Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma
Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma
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DOI：
10.1200/jco.2005.03.0536
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发表时间：
2005-12-20
影响因子：
45.3
通讯作者：
Coffey, RJ
中科院分区：
文献类型：
--
作者：
Rothenberg, ML;LaFleur, B;Coffey, RJ
目的：本试验的临床目的是评估吉非替尼在转移性结直肠癌患者中的疗效，这些患者尽管接受过既往治疗，但病情仍有进展。在可能的情况下进行连续肿瘤活检，并分析表皮生长因子受体（EGFR）信号通路的激活。系列血清样品进行测量双调蛋白和转化生长因子-α（TGF α）。患者和方法115例患者随机分配接受吉非替尼250或500毫克口服每天一次。110例患者可评估临床疗效。结果中位无进展生存期为1.9个月（95% CI，1.8 ~ 2.1个月），4个月无进展生存率为13% ± 5%。1例患者达到放射学部分缓解（RR = 1%; 95% CI，0.01%-5%）。中位生存期为6.3个月（95% CI，5.1至8.2个月）。最常见的不良反应是皮疹、腹泻和疲劳。在活检队列中，吉非替尼治疗1周后，总EGFR或活化EGFR、活化Akt、活化MAP-激酶或Ki 67的表达没有降低。然而，在PFS高于中位数的患者中观察到治疗后活化Akt和Ki 67水平降低的趋势，尽管这些未达到0.05水平的显着性。结论吉非替尼作为单一药物在既往接受过治疗的结直肠癌患者中无活性。在肿瘤样本中，吉非替尼不能抑制其近端靶点EGFR的激活。在实现较长无进展生存期的患者中观察到细胞存活和增殖的下游调节因子抑制的趋势。
Purpose The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGF alpha).Patients and Methods One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome,Results Median progression-free survival was 1.9 months (95% Cl, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1 %; 95% Cl, 0.01 % to 5%). Median survival was 6.3 months (95% Cl, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance.Conclusion Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.