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新药讨论:AZD6244

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12766 8 成长的烦恼 发表于 2012-6-28 21:20:37 | 查看全部 | 阅读模式 来自: 江苏苏州

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本帖最后由 成长的烦恼 于 2012-6-28 22:37 编辑 7 E. K5 C; x9 r: A
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A phase I study of selumetinib (AZD6244/ARRY-142866) in combination with cetuximab (cet) in refractory solid tumors and KRAS mutant colorectal cancer (CRC).
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Background: KRAS mutations have been recognized as clinically important predictors of resistance to EGFR-directed therapies in CRC. Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor receptor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cet in KRAS mutant CRC. A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cet, with an expanded cohort in KRAS mutant CRC at the MTD dose to evaluate preliminary anti-tumor activity. Methods: In the dose escalation portion, patients (pts) with advanced solid tumors received fixed dose cet with escalating doses of selumetinib in cohorts of 3-6 pts. In the expansion cohort, 14 pts with KRAS mutant CRC were enrolled at the MTD level. Results: 15 pts (9 M, 6 F), average age of 60 (41-73) years were treated at 3 dose levels in the dose escalation cohort and 14 pts were treated in the expansion cohort. Pts had the following tumor types: CRC 73%, NSCLC 13%, and H&N 13%, and had received a median of 4 (1-8) prior lines of therapy. 33% (only CRC) had prior EGFR-directed therapies. ECOG PS 0 (40%), 1 (53%), 2 (7%). 13 of 15 pts were evaluable for tolerability and response. One DLT for grade 4 hypomagnesemia occurred, and no other grade 4 toxicities were seen. Grade 3 (20%) toxicities included; rash, hyponatremia, and headache. The most common cycle 1 grade 1 and 2 adverse events included acneiform rash (100%), fatigue (54%), nausea/vomiting, (54%), diarrhea (54%), dry skin (46%), fever (23%), and hypomagnesemia (15%). Most pts (60%) required no dose modifications. The MTD was established at selumetinib 75 mg PO BID and cet 250 mg/m2 weekly following a 400 mg/m2load. Best response included 2 PR in pts with CRC and SD in 4 pts (1 SCC of the tonsil, 1 NSCLC, and 2 CRC). Conclusions: The combination of selumetinib and cet is well tolerated, and preliminary anti-tumor activity was observed in multiple pts. Results of the KRAS mutant CRC expansion cohort will be presented.% @7 k! n# ?: D
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KRAS基因突变是目前肠癌等类似病症药物治疗的盲点,因为RAS的突变可能造成了通路的不畅,进而使得EGFR受体的靶向药物通通失效。虽然不见得找到了机制,但科学家设计了从MEK这个RAS的下游节点进行抑制的药物。上述AZD6244就是这样的药物。AZD6244联合爱必妥的治疗方案虽然从成本上来看豪华无比,但其I期实验结果的也还算是有所回报。至少为今后突变型患者提供了一些治疗思路。期待二期实验的展开。# x! _( l6 P; W: E0 [! Y4 C
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QQ:412286151;QQ群:203323347 肠转患者和家属交流群

8条精彩回复,最后回复于 2019-5-7 22:35

睡睡爱爸爸  初中一年级 发表于 2013-10-26 23:23:49 | 显示全部楼层 来自: 黑龙江哈尔滨
AZD6244联合爱必妥的治疗方案虽然从成本上来看豪华无比  什么价位的呢?
我家住在太湖边  初中一年级 发表于 2013-11-11 20:16:57 | 显示全部楼层 来自: 江苏苏州
我刚来,您已经走了。怀念这个版主!
累计签到:10 天
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[LV.3]与爱熟人
jiyizhe1234  初中三年级 发表于 2017-10-26 16:17:23 | 显示全部楼层 来自: 江苏无锡
6244现在可以买到了,9291耐药后联合6244 论坛中有效的很多
累计签到:3 天
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[LV.2]与爱新人
master云  小学六年级 发表于 2018-3-29 22:16:15 来自手机 | 显示全部楼层 来自: 重庆
jiyizhe1234 发表于 2017-10-26 16:17
) f% j0 A' ]; i0 k+ `9 {. v, K. J+ B7 w6244现在可以买到了,9291耐药后联合6244 论坛中有效的很多

) B+ ?/ @. e$ Q2 C& l  e9 M, F哪里买6244啊?
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[LV.7]狂热爱粉
行者老金  大学四年级 发表于 2018-4-1 10:11:55 | 显示全部楼层 来自: 广东东莞
master云 发表于 2018-3-29 22:16$ _- e  d0 _, q- r0 T3 r! Y% _$ b
哪里买6244啊?
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建议给发帖人发站内信询问
肠癌患者,2010年8月14号手术,3C分期;
baloney  小学三年级 发表于 2018-5-22 18:26:04 来自手机 | 显示全部楼层 来自: 山东济南
也想问在哪有?6244治疗kras突变
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[LV.4]与爱新星
长弓  小学五年级 发表于 2018-6-23 09:29:02 | 显示全部楼层 来自: 山东淄博
jiyizhe1234 发表于 2017-10-26 16:17( g" K  b0 @& U( Z# J( J
6244现在可以买到了,9291耐药后联合6244 论坛中有效的很多

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好事情啊,又多一个选择
LM

举报 使用道具

回复 支持 1 反对 0
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[LV.4]与爱新星
2017  高中二年级 发表于 2019-5-7 22:35:35 | 显示全部楼层 来自: 广西玉林
好消息。要多一点希望。
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