Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer
Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer
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DOI：
10.1200/jco.2007.14.7116
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发表时间：
2008-04-01
影响因子：
45.3
通讯作者：
Chang, David D.
中科院分区：
文献类型：
--
作者：
Amado, Rafael G.;Wolf, Michael;Chang, David D.
目的Panitumumab是一种针对表皮生长因子受体(EGFR)的全人抗体，在转移性结直肠癌(MCRC)患者中具有活性。KRAS是一种EGFR下游的小G蛋白，KRAS的激活突变与mCRC对抗EGFR抗体的不良反应有关，但它们作为选择标记的作用尚未在随机试验中建立。患者和方法通过聚合酶链式反应从肿瘤切片上检测KRAS突变，该试验是在一项III期mCRC试验中收集的，比较了Panitumab单一治疗和最佳支持治疗(BSC)。结果463例患者(208例帕尼图单抗，219例BSC)中，427例(92%)患者存在KRAS状态。43%的患者存在KRAS突变。野生型(WT)KRAS组对PFS的治疗效果(危险比[HR]，0.45；95%CI：0.34~0.59)显著高于突变组(HR，0.99；95%CI，0.73~1.36)(P<；0.0001)。WT KRAS组PFS的中位数Panitumab为12.3周，BSC为7.3周。WT组和突变组对Panitumab的应答率分别为17%和0%。WT KRAS患者的总生存期较长(HR为0.67；95%CI为0.55~0.82；联合治疗组)。与更长的暴露时间一致，WT KRAS组发生了更多与III级治疗相关的毒性。西药KRAS组与一般人群的毒性无显著差异。结论帕尼单抗治疗mCRC仅限于WT KRAS肿瘤患者。在选择mCRC患者作为帕尼单抗治疗的候选者时，应考虑KRAS状态。
Purpose Panitumumab, a fully human antibody against the epidermal growth factor receptor ( EGFR), has activity in a subset of patients with metastatic colorectal cancer ( mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials.Patients and Methods KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care ( BSC). We tested whether the effect of panitumumab on progression- free survival ( PFS) differed by KRAS status.Results KRAS status was ascertained in 427 ( 92%) of 463 patients ( 208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild- type ( WT) KRAS group ( hazard ratio [ HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater ( P < .0001) than in the mutant group ( HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival ( HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population.Conclusion Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.