Cabozantinib, a multi-kinase inhibitor, is approved in the United States and European Union for treatment of patients with hepatocellular carcinoma following prior sorafenib treatment. In the Phase III CELESTIAL trial, hepatocellular carcinoma patients receiving cabozantinib showed longer overall survival (OS) and progression-free survival (PFS) than those receiving placebo. The approved cabozantinib (Cabometyx^®) dose is 60 mg once daily with allowable dose modifications to manage adverse events (AE). Time-to-event Cox proportional hazard exposure–response (ER) models were developed to characterize the relationship between predicted cabozantinib exposure and the likelihood of various efficacy and safety endpoints. The ER models were used to predict hazard ratios (HR) for efficacy and safety endpoints for starting doses of 60, 40, or 20 mg daily. Statistically significant relationships between cabozantinib exposure and efficacy and safety endpoints were observed. For efficacy endpoints, predicted HR were lower for OS and PFS at 40 and 60 mg relative to the 20 mg dose: HR for death (OS) are 0.84 (40 mg) and 0.70 (60 mg); HR for disease progression/death (PFS) are 0.73 (40 mg) and 0.62 (60 mg). For safety endpoints, predicted HR were lower for palmar-plantar erythrodysaesthesia (PPE), diarrhea, and hypertension at 20 or 40 mg relative to the 60 mg dose: HR for PPE are 0.31 (20 mg) and 0.66 (40 mg); HR for diarrhea are 0.61 (20 mg) and 0.86 (40 mg); HR for hypertension are 0.46 (20 mg) and 0.76 (40 mg). The rate of dose modifications was predicted to increase in patients with lower cabozantinib apparent clearance. OS and PFS showed the greatest benefit at the 60 mg dose. However, higher cabozantinib exposure was predicted to increase the likelihood of AE and subsequent dose reductions appeared to decrease these risks.

中文翻译：

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Cabozantinib暴露-反应分析对晚期肝细胞癌患者的疗效和安全性。

卡博替尼是一种多激酶抑制剂，已在美国和欧盟获得批准，可用于先前索拉非尼治疗后的肝细胞癌患者。在CELESTIAL III期试验中，接受卡博替尼的肝细胞癌患者的总生存期（OS）和无进展生存期（PFS）比接受安慰剂的患者更长。经批准的卡博替尼（Cabometyx ^®）剂量为每天60 mg，可调整剂量以控制不良事件（AE）。建立事件时间考克斯比例风险暴露-反应（ER）模型来表征预测的卡博替尼暴露与各种功效和安全性终点的可能性之间的关系。ER模型用于预测每日60、40或20 mg起始剂量的功效和安全性终点的危险比（HR）。观察到卡巴替尼的暴露与疗效和安全性终点之间的统计学上显着的关系。对于功效终点，相对于20 mg剂量，OS和PFS在40和60 mg时的预测HR较低：死亡HR（OS）为0.84（40 mg）和0.70（60 mg）；疾病进展/死亡（PFS）的HR为0.73（40 mg）和0.62（60 mg）。对于安全端点，相对于60 mg剂量，掌或足底红发感觉（PPE），腹泻和高血压的预期HR相对于60 mg剂量较低：PPE的HR为0.31（20 mg）和0.66（40 mg）；腹泻的HR为0.61（20 mg）和0.86（40 mg）；高血压的HR为0.46（20毫克）和0.76（40毫克）。降低卡波替尼表观清除率的患者的剂量修改率预计会增加。OS和PFS在60 mg剂量下显示出最大的益处。但是，预计较高的卡巴替尼暴露量会增加AE的可能性，随后减少剂量似乎可以降低这些风险。76（40毫克）。降低卡波替尼表观清除率的患者的剂量修改率预计会增加。OS和PFS在60 mg剂量下显示出最大的益处。但是，预计较高的卡巴替尼暴露量会增加AE的可能性，随后减少剂量似乎可以降低这些风险。76（40毫克）。降低卡波替尼表观清除率的患者的剂量修改率预计会增加。OS和PFS在60 mg剂量下显示出最大的益处。但是，预计较高的卡巴替尼暴露量会增加AE的可能性，随后减少剂量似乎可以降低这些风险。