晚期NSCLC患者肿瘤分子特征与盐酸埃克替尼疗效相关性分析
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摘要
目的：盐酸埃克替尼(Icotinib)是一种新的表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI),临床前实验及同类药的研究提示其可与EGFR酪氨酸激酶特异性结合,阻断EGFR相关的信号传导,从而抑制肿瘤细胞生长。本研究旨在研究盐酸埃克替尼在中国非小细胞肺癌(NSCLC)患者中的安全性、耐受性和疗效。
方法：单中心、开放的I期研究,采取剂量递增的方法,对连续口服不同剂量盐酸埃克替尼片的中国非小细胞肺癌患者,评估其安全性和耐受性,直至疾病进展或出现不能耐受的毒性反应止
结果：40名NSCLC患者入组。客观疗效：150mmg组：1例完全缓解(CR)并持续了44周,6例部分缓解(PR),8例疾病稳定(SD);200mg组9例中1例患者获得了PR,4例获得SD;125mg剂量组8例患者中2例获得PR,6例获得SD；三个不同剂量组患者的疗效在统计学上未见明显差异,P=0.2724。总ORR为25%。总DCR为70.00%。疗效与病理类型、吸烟史、既往化疗次数等未见显著相关性。至截至日期(2011-4-1),40名患者的中位无疾病进展时间(PFS)为160天(95%CI：72-236天)；中位总生存(OS)453.5天(95%CI：226-582天)。35%的患者出现了不良反应,主要有皮疹(25%)、腹泻、恶心、腹胀等。
结论：埃克替尼安全性和耐受性均较好,最常见的不良反应是为皮疹、腹泻。所有剂量组都显示出了明显的抗肿瘤活性。疗效与病理类型、吸烟史、既往化疗次数等未见显著相关性。可能与病例数较少有关,需要进一步扩大样本量进行验证。
目的：探讨酪氨酸激酶抑制剂小分子化合物盐酸埃克替尼与疗效相关基因突变和mRNA表达的相关性。
方法：从参加埃克替尼Ⅰ期临床试验的40例晚期NSCLC患者中,筛选出符合实验要求的14例患者的肿瘤组织标本。利用分支DNA-液相芯片技术,检测肿瘤组织EGFR mRNA表达；利用突变富集-液相芯片技术,检测肿瘤组织EGFR、KRAS、BRAF基因突变。
结果：EGFR的突变率为50%(3例EGFR外显子19缺失,2例EGFR外显子21突变57.1%)；2例KRAS突变。未检测到20外显子和BRAF的突变。突变患者的客观疗效分别为PD 14.29%,SD 42.86%, PR 28.57%, CR 14.29%;7例野生型者的客观疗效分别为PD 57.14%, SD 42.86%,两者有统计学差异(P=0.0407),突变型疗效优于野生型；中位PFS分别为183天和39天,统计学无差异(P=0.5858)。EGFR基因突变患者中位总生存(OS)440天,野生型患者中位OS为140天。EGFR mRNA表达对客观疗效,PFS. OS均未显现出统计学差异。14例患者中只有2例检测到KRAS基因突变(G12S),1例为SD,1例为PD。KRAS基因突变患者的中位PFS为188天(95% CI,27-349天),野生型患者的中位PFS为130.5天(95% CI,24-313天)(P=0.9836)。KRAS基因突变患者的中位OS为387.5天(95% CI,140-635天),野生型患者的中位OS为356天(95% CI,39-733天),(P=0.8892)。14例患者未检测到BRAF基因突变。
结论：1EGFR的突变可能是埃克替尼二线以后治疗晚期NSCLC疗效、PFS和OS的阳性预测因子2EGFR mRNA的高表达对疗效、PFS和OS有一定的阳性预测作用,但样本量较小,需要扩大样本继续证实。3KRAS和EGFR基因20外显子突变作为埃克替尼疗效不佳的预测指标尚证据不足。4.由于病例数少,EGFR突变和EGFR mRNA的表达水平之间尚未见到相关性。
盐酸埃克替尼是第一个国产靶向治疗非小细胞肺癌,口服的小分子酪氨酸激酶抑制剂。与特罗凯具有相似的作用机制,其特点是在不同水平特异性、竞争性的结合在EGFR激酶功能区,抑制其激酶活性从而阻断癌细胞增殖、转移等相关信号的传导。主要不良反应是皮疹和腹泻,无骨髓抑制作用。本文对该药的理化性质、作用机制、临床前研究、药动学和药效学、临床研究及药物不良反应进行了综述。
Background:Icotinib is a new epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It is confirmed by pre-clinical experiment and analog research that icotinib can inhibit cancer cells growth, division, proliferation and metastasis by specially binding to EGFR tyrosine kinase and inhibiting the signal transduction relative to EGFR. This research is to observe the safety, toleration and dose correlated biological effect of icotinib in treatment for non-small cell lung cancer (NSCLC) in Chinese.
Method:The research is a single center phaseⅠopen clinical trial. The selected Chinese patients suffered NSCLC keep on take different doses of Icotinib. It wouldn't quit until disease progression or intolerable toxic reaction appearance. Then the safety and toleration would be evaluated.
Result:40 NSCLC patients are selected in this trial. Objective therapeutic effect:1 patient of dose group 150mg bid appears complete remission (CR) and the state lasts 44 weeks; 6 patients appear partial remission (PD); 8 patients appear stable disease (SD); and other 8 patients appear progressive disease(PD). In 9 patients of dose group 200mg bid,1 patient appears PR,4 patients appear SD, and 4 patients appear PD. In 8 patients of dose group 125mg tid,2 patient appears PR, and 6 patients appear SD. Statistics significant deviation isn't observed among three dose groups, P=0.2724. The total ORR is 25%. The total DCR is 70.00%. The therapeutic effect isn't correlated with pathology type, smoking history and chemotherapy history. By time April 1st 2011, the median progression free survival (PFS) of 40 patients is 160 days (95%CI:72～236 days). The median overall survival of40 patients is 453.5 days (95%CI:226～582 days). Adverse effect (AE) appears in 35% patients. It includes skin rash (25%), diarrhea, nausea, abdominal distension and etc.
Conclusion:Icotinib was safe and tolerable. The common adverse effect is light and reversible skin rash, diarrhea, nausea, abdominal distension and etc. Icotinib is observed conspicuous antineoplasmic activity in all dose groups. The therapeutic effect isn't correlated with pathology type, smoking history and chemotherapy history. Maybe the small sample size is too small to observe the correlation.
The molecular characters of Tumor specimens in advanced non-small cell lung cancer and relationship with clinical response to icotinib hydrochloride
Background:In this study, we examined the role of EGFR, KRAS, BRAF somatic mutations and EGFR mRNA expression in tumor specimens from advanced non-small cell lung cancer (NSCLC) patients as predicators of the efficacy of icotinib hydrochloride.
Methods:Tumor paraffin-embedded specimens, obtained from 14 of 40 patients with advanced NSCLC who enrolled in the stage I clinical trail of icotinib hydrochloride, were analyzed. Gene somatic mutations were evaluated by Mutant-Enriched Liquidchip (MEL) Technology, and EGFR mRNA expression was measured by Branched DNA Liquidchip (MBL) Technology.
Results:50% of the tumors were EGFR mutated (3 exon19 deletion and 4 exon21 mutation),2 were KRAS mutated. No mutation of EGFR exon20 or BRAF was detected. The objective response was PD 14.29%, SD 42.86%, PR 28.57% and CR 14.29% in patients with EGFR mutation; and PD 57.14%, SD 42.86%in patients with wild-type EGFR (P=0.0407). EGFR mutations were associated with better than the wild-type. Progress-free survival (PFS) (183 days vs 39 days) with no statistically significance (P=0.5858), and overall survival (OS) (440 days vs.140 days) (P=0.1578). EGFR mRNA expression levels were not statistically association was observed with response, PFS or OS. In the 14 patients, K-RAS mutations (G12S) were detected in two patients, one patient of SD and the other patient of PD. Median PFS in patients with K-RAS mutations was 188 days (95% CI,27-349days), and median PFS in KRAS wild-type patients was 130.5 days (95% CI,24-313days) (P=0.9836). OS of these two patients with K-RAS mutations were 387.5days and 356 days(P=0.8892). BRAF mutations were not detected in these 14 patients.
Conclusion:EGFR mutations are predictive biomarkers for response to icotinib hydrochloride as second line treatment or above. EGFR mRNA high expression has a potential to predict the therapeutic response, PFS and OS. However, the sample size is relative small;it needs to be increased to prove the result. The predictive value of KRAS gene mutations or EGFR exons 20 mutations for icotinib was evidence insufficient.Also due to the limitation of sample size, there is no correlation between EGFR mutation and EGFR mRNA expression observed.
Icotinib Hydrochloride is the first targeted therapy of non-small cell lung cancer, oral small molecule tyrosine kinase inhibitors. And Tarceva has a similar mechanism, characterized by different levels of specificity and competitive binding in the EGFR kinase function area, and thus inhibit its kinase activity block cancer cell proliferation, migration and related signal transduction. The main adverse reactions are rash and diarrhea, no bone marrow suppression. This article provides an overview of the physicochemical properties,action mechanisms,preclinical study,pharmacokinetics and pharmacodynamics,clinical study and the untoward reactions of Icotinib Hydrochloride.
方法：单中心、开放的I期研究,采取剂量递增的方法,对连续口服不同剂量盐酸埃克替尼片的中国非小细胞肺癌患者,评估其安全性和耐受性,直至疾病进展或出现不能耐受的毒性反应止
结果：40名NSCLC患者入组。客观疗效：150mmg组：1例完全缓解(CR)并持续了44周,6例部分缓解(PR),8例疾病稳定(SD);200mg组9例中1例患者获得了PR,4例获得SD;125mg剂量组8例患者中2例获得PR,6例获得SD；三个不同剂量组患者的疗效在统计学上未见明显差异,P=0.2724。总ORR为25%。总DCR为70.00%。疗效与病理类型、吸烟史、既往化疗次数等未见显著相关性。至截至日期(2011-4-1),40名患者的中位无疾病进展时间(PFS)为160天(95%CI：72-236天)；中位总生存(OS)453.5天(95%CI：226-582天)。35%的患者出现了不良反应,主要有皮疹(25%)、腹泻、恶心、腹胀等。
结论：埃克替尼安全性和耐受性均较好,最常见的不良反应是为皮疹、腹泻。所有剂量组都显示出了明显的抗肿瘤活性。疗效与病理类型、吸烟史、既往化疗次数等未见显著相关性。可能与病例数较少有关,需要进一步扩大样本量进行验证。
目的：探讨酪氨酸激酶抑制剂小分子化合物盐酸埃克替尼与疗效相关基因突变和mRNA表达的相关性。
方法：从参加埃克替尼Ⅰ期临床试验的40例晚期NSCLC患者中,筛选出符合实验要求的14例患者的肿瘤组织标本。利用分支DNA-液相芯片技术,检测肿瘤组织EGFR mRNA表达；利用突变富集-液相芯片技术,检测肿瘤组织EGFR、KRAS、BRAF基因突变。
结果：EGFR的突变率为50%(3例EGFR外显子19缺失,2例EGFR外显子21突变57.1%)；2例KRAS突变。未检测到20外显子和BRAF的突变。突变患者的客观疗效分别为PD 14.29%,SD 42.86%, PR 28.57%, CR 14.29%;7例野生型者的客观疗效分别为PD 57.14%, SD 42.86%,两者有统计学差异(P=0.0407),突变型疗效优于野生型；中位PFS分别为183天和39天,统计学无差异(P=0.5858)。EGFR基因突变患者中位总生存(OS)440天,野生型患者中位OS为140天。EGFR mRNA表达对客观疗效,PFS. OS均未显现出统计学差异。14例患者中只有2例检测到KRAS基因突变(G12S),1例为SD,1例为PD。KRAS基因突变患者的中位PFS为188天(95% CI,27-349天),野生型患者的中位PFS为130.5天(95% CI,24-313天)(P=0.9836)。KRAS基因突变患者的中位OS为387.5天(95% CI,140-635天),野生型患者的中位OS为356天(95% CI,39-733天),(P=0.8892)。14例患者未检测到BRAF基因突变。
结论：1EGFR的突变可能是埃克替尼二线以后治疗晚期NSCLC疗效、PFS和OS的阳性预测因子2EGFR mRNA的高表达对疗效、PFS和OS有一定的阳性预测作用,但样本量较小,需要扩大样本继续证实。3KRAS和EGFR基因20外显子突变作为埃克替尼疗效不佳的预测指标尚证据不足。4.由于病例数少,EGFR突变和EGFR mRNA的表达水平之间尚未见到相关性。
盐酸埃克替尼是第一个国产靶向治疗非小细胞肺癌,口服的小分子酪氨酸激酶抑制剂。与特罗凯具有相似的作用机制,其特点是在不同水平特异性、竞争性的结合在EGFR激酶功能区,抑制其激酶活性从而阻断癌细胞增殖、转移等相关信号的传导。主要不良反应是皮疹和腹泻,无骨髓抑制作用。本文对该药的理化性质、作用机制、临床前研究、药动学和药效学、临床研究及药物不良反应进行了综述。
Background:Icotinib is a new epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It is confirmed by pre-clinical experiment and analog research that icotinib can inhibit cancer cells growth, division, proliferation and metastasis by specially binding to EGFR tyrosine kinase and inhibiting the signal transduction relative to EGFR. This research is to observe the safety, toleration and dose correlated biological effect of icotinib in treatment for non-small cell lung cancer (NSCLC) in Chinese.
Method:The research is a single center phaseⅠopen clinical trial. The selected Chinese patients suffered NSCLC keep on take different doses of Icotinib. It wouldn't quit until disease progression or intolerable toxic reaction appearance. Then the safety and toleration would be evaluated.
Result:40 NSCLC patients are selected in this trial. Objective therapeutic effect:1 patient of dose group 150mg bid appears complete remission (CR) and the state lasts 44 weeks; 6 patients appear partial remission (PD); 8 patients appear stable disease (SD); and other 8 patients appear progressive disease(PD). In 9 patients of dose group 200mg bid,1 patient appears PR,4 patients appear SD, and 4 patients appear PD. In 8 patients of dose group 125mg tid,2 patient appears PR, and 6 patients appear SD. Statistics significant deviation isn't observed among three dose groups, P=0.2724. The total ORR is 25%. The total DCR is 70.00%. The therapeutic effect isn't correlated with pathology type, smoking history and chemotherapy history. By time April 1st 2011, the median progression free survival (PFS) of 40 patients is 160 days (95%CI:72～236 days). The median overall survival of40 patients is 453.5 days (95%CI:226～582 days). Adverse effect (AE) appears in 35% patients. It includes skin rash (25%), diarrhea, nausea, abdominal distension and etc.
Conclusion:Icotinib was safe and tolerable. The common adverse effect is light and reversible skin rash, diarrhea, nausea, abdominal distension and etc. Icotinib is observed conspicuous antineoplasmic activity in all dose groups. The therapeutic effect isn't correlated with pathology type, smoking history and chemotherapy history. Maybe the small sample size is too small to observe the correlation.
The molecular characters of Tumor specimens in advanced non-small cell lung cancer and relationship with clinical response to icotinib hydrochloride
Background:In this study, we examined the role of EGFR, KRAS, BRAF somatic mutations and EGFR mRNA expression in tumor specimens from advanced non-small cell lung cancer (NSCLC) patients as predicators of the efficacy of icotinib hydrochloride.
Methods:Tumor paraffin-embedded specimens, obtained from 14 of 40 patients with advanced NSCLC who enrolled in the stage I clinical trail of icotinib hydrochloride, were analyzed. Gene somatic mutations were evaluated by Mutant-Enriched Liquidchip (MEL) Technology, and EGFR mRNA expression was measured by Branched DNA Liquidchip (MBL) Technology.
Results:50% of the tumors were EGFR mutated (3 exon19 deletion and 4 exon21 mutation),2 were KRAS mutated. No mutation of EGFR exon20 or BRAF was detected. The objective response was PD 14.29%, SD 42.86%, PR 28.57% and CR 14.29% in patients with EGFR mutation; and PD 57.14%, SD 42.86%in patients with wild-type EGFR (P=0.0407). EGFR mutations were associated with better than the wild-type. Progress-free survival (PFS) (183 days vs 39 days) with no statistically significance (P=0.5858), and overall survival (OS) (440 days vs.140 days) (P=0.1578). EGFR mRNA expression levels were not statistically association was observed with response, PFS or OS. In the 14 patients, K-RAS mutations (G12S) were detected in two patients, one patient of SD and the other patient of PD. Median PFS in patients with K-RAS mutations was 188 days (95% CI,27-349days), and median PFS in KRAS wild-type patients was 130.5 days (95% CI,24-313days) (P=0.9836). OS of these two patients with K-RAS mutations were 387.5days and 356 days(P=0.8892). BRAF mutations were not detected in these 14 patients.
Conclusion:EGFR mutations are predictive biomarkers for response to icotinib hydrochloride as second line treatment or above. EGFR mRNA high expression has a potential to predict the therapeutic response, PFS and OS. However, the sample size is relative small;it needs to be increased to prove the result. The predictive value of KRAS gene mutations or EGFR exons 20 mutations for icotinib was evidence insufficient.Also due to the limitation of sample size, there is no correlation between EGFR mutation and EGFR mRNA expression observed.
Icotinib Hydrochloride is the first targeted therapy of non-small cell lung cancer, oral small molecule tyrosine kinase inhibitors. And Tarceva has a similar mechanism, characterized by different levels of specificity and competitive binding in the EGFR kinase function area, and thus inhibit its kinase activity block cancer cell proliferation, migration and related signal transduction. The main adverse reactions are rash and diarrhea, no bone marrow suppression. This article provides an overview of the physicochemical properties,action mechanisms,preclinical study,pharmacokinetics and pharmacodynamics,clinical study and the untoward reactions of Icotinib Hydrochloride.
引文
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