胃肠道间质瘤(gastrointestinal stromal tumor,GIST)是一类位于消化道的间叶细胞肿瘤。对于不可切除、转移或复发的GIST患者,伊马替尼、舒尼替尼和瑞戈非尼分别是其标准的一、二和三线治疗药物。由于GIST患者在治疗过程中易出现耐药现...胃肠道间质瘤(gastrointestinal stromal tumor,GIST)是一类位于消化道的间叶细胞肿瘤。对于不可切除、转移或复发的GIST患者,伊马替尼、舒尼替尼和瑞戈非尼分别是其标准的一、二和三线治疗药物。由于GIST患者在治疗过程中易出现耐药现象,尤其是对于三线治疗失败后的患者,目前尚无有效的治疗药物。Ripretinib是由Deciphera制药公司研发的一种KIT/PDGFRα激酶开关调控抑制剂,其在一项Ⅲ期临床研究(注册号:NCT03353753;代号:INVICTUS)中无进展生存期(progression-free survival,PFS)为6.3个月,总生存期(overall survival,OS)为15.1个月。该公司已向美国食品药品监督管理局(Food and Drug Administration,FDA)提交该药的新药上市申请(new drug application,NDA),其有望成为晚期GIST患者多线治疗后新的治疗选择。本文就ripretinib的基本信息、作用机制、临床前研究和临床试验情况作一概述。展开更多
BACKGROUND Imatinib(IMA)has received approval as the primary treatment for gastrointestinal stromal tumors(GIST).Nonetheless,approximately half of the patients with advanced GIST show disease advancement following IMA...BACKGROUND Imatinib(IMA)has received approval as the primary treatment for gastrointestinal stromal tumors(GIST).Nonetheless,approximately half of the patients with advanced GIST show disease advancement following IMA treatment.Presently,the efficacy of secondary and tertiary medications in addressing various GIST secondary mutations is somewhat restricted.Consequently,there is a significant medical demand for the creation of kinase inhibitors that extensively block secondary drug-resistant mutations in advanced GIST.Ripretinib(RPT)is a new,switch-control tyrosine kinase inhibitors that can suppress different mutations of KIT and PDGFRA via a dual mechanism of action.AIM To investigate the literature on RPT to assess an effective,safe,and successful treatment strategy against advanced GIST.METHODS The present systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.PubMed,Embase,Cochrane,Web of Science and ClinicalTrials.gov databases were screened from January 1,2003 to May 1,2024.RESULTS A total of 4 studies were included,with a total of 507 patients enrolled.The objective response rate(ORR)of the RPT-treated advanced GIST was 17%(95%CI:0.11-0.27),while the disease control rate(DCR)was 66%(95%CI:0.59-0.73).The overall occurrence of adverse events with varying degrees was 97%(95%CI:0.93-1),whereas that of grade≥3 adverse reactions was 42%(95%CI:0.28-0.63).The sensitivity analysis revealed that omitting some studies did not yield statistically notable variances in the aggregate data regarding the ORR,DCR,and the occurrence of adverse events of grade 3 or higher.The publication bias was absent because no significant asymmetry was observed in Begg’s funnel plot in all studies.CONCLUSION RPT has favorable efficacy profiles in GIST patients,but the adverse reactions are obvious,and patient management needs to be strengthened to achieve better safety and tolerability.展开更多
目的探索真实世界中瑞派替尼在晚期胃肠间质瘤(gastrointestinal stromal tumor,GIST)患者中的药代动力学(pharmacokinetics,PK)特征。方法收集自2023年11月至2025年3月于中山大学附属第一医院接受瑞派替尼治疗的晚期GIST患者的全点PK数...目的探索真实世界中瑞派替尼在晚期胃肠间质瘤(gastrointestinal stromal tumor,GIST)患者中的药代动力学(pharmacokinetics,PK)特征。方法收集自2023年11月至2025年3月于中山大学附属第一医院接受瑞派替尼治疗的晚期GIST患者的全点PK数据(n=8)和稳态谷浓度(trough concentration,C_(min))血液标本(n=54),采用已经验证的液相色谱-串联质谱法进行瑞派替尼和DP-5439的浓度测定。描述患者服用瑞派替尼后的PK特征,对比不同剂量治疗下患者的稳态C_(min)的区别,探索瑞派替尼和其代谢物DP-5439 PK参数的相关性,以及可能影响其PK的临床特征。结果8例患者的全点药动学曲线提示,瑞派替尼和DP-5439在服用单剂量瑞派替尼后的24 h即下一剂量前达到C_(min)。瑞派替尼和DP-5439的中位达峰时间(time to maximum concentration,Tmax)均为3.16 h。接受瑞派替尼150 mg每天1次治疗的患者的瑞派替尼、DP-5439和两者总和的稳态C_(min)、血浆药物浓度峰值(maximum plasma concentration,C_(max))与其0~24 h血药浓度-时间曲线下面积(area under the concentration-time curve from 0 to 24 hours,AUC_(0-24 h))之间高度相关(均r>0.85,均P<0.05)。接受150 mg每天1次治疗的患者(n=44)的瑞派替尼、DP-5439和总C_(min)的中位数(范围)分别为381.66(40.90~1045.48)、589.08(25.28~1168.11)和998.00(66.18~2381.48)ng/mL,变异系数(coefficient of variation,CV)分别为59.4%、57.2%和53.6%。300 mg剂量组(n=11)瑞派替尼、DP-5439和总C_(min)的中位数(范围)分别为1024.51(251.36~2030.51)、1122.34(111.54~2682.57)和1924.58(404.37~4766.08)ng/mL,CV分别为59.5%、57.3%和54.8%。单因素分析显示,瑞派替尼和DP-5439的剂量校正C_(min)在患者年龄、BMI和既往术中联合胃肠道脏器切除方面比较,差异均无统计学意义(均P>0.05),而在性别方面,男性低于女性(P<0.05)。多元线性回归分析显示,男性患者DP-5439的中位剂量校正C_(min)低于女性患者(P=0.024),但在瑞派替尼中未观察到差异具有统计学意义(P>0.05)。结论在晚期GIST患者中,瑞派替尼和DP-5439均于服用单剂量后24 h即下一剂给药前达到C_(min)。瑞派替尼、DP-5439和总C_(min)与其AUC_(0-24 h)之间具有相关性,可将C_(min)作为瑞派替尼暴露量的指标。瑞派替尼在晚期GIST患者中的PK特征具有个体差异性。展开更多
文摘胃肠道间质瘤(gastrointestinal stromal tumor,GIST)是一类位于消化道的间叶细胞肿瘤。对于不可切除、转移或复发的GIST患者,伊马替尼、舒尼替尼和瑞戈非尼分别是其标准的一、二和三线治疗药物。由于GIST患者在治疗过程中易出现耐药现象,尤其是对于三线治疗失败后的患者,目前尚无有效的治疗药物。Ripretinib是由Deciphera制药公司研发的一种KIT/PDGFRα激酶开关调控抑制剂,其在一项Ⅲ期临床研究(注册号:NCT03353753;代号:INVICTUS)中无进展生存期(progression-free survival,PFS)为6.3个月,总生存期(overall survival,OS)为15.1个月。该公司已向美国食品药品监督管理局(Food and Drug Administration,FDA)提交该药的新药上市申请(new drug application,NDA),其有望成为晚期GIST患者多线治疗后新的治疗选择。本文就ripretinib的基本信息、作用机制、临床前研究和临床试验情况作一概述。
文摘BACKGROUND Imatinib(IMA)has received approval as the primary treatment for gastrointestinal stromal tumors(GIST).Nonetheless,approximately half of the patients with advanced GIST show disease advancement following IMA treatment.Presently,the efficacy of secondary and tertiary medications in addressing various GIST secondary mutations is somewhat restricted.Consequently,there is a significant medical demand for the creation of kinase inhibitors that extensively block secondary drug-resistant mutations in advanced GIST.Ripretinib(RPT)is a new,switch-control tyrosine kinase inhibitors that can suppress different mutations of KIT and PDGFRA via a dual mechanism of action.AIM To investigate the literature on RPT to assess an effective,safe,and successful treatment strategy against advanced GIST.METHODS The present systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.PubMed,Embase,Cochrane,Web of Science and ClinicalTrials.gov databases were screened from January 1,2003 to May 1,2024.RESULTS A total of 4 studies were included,with a total of 507 patients enrolled.The objective response rate(ORR)of the RPT-treated advanced GIST was 17%(95%CI:0.11-0.27),while the disease control rate(DCR)was 66%(95%CI:0.59-0.73).The overall occurrence of adverse events with varying degrees was 97%(95%CI:0.93-1),whereas that of grade≥3 adverse reactions was 42%(95%CI:0.28-0.63).The sensitivity analysis revealed that omitting some studies did not yield statistically notable variances in the aggregate data regarding the ORR,DCR,and the occurrence of adverse events of grade 3 or higher.The publication bias was absent because no significant asymmetry was observed in Begg’s funnel plot in all studies.CONCLUSION RPT has favorable efficacy profiles in GIST patients,but the adverse reactions are obvious,and patient management needs to be strengthened to achieve better safety and tolerability.
文摘目的探索真实世界中瑞派替尼在晚期胃肠间质瘤(gastrointestinal stromal tumor,GIST)患者中的药代动力学(pharmacokinetics,PK)特征。方法收集自2023年11月至2025年3月于中山大学附属第一医院接受瑞派替尼治疗的晚期GIST患者的全点PK数据(n=8)和稳态谷浓度(trough concentration,C_(min))血液标本(n=54),采用已经验证的液相色谱-串联质谱法进行瑞派替尼和DP-5439的浓度测定。描述患者服用瑞派替尼后的PK特征,对比不同剂量治疗下患者的稳态C_(min)的区别,探索瑞派替尼和其代谢物DP-5439 PK参数的相关性,以及可能影响其PK的临床特征。结果8例患者的全点药动学曲线提示,瑞派替尼和DP-5439在服用单剂量瑞派替尼后的24 h即下一剂量前达到C_(min)。瑞派替尼和DP-5439的中位达峰时间(time to maximum concentration,Tmax)均为3.16 h。接受瑞派替尼150 mg每天1次治疗的患者的瑞派替尼、DP-5439和两者总和的稳态C_(min)、血浆药物浓度峰值(maximum plasma concentration,C_(max))与其0~24 h血药浓度-时间曲线下面积(area under the concentration-time curve from 0 to 24 hours,AUC_(0-24 h))之间高度相关(均r>0.85,均P<0.05)。接受150 mg每天1次治疗的患者(n=44)的瑞派替尼、DP-5439和总C_(min)的中位数(范围)分别为381.66(40.90~1045.48)、589.08(25.28~1168.11)和998.00(66.18~2381.48)ng/mL,变异系数(coefficient of variation,CV)分别为59.4%、57.2%和53.6%。300 mg剂量组(n=11)瑞派替尼、DP-5439和总C_(min)的中位数(范围)分别为1024.51(251.36~2030.51)、1122.34(111.54~2682.57)和1924.58(404.37~4766.08)ng/mL,CV分别为59.5%、57.3%和54.8%。单因素分析显示,瑞派替尼和DP-5439的剂量校正C_(min)在患者年龄、BMI和既往术中联合胃肠道脏器切除方面比较,差异均无统计学意义(均P>0.05),而在性别方面,男性低于女性(P<0.05)。多元线性回归分析显示,男性患者DP-5439的中位剂量校正C_(min)低于女性患者(P=0.024),但在瑞派替尼中未观察到差异具有统计学意义(P>0.05)。结论在晚期GIST患者中,瑞派替尼和DP-5439均于服用单剂量后24 h即下一剂给药前达到C_(min)。瑞派替尼、DP-5439和总C_(min)与其AUC_(0-24 h)之间具有相关性,可将C_(min)作为瑞派替尼暴露量的指标。瑞派替尼在晚期GIST患者中的PK特征具有个体差异性。
