Hospital General Universitario de Alicante, Alicante, Spain.
Lung Cancer. 2012 Jun;76(3):354-61. doi: 10.1016/j.lungcan.2011.12.002. Epub 2011 Dec 23.
Previous studies in sarcoma found that a composite gene signature, including high expression of nucleotide excision repair (NER) genes (XPG and/or ERCC1) and low expression of homologous recombination repair (HR) genes (BRCA1), identifies a highly sensitive population of patients with significantly improved outcome to trabectedin. This exploratory phase II trial evaluated a customized trabectedin treatment according to this gene signature in patients with non-small cell lung cancer (NSCLC) after the failure of standard platinum-based treatment.
Patients were selected according to their mRNA expression (elevated XPG and/or ERCC1, with low BRCA1) using the following values as cutoff: XPG=0.99, ERCC1=3.47 and BRCA1=12.00. Trabectedin was administered as a 1.3mg/m(2) 3-hour intravenous infusion every 3 weeks (q3wk). The primary efficacy endpoint was the progression-free survival rate at 3 months. Objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) was a secondary efficacy endpoint.
Two of 18 evaluable patients (11.1%; 95% CI, 1.38-34.7%) achieved progression-free survival rate at 3 months. The primary efficacy objective (at least 3 of 18 patients being progression-free at 3 months) was not met, and therefore the trial was early finalized. No objective responses per RECIST were achieved. Four patients had stable disease. Median PFS was 1.3 months, and median overall survival was 5.9 months. Trabectedin was usually well tolerated, with a safety profile similar to that described in patients with other tumor types.
Customized treatment with trabectedin 1.3mg/m(2) 3-h q3wk according to composite gene signature (XPG and/or ERCC1 overexpression, and BRCA1 underexpression) was well tolerated, but had modest activity in NSCLC patients pretreated with platinum. Therefore, further clinical trials with trabectedin as single agent in this indication are not warranted.
先前在肉瘤中的研究发现，一种复合基因特征，包括核苷酸切除修复（NER）基因（XPG 和/或 ERCC1）高表达和同源重组修复（HR）基因（BRCA1）低表达，可识别出对 trabectedin 具有显著改善预后的高度敏感的患者群体。这项探索性的 II 期试验评估了根据非小细胞肺癌（NSCLC）患者在标准铂类治疗失败后的这种基因特征，为患者定制 trabectedin 治疗方案。
使用以下临界值根据患者的 mRNA 表达（XPG 和/或 ERCC1 升高，BRCA1 降低）选择患者：XPG=0.99，ERCC1=3.47 和 BRCA1=12.00。trabectedin 以 1.3mg/m2 静脉输注 3 小时，每 3 周（q3wk）一次。主要疗效终点是 3 个月时的无进展生存率。根据实体瘤反应评估标准（RECIST）的客观缓解是次要疗效终点。
18 名可评估患者中有 2 名（11.1%；95%CI，1.38-34.7%）在 3 个月时无进展生存率。主要疗效目标（至少 18 名患者中的 3 名在 3 个月时无进展）未达到，因此试验提前结束。根据 RECIST，没有达到客观缓解。4 名患者病情稳定。中位 PFS 为 1.3 个月，中位总生存期为 5.9 个月。trabectedin 通常耐受良好，安全性与其他肿瘤类型患者的相似。
根据复合基因特征（XPG 和/或 ERCC1 过表达，BRCA1 低表达），以 1.3mg/m2 3 小时 q3wk 的剂量定制 trabectedin 治疗方案，耐受性良好，但在铂类预处理的 NSCLC 患者中活性中等。因此，在该适应症中，不建议进一步进行 trabectedin 单药的临床试验。
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