A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study
A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study
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DOI：
10.1093/annonc/mdi365
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发表时间：
2005-11-01
影响因子：
50.5
通讯作者：
Adjei, AA
中科院分区：
文献类型：
--
作者：
Dy, GK;Miller, AA;Adjei, AA
背景资料：本研究的目的是评估甲磺酸伊马替尼在复发性和难治性c-kit表达的小细胞肺癌患者中的临床活性。患者和方法：将c-kit表达的小细胞肺癌患者（免疫组化>= 1+）分为两组。A组包括< 3 months and arm B included patients with disease progression >既往治疗后疾病进展≥ 3个月的患者。伊马替尼以400 mg b.i.d.的剂量给药。周期为28天。采用单阶段Simon设计和计划的中期分析来评估每组16周的无进展率。结果：共有29名可评估患者进入研究（A组7名，中位年龄68岁; B组22名，中位年龄64.5岁）。两组中位治疗周期数均为1个。在15例（52%）患者中观察到3+级非血液学不良事件，恶心、呕吐、呼吸困难、疲乏、厌食和脱水各至少有10%的患者发生。A组和B组的中位生存期分别为3.9和5.3个月，中位至进展时间分别为1和1.1个月。由于显著的早期疾病进展（29%）、早期死亡（29%）和患者拒绝（42%），A组的入组在中期分析之前暂时暂停。没有客观的反应，也没有证实稳定的疾病>= 6 weeks被认为是在任何arm. Accrual永久终止两个arms，只有一个病人是无进展的16 weeks.Conclusion：伊马替尼未能表现出任何临床活性，尽管患者选择c-kit表达小细胞肺癌。我们的研究结果加强了集体证据，即基于靶向表达而不是途径激活（例如，通过激活突变）来预测新型治疗药物的疗效可能不是药物开发的有效范例。
Background: The aim of the present study was to evaluate the clinical activity of imatinib mesylate in patients with recurrent and refractory c-kit-expressing small-cell lung cancer.Patients and methods: Patients with c-kit-expressing SCLC (>= 1+ by immunohistochemistry) were enrolled in two groups. Arm A included patients with disease progression < 3 months and arm B included patients with disease progression >= 3 months after previous treatment. Imatinib was administered at a dose of 400 mg b.i.d. continuously, with a cycle length of 28 days. A single stage Simon design with a planned interim analysis was used to evaluate the 16-week progression free rate in each arm.Results: A total of 29 evaluable patients were entered into the study (seven in arm A, median age 68; 22 in arm B, median age 64.5). Median number of treatment cycles was one in both arms. Grade 3+ non-hematologic adverse events were seen in 15 (52%) patients, with nausea, vomiting, dyspnea, fatigue, anorexia and dehydration each occurring in at least 10% of patients. Median survival was 3.9 and 5.3 months and median time to progression was 1 and 1.1 months for arms A and B, respectively. Enrollment to arm A was temporarily suspended prior to reaching interim analysis due to striking early disease progression (29%), early deaths (29%) and patient refusal (42%). No objective responses and no confirmed stable disease >= 6 weeks were seen in either arm. Accrual was permanently terminated to both arms as only one patient was progression-free at 16 weeks.Conclusion: Imatinib failed to demonstrate any clinical activity in spite of patient selection for c-kit-expressing SCLC. Our results strengthen the collective evidence that prediction of efficacy of novel therapeutic agents based on target expression, rather than pathway activation (for example, through activating mutations), may not be a valid paradigm for drug development.