根据 ERCC1 和 RRM1 SNPs 定制一线化疗在晚期非小细胞肺癌患者中的 II 期临床试验。
Phase II trial of customized first line chemotherapy according to ERCC1 and RRM1 SNPs in patients with advanced non-small-cell lung cancer.
机构信息
Department of Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, Largo Brambilla 3, Firenze, Italy.
出版信息
Lung Cancer. 2013 Nov;82(2):288-93. doi: 10.1016/j.lungcan.2013.08.018. Epub 2013 Sep 3.
OBJECTIVES
Customized chemotherapy has several advantages: patients are more likely to be treated with the most effective agents and can be spared the toxicity of ineffective drugs. Based on the literature, excision repair cross complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) genes represent predictive biomarkers of response to platinum compound and gemcitabine, in NSCLC.
MATERIALS AND METHODS
We had planned a phase II trial (Simon design) to evaluate combination chemotherapy according to single nucleotide polymorphisms (SNPs) of ERCC1 (118T/C and 8092C/A) and RRM1 (-37C/A and -524T/C) in naïve patients affected by advanced NSCLC. ERCC1 and RRM1 SNPs assessment was performed in peripheral blood lymphocytes (PBLs). Combination chemotherapy was selected based on ERCC1 and RRM1 SNPs: we assume that patients with one or two C alleles at position 118 and with one or two A alleles at position 8092 in ERCC1 gene would correspond to Cisplatin non-responder and than with two A alleles at -37 and two C alleles at -524 in RRM1 gene to gemcitabine non-responder. Four schedules were provided: cisplatin+gemcitabine, cisplatin+docetaxel, gemcitabine+docetaxel; docetaxel+vinorelbine. Primary endpoint was overall response (ORR) in the intention-to-treat population.
RESULTS
42 patients were enrolled from January 2010 to November 2011; 40 patients received at least 1 cycle of chemotherapy; median age was 66 years (range: 47-72); 36(90%) had stage IV, 4(10%) IIIB; 23(58%) had adenocarcinoma, 14(35%) squamous carcinoma. Twenty-five (62%) patients received treatment A, 3(8%) treatment B, 11(28%) treatment C, 1(23%) treatment D. ORR was 55%, analysis in squamous patients subgroups showed 71.4% ORR. The median follow-up was 19.7 months, PFS was 23 weeks (95% CI = 15-26) and OS was 40.4 weeks (95% CI = 32-55). Treatment was well tolerated.
CONCLUSION
We observed an increase of ORR in NSCLC patients when they were treated with chemotherapy according to ERCC1 and RRM1 SNPs status.
目的
个体化化疗有几个优点：患者更有可能接受最有效的药物治疗，并且可以避免无效药物的毒性。基于文献，切除修复交叉互补组 1（ERCC1）和核苷酸还原酶 M1（RRM1）基因是预测非小细胞肺癌对铂类化合物和吉西他滨反应的生物标志物。
材料和方法
我们计划进行一项 II 期试验（Simon 设计），以评估根据 ERCC1（118T/C 和 8092C/A）和 RRM1（-37C/A 和-524T/C）单核苷酸多态性（SNP）在初治晚期 NSCLC 患者中进行联合化疗。在周围血淋巴细胞（PBLs）中进行 ERCC1 和 RRM1 SNP 评估。根据 ERCC1 和 RRM1 SNPs 选择联合化疗：我们假设 ERCC1 基因位置 118 位有一个或两个 C 等位基因，位置 8092 位有一个或两个 A 等位基因的患者对应顺铂无反应者，而 RRM1 基因位置-37 位有两个 A 等位基因和-524 位有两个 C 等位基因的患者对应吉西他滨无反应者。提供了四种方案：顺铂+吉西他滨、顺铂+多西他赛、吉西他滨+多西他赛；多西他赛+长春瑞滨。主要终点是意向治疗人群的总缓解率（ORR）。
结果
2010 年 1 月至 2011 年 11 月共纳入 42 例患者；40 例患者接受了至少 1 个周期的化疗；中位年龄为 66 岁（范围：47-72）；36（90%）例为 IV 期，4（10%）例为 IIIB 期；23（58%）例为腺癌，14（35%）例为鳞状细胞癌。25（62%）例患者接受 A 治疗方案，3（8%）例接受 B 治疗方案，11（28%）例接受 C 治疗方案，1（23%）例接受 D 治疗方案。ORR 为 55%，在鳞状细胞癌亚组分析中，ORR 为 71.4%。中位随访时间为 19.7 个月，无进展生存期为 23 周（95%CI=15-26），总生存期为 40.4 周（95%CI=32-55）。治疗耐受性良好。
结论
我们观察到，根据 ERCC1 和 RRM1 SNP 状态，非小细胞肺癌患者接受化疗时，ORR 增加。
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