Dabrafenib 治疗BRAF600位缬氨酸突变为谷氨酸或赖氨酸的黑素瘤脑转移患者：一项多中心、开放性II期临床试验

Dabrafenib 治疗BRAF600位缬氨酸突变为谷氨酸或赖氨酸的黑素瘤脑转移患者：一项多中心、开放性II期临床试验Dabrafenib 治疗BRAF600位缬氨酸突变为谷氨酸或赖氨酸的黑素瘤脑转移患者：一项多中心、开放性II期临床试验 Dabrafenib 治疗BRAF600位缬氨酸突变为谷氨酸或赖氨酸的黑素瘤脑转移患者:一项多中心、开放性II期临床试验摘要背景转移性黑色素瘤患者中，脑转移非常普遍。在确诊后，中位总生存期多为17-22周。我们评估了dabrafenib对BRAF600位缬氨酸突变为谷氨酸或赖氨酸的黑素瘤脑转移患者的作用。方法在6个国家的24个中心中，我们开展了一项多中心、开放性II期临床试验...

Dabrafenib 治疗BRAF600位缬氨酸突变为谷氨酸或赖氨酸的黑素瘤脑转移患者：一项多中心、开放性II期临床试验 Dabrafenib 治疗BRAF600位缬氨酸突变为谷氨酸或赖氨酸的黑素瘤脑转移患者:一项多中心、开放性II期临床试验摘要背景转移性黑色素瘤患者中，脑转移非常普遍。在确诊后，中位总生存期多为17-22周。我们评估了dabrafenib对BRAF600位缬氨酸突变为谷氨酸或赖氨酸的黑素瘤脑转移患者的作用。方法在6个国家的24个中心中，我们开展了一项多中心、开放性II期临床试验。我们纳入了经组织学证实为BRAFVal600Glu或Val600Lys突变的黑色素瘤患者以及至少一例的无症状脑转移(直径?5 mm 并 ?40 mm)。合适的患者年龄在18岁及以上，美国东部肿瘤协作组全身功能状态评分为0或1，器官功能正常。患者被分为两组:A组中的患者尚未接受针对脑转移的局部治疗，B组中的患者在接受局部治疗后仍有进行性脑转移。患者接受每日两次150ml的口服abrabenib直到产生疾病发展，死亡或者不可接受的副反应。主要终点为Val600Glu BRAF突变黑色素瘤患者取得颅内缓解的比例(根据修订版的实体瘤疗效评价标准 (RECIST 1.1)评估为完全缓解和部分缓解)。在效果和安全性分析中，我们将至少接受一剂dabrafenib的患者计入。本研究在ClinicalTrials.gov注册，注册号为NCT01266967。发现在2011年2月2日到2011年8月5日之间，我们共纳入了172名患者:A组有89(52%)人， B组有83(48%)人。其中139 (81%)人患有Val600Glu BRAF突变的黑色素瘤。A组的74例Val600Glu BRAF突变黑素瘤患者中有29例(39?2%, 95% CI 28?0—51?2)取得颅内疗效，在B组的65例中有20(30?8%, 19?9—43?4)例。A组15例Val600Lys BRAF突变患者中有1例(6?7%, 0?2—31?9)患者取得颅内疗效，而B组18例类似患者中有4例(22?2%, 6?4—47?6)。38(22%)名患者出现3级或更严重的治疗相关副作用。11名(6%)患者发育出鳞细胞癌(A组5[6%]例，其中一例同时患有角化棘皮瘤;B组6[7%]例)。A组出现4例治疗相关四级不良反应:一例血淀粉酶增加，一例痉挛，一例脂酶增加，一例中性粒细胞减少。B组出现2例治疗相关四级不良反应:一例中性粒细胞减少症，一例颅内大出血。51 (30%)名患者有严重的不良反应。其中，三种最常见的严重不良反应为:发热(10例[6%])，颅内大出血(10例[6%]，其中一例与治疗相关), 鳞细胞癌(11例[6%]) 说明 Dabrafenib 治疗Val600Glu BRAF突变黑素瘤脑转移患者(不论之前是未接受治疗或接受治疗未取得疗效)时有活性和可接受的安全性。基金 GlaxoSmithKline. The Lancet Oncology, Volume 13, Issue 11, Pages 1087 - 1095, November 2012 doi:10.1016/S1470-2045(12)70431-XCite or Link Using DOI This article can be found in the following collections: Neurology (Neuro-oncology); Oncology (Skin cancer, Neuro-oncology) Published Online: 08 October 2012 Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial Dr Georgina V Long PhD a , Uwe Trefzer MD b, Michael A Davies MD c, Prof Richard F Kefford PhD a, Paolo A Ascierto MD d, Paul B Chapman MD e, Igor Puzanov MD f, Axel Hauschild MD g, Caroline Robert PhD h, Alain Algazi MD i, Prof Laurent Mortier MD j, Hussein Tawbi PhD k l, Tabea Wilhelm MD b, Lisa Zimmer MD m, Julie Switzky MSN n, Suzanne Swann PhD n, Anne-Marie Martin PhD n, Mary Guckert MSN n, Vicki Goodman MD n, Michael Streit MD n, Prof John M Kirkwood MD k l †, Prof Dirk Schadendorf MD m † Summary Background Brain metastases are common in patients with metastatic melanoma and median overall survival from their diagnosis is typically 17—22 weeks. We assessed dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain. Methods We undertook a multicentre, open-label, phase 2 trial in 24 centres in six countries. We enrolled patients with histologically confirmed Val600Glu or Val600Lys BRAF-mutant melanoma and at least one asymptomatic brain metastasis (?5 mm and ?40 mm in diameter). Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had adequate organ function. Patients were split into two cohorts: those in cohort A had not received previous local treatment for brain metastases and those in cohort B had progressive brain metastases after previous local treatments. Patients received 150 mg oral dabrafenib twice a day until disease progression, death, or unacceptable adverse events. The primary endpoint was the proportion of patients with Val600Glu BRAF-mutant melanoma who achieved an overall intracranial response, which was defined as a complete response or partial response assessed with a modified form of Response Evaluation Criteria in Solid Tumors (RECIST 1.1). We included patients who received at least one dose of dabrafenib in efficacy and safety analyses. This study is registered with ClinicalTrials.gov, number NCT01266967. Findings Between Feb 2, 2011, and Aug 5, 2011, we enrolled 172 patients: 89 (52%) in cohort A and 83 (48%) in cohort B. 139 (81%) had Val600Glu BRAF-mutant melanoma. 29 (39?2%, 95% CI 28?0—51?2) of 74 patients with Val600Glu BRAF-mutant melanoma in cohort A achieved an overall intracranial response, as did 20 (30?8%, 19?9—43?4) of 65 in cohort B. One (6?7%, 0?2—31?9) of 15 patients with Val600Lys BRAF-mutant melanoma achieved an overall intracranial response in cohort A, as did four (22?2%, 6?4—47?6) of 18 such patients in cohort B. Treatment-related adverse events of grade 3 or worse occurred in 38 (22%) patients. Eleven (6%) patients developed squamous-cell carcinoma (five [6%] patients in cohort A, of whom one also had keratoacanthoma; six [7%] in cohort B). Four grade 4 treatment-related adverse events occurred in cohort A: one blood amylase increase, one convulsion, one lipase increase, and one neutropenia. Two grade 4 events occurred in cohort B: one agranulocytosis and one intracranial haemorrhage. 51 (30%) patients had a serious adverse event. The three most frequent serious adverse events were pyrexia (ten [6%] patients), intracranial haemorrhage (ten [6%]; one treatment-related), and squamous-cell carcinoma (11 [6%]). Interpretation Dabrafenib has activity and an acceptable safety profile in patients with Val600Glu BRAF-mutant melanoma and brain metastases irrespective of whether they are untreated or have been previously treated but have progressed. Funding GlaxoSmithKline.

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Dabrafenib 治疗BRAF600位缬氨酸突变为谷氨酸或赖氨酸的黑素瘤脑转移患者：一项多中心、开放性II期临床试验

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