Inhibition of mutated, activated BRAF in metastatic melanoma.
Inhibition of mutated, activated BRAF in metastatic melanoma.
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DOI：
10.1056/nejmoa1002011
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发表时间：
2010-08-26
期刊：
影响因子：
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通讯作者：
Chapman PB
中科院分区：
文献类型：
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作者：
Flaherty KT;Puzanov I;Kim KB;Ribas A;McArthur GA;Sosman JA;O'Dwyer PJ;Lee RJ;Grippo JF;Nolop K;Chapman PB
在大多数黑色素瘤中，对编码丝氨酸 - 苏氨酸蛋白激酶B - RAF（BRAF）的基因的体细胞突变的鉴定为测试针对这种疾病的癌基因靶向治疗提供了机会。
我们进行了一项多中心、1期剂量递增试验，研究PLX4032（也称为RG7204），这是一种口服的突变型BRAF抑制剂，随后是一个扩展阶段，涉及在无不良反应情况下可给予的最大剂量（推荐的2期剂量）。患者每日两次接受PLX4032治疗，直至疾病进展。对所有患者进行了药代动力学分析和肿瘤反应评估。在选定的患者中，在治疗前和治疗期间进行肿瘤活检以验证BRAF抑制情况。
共有55名患者（其中49人患有黑色素瘤）参与了剂量递增阶段，另外32名患有BRAF V600E突变的转移性黑色素瘤患者参与了扩展阶段。推荐的2期剂量为每日两次960mg，剂量增加受2级或3级皮疹、疲劳和关节痛的限制。在剂量递增队列中，在16名肿瘤携带V600E BRAF突变且每日两次接受240mg或更多PLX4032的黑色素瘤患者中，10人有部分缓解，1人有完全缓解。在扩展队列的32名患者中，24人有部分缓解，2人有完全缓解。所有患者的估计中位无进展生存期超过7个月。
在肿瘤携带V600E BRAF突变的患者中，用PLX4032治疗转移性黑色素瘤使大多数患者的肿瘤完全或部分消退。（由Plexxikon和罗氏制药公司资助）
The identification of somatic mutations in the gene encoding the serine–threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease. We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)