Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Lancet. 2012 May 19;379(9829):1893-901. doi: 10.1016/S0140-6736(12)60398-5.
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.
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.
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.
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.
GlaxoSmithKline.
达拉非尼是一种 BRAF 激酶抑制剂，对突变型 BRAF 具有选择性。我们旨在评估其安全性和耐受性，并确定不能治愈的实体瘤患者（尤其是黑色素瘤患者和未经治疗的无症状脑转移患者）的推荐 2 期剂量。
我们于 2009 年 5 月 27 日至 2012 年 3 月 20 日在澳大利亚和美国的 8 个研究中心进行了 1 期试验。入组患者患有不能治愈的实体瘤，年龄 18 岁或以上，且器官功能良好。由于野生型 BRAF 患者无活性，因此在研究后期才需要 BRAF 突变才能纳入研究。我们使用加速剂量滴定法，第 1 个剂量组接受每日 12mg 达拉非尼，21 天为 1 个周期。一旦确定了剂量，我们就将队列扩大到包括最多 20 名患者。根据初步数据，我们选择了推荐的 2 期剂量。在三个队列中研究了推荐的 2 期剂量的疗效：BRAF 突变型肿瘤患者，包括非 Val600Glu 突变的患者，队列包括转移性黑色素瘤、未治疗脑转移的黑色素瘤和非黑色素瘤实体瘤。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT00880321。
我们共纳入 184 名患者，其中 156 名患有转移性黑色素瘤。最常见的 2 级或更高级别的治疗相关不良事件为皮肤鳞状细胞癌（20 例，11%）、疲劳（14 例，8%）和发热（11 例，6%）。13 例（7%）患者需要减少剂量。无因不良事件导致的死亡或停药，140 例（76%）患者无 2 级或更高级别的治疗相关不良事件。剂量增加至每日两次 300mg，未记录到最大耐受剂量。基于安全性、药代动力学和反应数据，我们选择了推荐的 2 期剂量 150mg，每日两次。在 36 名 Val600 BRAF 突变型黑色素瘤患者中，推荐的 2 期剂量下，25 名（69%，95%CI 51.9-83.7）患者有反应，18 名（50%，32.9-67.1）患者有确认的反应。27 名 Val600Glu BRAF 突变型黑色素瘤患者中有 21 名（78%，57.7-91.4）有反应，15 名（56%，35.3-74.5）有确认的反应。Val600 BRAF 突变型黑色素瘤患者的反应持久，17 名患者（47%）的治疗时间超过 6 个月。在非 Val600Glu BRAF 突变患者中也观察到了反应。在未治疗脑转移的黑色素瘤患者中，10 名患者中有 9 名脑转移瘤的大小缩小。在 28 名 BRAF 突变型非黑色素瘤实体瘤患者中，胃肠道间质瘤、甲状腺乳头状癌、非小细胞肺癌、卵巢癌和结直肠癌患者出现了明显的抗肿瘤活性。
达拉非尼在患有实体瘤的患者中是安全的，并且是 Val600 突变型 BRAF 的有效抑制剂，在黑色素瘤、脑转移和其他实体瘤患者中观察到了反应。
葛兰素史克公司。
