性和耐受性,，并為II期臨床試驗提供劑量參考，研究者招募了184名實體腫瘤患者進(jìn)行試驗,，其中156名具有轉(zhuǎn)移性黑色素瘤,。根據(jù)加速劑量滴定法（accelerated dose titration method），經(jīng)過系統(tǒng)的Dabrafenib治療,，研究者未發(fā)現(xiàn)因藥物副作用終止治療和死亡的病例,。而且，Dabrafenib還對BRAF突變型的其他實體腫瘤如：胃腸實體瘤,，非小細(xì)胞肺癌,，卵巢癌等也有明顯的抗癌作用。（生物谷Bioon.com）

doi:10.1016/S0140-6736(12)60398-5
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Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial

Original TextDr Gerald S Falchook MD , Georgina V Long PhD , Prof Razelle Kurzrock MD , Kevin B Kim MD , Tobias H Arkenau PhD e, Michael P Brown PhD f, Omid Hamid MD , Jeffrey R Infante MD , Michael Millward MD i j, Anna C Pavlick MD , Steven J O’Day MD g, Samuel C Blackman PhD , C Martin Curtis BA l, Peter Lebowitz PhD , Bo Ma PhD , Daniele Ouellet PhD l, Prof Richard F Kefford PhD

Background

Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases.

Methods

We undertook a phase 1 trial between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function. BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose. Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours, including those with non-Val600Glu mutations, in three cohorts: metastatic melanoma, melanoma with untreated brain metastases, and non-melanoma solid tumours. This study is registered with ClinicalTrials.gov, number NCT00880321.

Findings

We enrolled 184 patients, of whom 156 had metastatic melanoma. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51·9—83·7) and confirmed responses in 18 (50%, 32·9—67·1). 21 (78%, 57·7—91·4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35·3—74·5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer.

Interpretation

Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours.