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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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