HA121-28,a promising multikinase inhibitor,mainly targets rearranged during transfection(RET)fusions and selectively targets vascular endothelial growth factor receptor-2,endothelial growth factor receptor,and fibrobl...HA121-28,a promising multikinase inhibitor,mainly targets rearranged during transfection(RET)fusions and selectively targets vascular endothelial growth factor receptor-2,endothelial growth factor receptor,and fibroblast growth factor receptor 1-3.The safety,pharmacokinetics,and efficacy of HA121-28 were assessed in advanced solid tumors(phase 1,ClinicalTrials.gov NCT03994484)and advanced RET fusion-positive non-small-cell lung cancer(RET-TKI naive NSCLC,phase 2,ClinicalTrials.gov NCT05117658).HA121-28 was administered orally in doses range from 25 to 800 mg under the 21-day on/7-day off scheme for a 28-day cycle in phase 1 trial.The recommended dose identified in phase 1(450 mg)was administered for patients during phase 2.The primary endpoints were the maximum tolerated dose(MTD)in phase 1 and the objective response rate(ORR)in phase 2.162 patients were enrolled in phase 1 and 48 in phase 2.A total of 600 mg once daily was set as MTD.Across 100-800 mg,the exposure of HA121-28 increased in a dose-dependent manner.Consistent between both trials,diarrhea,rash,and prolonged QTc interval,were the most reported treatment-emergent adverse events.40.0%(phase 1)and 62.5%(phase 2)patients experienced grade≥3 treatment-related adverse events,respectively.The overall ORR was 26.8%and the median progression-free survival(PFS)was 5.5 months among 97 NSCLC patients with advanced RET fusion receiving a dose at≥450 mg once daily.HA121-28 showed encouraging efficacy in advanced RET fusion NSCLC and its toxicity was tolerable in most patients.Nevertheless,cardiotoxicity is a notable concern that warrants careful attention.展开更多
基金funded by Sun Yat-sen University clinical research 5010 program(84000-31630002)Cancer Innovative Research Program of Sun Yat-sen University Cancer Center(CIRP-SYSUCC-0004)+4 种基金the National Natural Science Foundation of China(82073396)CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2M-5-036)the Guangdong Basic and Applied Basic Research Foundation(2021A1515110697)the Guangzhou Key Research and Development Plan(202206010141)CSPC ZhongQi Pharmaceutical Technology(Shijiazhuang)Co.
文摘HA121-28,a promising multikinase inhibitor,mainly targets rearranged during transfection(RET)fusions and selectively targets vascular endothelial growth factor receptor-2,endothelial growth factor receptor,and fibroblast growth factor receptor 1-3.The safety,pharmacokinetics,and efficacy of HA121-28 were assessed in advanced solid tumors(phase 1,ClinicalTrials.gov NCT03994484)and advanced RET fusion-positive non-small-cell lung cancer(RET-TKI naive NSCLC,phase 2,ClinicalTrials.gov NCT05117658).HA121-28 was administered orally in doses range from 25 to 800 mg under the 21-day on/7-day off scheme for a 28-day cycle in phase 1 trial.The recommended dose identified in phase 1(450 mg)was administered for patients during phase 2.The primary endpoints were the maximum tolerated dose(MTD)in phase 1 and the objective response rate(ORR)in phase 2.162 patients were enrolled in phase 1 and 48 in phase 2.A total of 600 mg once daily was set as MTD.Across 100-800 mg,the exposure of HA121-28 increased in a dose-dependent manner.Consistent between both trials,diarrhea,rash,and prolonged QTc interval,were the most reported treatment-emergent adverse events.40.0%(phase 1)and 62.5%(phase 2)patients experienced grade≥3 treatment-related adverse events,respectively.The overall ORR was 26.8%and the median progression-free survival(PFS)was 5.5 months among 97 NSCLC patients with advanced RET fusion receiving a dose at≥450 mg once daily.HA121-28 showed encouraging efficacy in advanced RET fusion NSCLC and its toxicity was tolerable in most patients.Nevertheless,cardiotoxicity is a notable concern that warrants careful attention.
