Kinase inhibition with BAY 43-9006 n renal cell carcinoma
Kinase inhibition with BAY 43-9006 n renal cell carcinoma
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DOI：
10.1158/1078-0432.ccr-040028
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发表时间：
2004-09-15
影响因子：
11.5
通讯作者：
Eisen, T
中科院分区：
文献类型：
--
作者：
Ahmad, T;Eisen, T
BAY 43-9006是CRAF、野生型BRAF、突变型V599 E BRAF、血管内皮生长因子受体（VEGFR）2、VEGFR 3、mVEGFR 2、FLT-3、血小板衍生生长因子受体、p38和c-kit以及其它激酶的口服抑制剂。BAY 43-9006的I期研究确定400 mg口服每日两次为推荐的11期剂量。BAY 43-9006 400 mg每日两次口服给药的11期研究结果在肾细胞癌患者中尤其值得关注。来自前41名肾细胞癌患者的数据显示，30%的患者病情稳定（定义为减少25%至生长25%），40%有反应（定义为减少>25%），30%有进展。疾病可以稳定超过一年。一些病变变成囊性，实际上可以扩大，同时发展成低密度核心。这种现象在用甲磺酸伊马替尼治疗胃肠道间质瘤中被认识到。BAY 43-9006的毒性作用是可控的，包括高血压、水肿、腹泻、手足综合征、皮疹和脱发（皮疹累及头皮）。存在快速耐受的印象，因此需要降低剂量的患者可以在几个月后恢复至全剂量。BAY 43-9006的III期随机、安慰剂对照试验已经开始，用于免疫治疗6个月内进展的肾细胞癌患者。干扰素、白细胞介素2、贝伐单抗和化疗的联合研究正在考虑中。BAY 439006在肾细胞癌中的治疗靶点尚不清楚。与黑色素瘤不同，在肾细胞癌中未发现BRAF突变。其他候选靶标包括VEGFR 2和VEGFR 3。
BAY 43-9006 is an oral inhibitor of CRAF, wild-type BRAF, mutant V599E BRAF, vascular endothelial growth factor receptor (VEGFR) 2, VEGFR3, mVEGFR2, FLT-3, platelet-derived growth factor receptor, p38, and c-kit among other kinases. A Phase I study of BAY 43-9006 identified 400 mg orally twice daily as the recommended Phase 11 dose. The Phase 11 results of a study of BAY 43-9006 at 400 mg orally twice daily were particularly interesting in patients with renal cell carcinoma. Data from the first 41 patients with renal cell carcinoma showed that 30% of patients had stable disease (defined as between 25% reduction and 25% growth), 40% had responded (defined as >25% reduction), and 30% had progressed. Disease could be stabilized for periods in excess of a year. Some lesions became cystic and could actually enlarge while developing a low attenuation core. This phenomenon is recognized in the treatment of gastrointestinal stromal tumors with imatinib mesylate. The toxic effects of BAY 43-9006 were manageable and included hypertension, edema, diarrhea, hand and foot syndrome, rash, and hair loss where the rash involved the scalp. There was an impression of tachyphylaxis such that patients who required a dose reduction could be restored to full dose after a few months. A Phase III randomized, placebo-controlled trial of BAY 43-9006 has started for patients whose renal cell carcinoma has progressed within 6 months of immunotherapy. Combination studies with interferon, interleukin 2, bevacizumab, and chemotherapy are under consideration. The therapeutic targets of BAY 439006 in renal cell carcinoma remain unclear. Unlike melanoma, BRAF mutations have not been found in renal cell carcinoma. Other candidate targets include VEGFR2 and VEGFR3.