Dy G K, Miller A A, Mandrekar S J, Aubry M-C, Langdon R M, Morton R F, Schild S E, Jett J R, Adjei A A
Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Ann Oncol. 2005 Nov;16(11):1811-6. doi: 10.1093/annonc/mdi365. Epub 2005 Aug 8.
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 with c-kit-expressing SCLC (> or =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 > or =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.
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 > or =6 weeks were seen in either arm. Accrual was permanently terminated to both arms as only one patient was progression-free at 16 weeks.
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.
本研究旨在评估甲磺酸伊马替尼对复发和难治性c-kit表达的小细胞肺癌患者的临床活性。
c-kit表达的小细胞肺癌患者（免疫组化≥1+）被分为两组。A组包括疾病进展时间<3个月的患者，B组包括先前治疗后疾病进展时间≥3个月的患者。伊马替尼以400mg每日两次的剂量持续给药，周期长度为28天。采用带有计划中期分析的单阶段西蒙设计来评估每组的16周无进展率。
共有29例可评估患者进入研究（A组7例，中位年龄68岁；B组22例，中位年龄64.5岁）。两组的中位治疗周期数均为1个。15例（52%）患者出现3级及以上非血液学不良事件，恶心、呕吐、呼吸困难、疲劳、厌食和脱水在至少10%的患者中均有发生。A组和B组的中位生存期分别为3.9个月和5.3个月，中位疾病进展时间分别为1个月和1.1个月。由于早期疾病进展显著（29%）、早期死亡（29%）和患者拒绝（42%），A组在达到中期分析前暂时停止入组。两组均未观察到客观缓解，也没有确认的疾病稳定≥6周的情况。由于只有一名患者在16周时无疾病进展，两组均永久停止入组。
尽管选择了c-kit表达的小细胞肺癌患者，但伊马替尼未能显示出任何临床活性。我们的结果强化了这样的总体证据，即基于靶点表达而非通路激活（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模式。
