Abstract：
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.
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.
摘要：
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。
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。
