Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Lung Cancer. 2024 Oct;196:107954. doi: 10.1016/j.lungcan.2024.107954. Epub 2024 Sep 12.
Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, causes distinct adverse events (AEs), including hyperlipidemia and central nervous system (CNS) disorders. Although dose modifications are recommended to manage these AEs, whether dose modifications can achieve optimal blood lorlatinib concentrations and reduce the incidence of lorlatinib-induced AEs remains unclear. Therefore, we investigated the association between lorlatinib exposure and AEs in each patient.
We retrospectively reviewed patients with advanced ALK-rearranged non-small cell lung cancer treated with lorlatinib between November 2018 and July 2022. Serum lorlatinib concentrations were assessed using high-performance liquid chromatography-tandem mass spectrometry. All AEs were evaluated using the Common Terminology Criteria for Adverse Events version 5.0.
The median age of the 55 eligible patients was 59 years (range: 23-79 years). All patients were administered lorlatinib after first line ALK-tyrosine kinase inhibitor failure. Grade ≥ 3 AEs occurred in 25 patients (25/55, 45 %), including hyperlipidemia in 17 (17/55, 31 %), CNS disorders in 7 (7/55, 13 %), and edema in 6 (6/55, 11 %). Dose modification was required in 23 patients (23/55, 42 %). Among the 36 patients with available data on serum lorlatinib levels at day 28 (±14) and no drug dose modifications, lorlatinib serum concentrations were significantly higher in patients with grade ≥ 3 AEs than in those without AEs (median: 462 ng/mL vs. 177 ng/mL, p < 0.01). In eight patients with data on serial lorlatinib serum concentrations following dose modifications, lorlatinib serum concentrations were effectively reduced, facilitating the ongoing administration of lorlatinib. Additionally, no significant difference was observed in the landmark analysis of progression-free survival between patients with dose modification within the first 16 weeks and those without (median: 24.8 months vs. 10.1 months, p = 0.46).
Dose modification of lorlatinib was associated with successful management of AEs and decreased serum concentration of lorlatinib.
洛拉替尼是一种第三代间变性淋巴瘤激酶（ALK）抑制剂，会引起独特的不良反应（AE），包括血脂异常和中枢神经系统（CNS）疾病。尽管建议进行剂量调整以管理这些 AE，但剂量调整是否能达到最佳的洛拉替尼血药浓度并降低洛拉替尼引起的 AE 发生率尚不清楚。因此，我们调查了每个患者的洛拉替尼暴露与 AE 之间的关系。
我们回顾性分析了 2018 年 11 月至 2022 年 7 月期间接受洛拉替尼治疗的晚期 ALK 重排非小细胞肺癌患者。使用高效液相色谱-串联质谱法评估血清洛拉替尼浓度。使用通用不良事件术语标准 5.0 评估所有 AE。
55 名合格患者的中位年龄为 59 岁（范围：23-79 岁）。所有患者在一线 ALK 酪氨酸激酶抑制剂治疗失败后均接受洛拉替尼治疗。25 名患者（25/55，45%）发生了≥3 级 AE，包括 17 名（17/55，31%）血脂异常、7 名（7/55，13%）CNS 疾病和 6 名（6/55，11%）水肿。23 名患者（23/55，42%）需要调整剂量。在 36 名有第 28 天（±14 天）血清洛拉替尼水平数据且未进行药物剂量调整的患者中，AE 患者的洛拉替尼血清浓度明显高于无 AE 患者（中位数：462ng/mL 比 177ng/mL，p<0.01）。在 8 名接受剂量调整后洛拉替尼血清浓度系列数据的患者中，洛拉替尼血清浓度得到有效降低，使洛拉替尼持续给药成为可能。此外，在第 16 周内进行剂量调整的患者和未进行剂量调整的患者的无进展生存期里程碑分析中，无显著差异（中位：24.8 个月比 10.1 个月，p=0.46）。
洛拉替尼剂量调整与 AE 管理成功和洛拉替尼血清浓度降低有关。
