Ivosidenib,an isocitrate dehydrogenase 1(IDH1)inhibitor,has demonstrated clinical benefits in a pivotal study(AG120-C-001)in patients with IDH1-mutated(mIDH1)acute myeloid leukemia(AML).A registry study(CS3010-101:NCT...Ivosidenib,an isocitrate dehydrogenase 1(IDH1)inhibitor,has demonstrated clinical benefits in a pivotal study(AG120-C-001)in patients with IDH1-mutated(mIDH1)acute myeloid leukemia(AML).A registry study(CS3010-101:NCT04176393)was conducted to assess the pharmacokinetic(PK)characteristics,safety,and efficacy of ivosidenib in Chinese patients with relapsed or refractory(R/R)mIDH1 AML.Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression.Ten subjects underwent intensive PK/progressive disease(PD)assessments.All subjects had the clinical response assessed at screening,every 28 days through month 12,and then every 56 days.Between November 12,2019,and April 2,2021,30 patients were enrolled;26(86.7%)had de novo AML and 18(60.0%)were transfusion-dependent at baseline.Following single and repeated doses of ivosidenib,median time to maximum plasma concentration(T_(max))was 4.0 and 2.0 hours,respectively.The inter-individual variability of pharmacokinetic exposure was moderate to high(coefficient of variation[CV],25%–53%).No obvious accumulation was observed after repeated doses at cycle 2 day 1.Regarding the clinical response,the CR+CRh rate was 36.7%(95%confidence interval[CI]:19.9%–56.1%),the median duration of CR+CRh was 19.7 months(95%CI:2.9 months–not reached[NR]),and median duration of response(DoR)was 14.3 months(95%CI:6.4 months–NR).Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months,as compared with primary data cutoff,and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.展开更多
目的挖掘和评价国内3种急性髓系白血病靶向治疗药物上市后不良反应信号。方法利用OpenVigil数据平台,从美国FDA不良事件报告系统分别获取维奈克拉、吉瑞替尼、艾伏尼布上市后药物不良反应(adverse drug reaction,ADR)报告。采用比例报...目的挖掘和评价国内3种急性髓系白血病靶向治疗药物上市后不良反应信号。方法利用OpenVigil数据平台,从美国FDA不良事件报告系统分别获取维奈克拉、吉瑞替尼、艾伏尼布上市后药物不良反应(adverse drug reaction,ADR)报告。采用比例报告比法和报告比值比法检测维奈克拉、吉瑞替尼、艾伏尼布ADR信号,并分别按照发生频次和信号强度进行排序。结果共收集以维奈克拉首要怀疑药物的ADR报告14193份,ADR信号219个;吉瑞替尼ADR报告1885份,ADR信号125个;艾伏尼布ADR报告699份,ADR信号41个。从ADR报告的基本情况来看,3种药物的患者人群均为男性比例高于女性,患者的年龄分布均集中在60~74岁。维奈克拉、吉瑞替尼、艾伏尼布发生频次最高ADR分别为“死亡”“血小板计数减少”“疲乏”;信号强度最高ADR分别为“FLT3基因突变”“原始粒细胞计数增加”“分化综合征”。3种药物发生频次前20的ADR信号共累及系统器官10个,包括各类检查、血液及淋巴系统疾病、感染及侵染类疾病等。维奈克拉与吉瑞替尼发生频次前20的ADR占比最高的系统器官为“血液及淋巴系统疾病”,艾伏尼布发生频次前20的ADR占比最高的系统器官为“各类检查”。结论建议临床应对维奈克拉致心房颤动,吉瑞替尼致脓毒症等ADR给予关注。展开更多
Cholangiocarcinoma(CCA)is an aggressive malignancy that arises from the biliary tract.Currently,the first-line therapy for advanced CCA is gemcitabine and cisplatin.However,5-year survival remains low.It has become ab...Cholangiocarcinoma(CCA)is an aggressive malignancy that arises from the biliary tract.Currently,the first-line therapy for advanced CCA is gemcitabine and cisplatin.However,5-year survival remains low.It has become abundantly clear that a“one size fits all”approach no longer applies to the treatment of individual cancers,given the large amount of tumor heterogeneity.As such,research in recent years has focused on developing effective targeted therapies through genetic profiling of CCA tumors.IDH1 and IDH2 mutations are commonly found in intrahepatic CCA(ICCA).IDH mutations prevent hepatic progenitor cell differentiation and result in the persistence of progenitor-like and stem cells.These are more prone to alterations that promote tumor initiation.As such,IDH has been identified as a promising target for ICCA treatment.We herein review the role of IDH mutations in ICCA development,recent data for IDH inhibitors in ICCA treatment,and challenges within the field of targeted therapy for ICCA.展开更多
文摘Ivosidenib,an isocitrate dehydrogenase 1(IDH1)inhibitor,has demonstrated clinical benefits in a pivotal study(AG120-C-001)in patients with IDH1-mutated(mIDH1)acute myeloid leukemia(AML).A registry study(CS3010-101:NCT04176393)was conducted to assess the pharmacokinetic(PK)characteristics,safety,and efficacy of ivosidenib in Chinese patients with relapsed or refractory(R/R)mIDH1 AML.Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression.Ten subjects underwent intensive PK/progressive disease(PD)assessments.All subjects had the clinical response assessed at screening,every 28 days through month 12,and then every 56 days.Between November 12,2019,and April 2,2021,30 patients were enrolled;26(86.7%)had de novo AML and 18(60.0%)were transfusion-dependent at baseline.Following single and repeated doses of ivosidenib,median time to maximum plasma concentration(T_(max))was 4.0 and 2.0 hours,respectively.The inter-individual variability of pharmacokinetic exposure was moderate to high(coefficient of variation[CV],25%–53%).No obvious accumulation was observed after repeated doses at cycle 2 day 1.Regarding the clinical response,the CR+CRh rate was 36.7%(95%confidence interval[CI]:19.9%–56.1%),the median duration of CR+CRh was 19.7 months(95%CI:2.9 months–not reached[NR]),and median duration of response(DoR)was 14.3 months(95%CI:6.4 months–NR).Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months,as compared with primary data cutoff,and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.
文摘目的挖掘和评价国内3种急性髓系白血病靶向治疗药物上市后不良反应信号。方法利用OpenVigil数据平台,从美国FDA不良事件报告系统分别获取维奈克拉、吉瑞替尼、艾伏尼布上市后药物不良反应(adverse drug reaction,ADR)报告。采用比例报告比法和报告比值比法检测维奈克拉、吉瑞替尼、艾伏尼布ADR信号,并分别按照发生频次和信号强度进行排序。结果共收集以维奈克拉首要怀疑药物的ADR报告14193份,ADR信号219个;吉瑞替尼ADR报告1885份,ADR信号125个;艾伏尼布ADR报告699份,ADR信号41个。从ADR报告的基本情况来看,3种药物的患者人群均为男性比例高于女性,患者的年龄分布均集中在60~74岁。维奈克拉、吉瑞替尼、艾伏尼布发生频次最高ADR分别为“死亡”“血小板计数减少”“疲乏”;信号强度最高ADR分别为“FLT3基因突变”“原始粒细胞计数增加”“分化综合征”。3种药物发生频次前20的ADR信号共累及系统器官10个,包括各类检查、血液及淋巴系统疾病、感染及侵染类疾病等。维奈克拉与吉瑞替尼发生频次前20的ADR占比最高的系统器官为“血液及淋巴系统疾病”,艾伏尼布发生频次前20的ADR占比最高的系统器官为“各类检查”。结论建议临床应对维奈克拉致心房颤动,吉瑞替尼致脓毒症等ADR给予关注。
文摘Cholangiocarcinoma(CCA)is an aggressive malignancy that arises from the biliary tract.Currently,the first-line therapy for advanced CCA is gemcitabine and cisplatin.However,5-year survival remains low.It has become abundantly clear that a“one size fits all”approach no longer applies to the treatment of individual cancers,given the large amount of tumor heterogeneity.As such,research in recent years has focused on developing effective targeted therapies through genetic profiling of CCA tumors.IDH1 and IDH2 mutations are commonly found in intrahepatic CCA(ICCA).IDH mutations prevent hepatic progenitor cell differentiation and result in the persistence of progenitor-like and stem cells.These are more prone to alterations that promote tumor initiation.As such,IDH has been identified as a promising target for ICCA treatment.We herein review the role of IDH mutations in ICCA development,recent data for IDH inhibitors in ICCA treatment,and challenges within the field of targeted therapy for ICCA.
