Tepotinib是一种高度选择性的MET抑制剂,已被批准用于治疗具有METex14跳跃改变的非小细胞肺癌(NSCLC)。本文提供的分析评估了泰泊替尼暴露之间的关系,以及疗效和安全性结果。
暴露-功效分析包括来自正在进行的2期研究(VISION)的数据,该研究调查了500mg/天的替泊替尼在NSCLC中的METex14跳跃改变。疗效终点包括客观反应,响应的持续时间,和无进展生存期。暴露-安全性分析包括来自VISION的数据,加上四项已完成的晚期实体瘤/肝细胞癌研究(30-1400mg)。安全性终点包括水肿,血清白蛋白,肌酐,淀粉酶,脂肪酶,丙氨酸氨基转移酶,天冬氨酸转氨酶,和使用Fridericia方法(QTcF)校正的QT间隔。
Tepotinib在500mg/天的暴露范围内的所有终点均表现出平坦的暴露-功效关系。在30-1400mg剂量下观察到的暴露范围内,Tepotinib还表现出所有终点的平坦暴露-安全性关系。水肿是最常报告的不良事件,也是替替尼剂量减少和中断的最常见原因;然而,低暴露时效果趋于稳定。使用30至1400mg替泊尼的数据进行的浓度-QTc分析得出,对于治疗(500mg)和超治疗(1000mg)剂量的平均暴露量,90%置信区间的上限小于10ms。
这些分析为500mg/天剂量的替泊替尼的获益/风险评估提供了重要的定量药理学支持,因为它适合于治疗具有METex14跳跃性改变的NSCLC。
NCT01014936、NCT01832506、NCT01988493、NCT02115373、NCT02864992。
Tepotinib is a highly selective MET inhibitor approved for treatment of non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Analyses presented herein evaluated the relationship between tepotinib exposure, and efficacy and safety outcomes.
Exposure-efficacy analyses included data from an ongoing phase 2 study (VISION) investigating 500 mg/day tepotinib in NSCLC harboring METex14 skipping alterations. Efficacy endpoints included objective response, duration of response, and progression-free survival. Exposure-safety analyses included data from VISION, plus four completed studies in advanced solid tumors/hepatocellular carcinoma (30-1400 mg). Safety endpoints included edema, serum albumin, creatinine, amylase, lipase, alanine aminotransferase, aspartate aminotransferase, and QT interval corrected using Fridericia\'s method (QTcF).
Tepotinib exhibited flat exposure-efficacy relationships for all endpoints within the exposure range observed with 500 mg/day. Tepotinib also exhibited flat exposure-safety relationships for all endpoints within the exposure range observed with 30-1400 mg doses. Edema is the most frequently reported adverse event and the most frequent cause of tepotinib dose reductions and interruptions; however, the effect plateaued at low exposures. Concentration-QTc analyses using data from 30 to 1400 mg tepotinib resulted in the upper bounds of the 90% confidence interval being less than 10 ms for the mean exposures at the therapeutic (500 mg) and supratherapeutic (1000 mg) doses.
These analyses provide important quantitative pharmacologic support for benefit/risk assessment of the 500 mg/day dosage of tepotinib as being appropriate for the treatment of NSCLC harboring METex14 skipping alterations.
NCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992.