Pfizer Inc., New York, New York, USA.
Clin Pharmacol Ther. 2021 Nov;110(5):1273-1281. doi: 10.1002/cpt.2228. Epub 2021 Jun 26.
Lorlatinib is a small molecule inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) tyrosine kinases and is approved for the treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC). In the phase I/II study (NCT01970865), potential exposure-response (E-R) relationships between lorlatinib and selected safety and efficacy end points were evaluated in patients with NSCLC. E-R relationships were assessed for safety end points with incidence > 10% in all treated patients (n = 328). In total, 4 safety end points were assessed: hypercholesterolemia grade ≥ 3, hypertriglyceridemia grade ≥ 3, weight gain grade ≥ 2, and treatment-emergent adverse events (TEAEs) grade ≥ 3. Using logistic regression, significant relationships were identified between lorlatinib plasma exposure and risk of hypercholesterolemia grade ≥ 3 (odds ratio (OR) 5.256) and risk of TEAE grade ≥ 3 (OR 3.214). The covariates baseline cholesterol and time on study prior to the event (TE) were associated with the probability of hypercholesterolemia grade ≥ 3. Baseline cholesterol and TE were found to have a statistically significant correlation with TEAE grade ≥ 3. Exposure-efficacy relationships were assessed for objective response rate (ORR; n = 197) and intracranial objective response rate (IC-ORR; n = 132). Lorlatinib plasma exposure was not identified as a statistically significant factor related to either efficacy end point. The only significant E-R relationships identified for efficacy were between baseline alkaline phosphatase and baseline amylase with IC-ORR (ORs 0.363 and 1.015, respectively). These findings support the lorlatinib indicated dose and dose modification guidelines regarding the management of lorlatinib-related AEs.
洛拉替尼是一种间变性淋巴瘤激酶（ALK）和 c-ROS 原癌基因 1（ROS1）酪氨酸激酶的小分子抑制剂，获批用于治疗 ALK 阳性晚期非小细胞肺癌（NSCLC）患者。在 I/II 期研究（NCT01970865）中，评估了洛拉替尼与 NSCLC 患者的某些安全性和疗效终点之间的潜在暴露-反应（E-R）关系。使用逻辑回归评估了 E-R 关系安全性终点，所有治疗患者（n=328）中发生率＞10%的终点。总共有 4 个安全性终点进行了评估：高胆固醇血症≥3 级、高三酰甘油血症≥3 级、体重增加≥2 级和治疗出现的不良事件（TEAE）≥3 级。逻辑回归发现，洛拉替尼血浆暴露与高胆固醇血症≥3 级风险（比值比[OR]5.256）和 TEAE≥3 级风险（OR3.214）之间存在显著关系。协变量基线胆固醇和研究开始前至事件发生时间（TE）与高胆固醇血症≥3 级的发生概率相关。发现基线胆固醇和 TE 与 TEAE≥3 级具有统计学显著相关性。对客观缓解率（ORR；n=197）和颅内客观缓解率（IC-ORR；n=132）评估了暴露-疗效关系。洛拉替尼血浆暴露未被确定为与任一疗效终点相关的统计学显著因素。唯一确定的疗效 E-R 关系是基线碱性磷酸酶和基线淀粉酶与 IC-ORR 之间的关系（OR 分别为 0.363 和 1.015）。这些发现支持洛拉替尼的推荐剂量和剂量调整指南，以管理洛拉替尼相关的 AE。
