达沙替尼治疗晚期NSCLC的II期临床研究

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Phase II study of dasatinib in patients with advanced non-small-cell lung cancer.
达沙替尼治疗晚期NSCLC的II期临床研究
PURPOSE: Src family kinases (SFKs) promote cancer progression and are commonly expressed in non-small-cell lung cancer (NSCLC), but the clinical effects of SFK inhibition in NSCLC are unknown. We conducted a phase II trial of the SFK inhibitor dasatinib for advanced NSCLC. We tested the hypotheses that the activation of epidermal growth factor receptor (EGFR) or SFK or modulation of serum cytokines may predict a response to dasatinib.
研究目的：Src家族激酶(SFKs)加速肿瘤进展，在NSCLC中广泛表达。但SFK抑制剂对NSCLC作用尚不明确。我们设计了SFK抑制剂达沙替尼对晚期NSCLC的II期临床试验，我们检验这一假说：EGFR或SFK得活化或血清细胞因子的调节可能预测达沙替尼的疗效。PATIENTS AND METHODS: Patients received dasatinib as first-line therapy. Response was measured by tumor size on computed tomography scans and by metabolic activity on positron emission tomography scans. Tissue samples taken before patients received dasatinib were tested for EGFR and Kras mutation and phosphorylated SFK expression.
患者和方法：患者接受达沙替尼一线治疗，用CT扫描的肿瘤大小和PET扫描的代谢活动来评价疗效。患者接受达沙替尼治疗前，组织取样检测EGFR和Kras突变以及磷酸化SFK表达等指标。RESULTS: Thirty-four patients were enrolled. The overall disease control rate (partial responses plus stable disease) for dasatinib was 43%. One patient had a partial response to therapy. Eleven patients (32%) had a metabolic response to dasatinib. SFK activation and EGFR and Kras mutations in tumor tissue did not predict response to dasatinib. Significant toxicities included fatigue and dyspnea. The presence of a pleural effusion before dasatanib therapy predicted the development of a clinically significant effusion during therapy.
结果：共入组34例患者。达沙替尼总体疾病控制率（PR+SD）为43%，1例患者PR，11例(32%)患者有代谢性疗效。肿瘤组织的SFK活化和EGFR、Kras突变不能预测达沙替尼疗效。主要毒性包括疲劳和呼吸困难。达沙替尼治疗前出现胸腔积液能预测治疗中积液显著增多。CONCLUSION: Dasatinib as a single agent had modest clinical activity that was lower than that generally observed in patients with NSCLC who receive chemotherapy. Pleural effusion was an expected and problematic toxicity that was successfully treated with steroids, diuretics, and dose interruptions. Marked activity in one patient and prolonged stable disease in four others suggested a potential subpopulation of patients with dasatinib-sensitive NSCLC.
结论：达沙替尼单药对NSCLC患者临床疗效适中，但弱于化疗。胸腔积液是一个可预见、较麻烦的不良反应，可通过甾体激素、利尿药和剂量中断成功治愈。试验中1例患者有显著疗效，4例患者SD延长，表明可能存在对达沙替尼敏感NSCLC患者亚组。