Weill Cornell Medicine, New York, New York.
Emory Winship Cancer Institute, Atlanta, Georgia.
Clin Cancer Res. 2024 Nov 1;30(21):4844-4855. doi: 10.1158/1078-0432.CCR-24-0028.
AZD5991, a human MCL-1 inhibitor, was assessed for safety, tolerability, pharmacokinetics, and antitumor activity as monotherapy and in combination with venetoclax in patients with relapsed or refractory hematologic malignancies.
In the monotherapy cohort (n = 61), patients with hematologic malignancies received AZD5991 intravenously in escalating doses either once or twice weekly, following intrapatient dose escalation, during a 3-week cycle. In the combination cohort (n = 17), patients with acute myeloid leukemia and myelodysplastic syndrome received escalating doses of AZD5991 and venetoclax during either a 3- or 4-week cycle. Primary objectives were safety and maximum tolerated dose; secondary objectives included plasma pharmacokinetics and antitumor activity.
The most common (≥30%) adverse events were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred because of adverse events: cardiac arrest, sepsis, tumor lysis syndrome, and acute respiratory failure; only tumor lysis syndrome was related to AZD5991. Dose-limiting toxicities occurred in five patients. Three patients with myelodysplastic syndrome achieved an objective response: one marrow complete remission without hematologic improvement, one partial remission with AZD5991 monotherapy, and one marrow complete remission with AZD5991 + venetoclax. Asymptomatic elevations of troponin I or T were observed in eight (10.3%) patients. Post hoc retrospective analysis revealed elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any AZD5991 dose at or after Cycle 1. No associations were found between elevated troponin and cardiovascular risk factors.
Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate.
AZD5991 是一种人源 MCL-1 抑制剂，在复发/难治性血液恶性肿瘤患者中，评估其单药治疗及与 Venetoclax 联合治疗的安全性、耐受性、药代动力学和抗肿瘤活性。
在单药治疗队列（n=61）中，血液恶性肿瘤患者在 3 周周期内，经患者内剂量递增后，以递增剂量每周一次或两次静脉注射 AZD5991。在联合治疗队列（n=17）中，急性髓系白血病和骨髓增生异常综合征患者在 3 或 4 周周期内接受递增剂量的 AZD5991 和 Venetoclax。主要目标是安全性和最大耐受剂量；次要目标包括血浆药代动力学和抗肿瘤活性。
最常见（≥30%）的不良事件是腹泻（59.0%）、恶心（55.1%）和呕吐（47.4%）。4 例死亡是由不良事件引起的：心搏骤停、脓毒症、肿瘤溶解综合征和急性呼吸衰竭；只有肿瘤溶解综合征与 AZD5991 相关。5 例患者发生剂量限制性毒性。3 例骨髓增生异常综合征患者获得客观缓解：1 例无血液学改善的骨髓完全缓解，1 例 AZD5991 单药治疗部分缓解，1 例 AZD5991+Venetoclax 骨髓完全缓解。8 例（10.3%）患者出现肌钙蛋白 I 或 T 无症状升高。事后回顾性分析显示，在首次 AZD5991 剂量之前，31 例患者中有 14 例和首次 AZD5991 剂量或之后第 1 周期后的 65 例患者中有 54 例患者出现肌钙蛋白 T 升高。未发现肌钙蛋白升高与心血管危险因素之间存在相关性。
AZD5991 治疗与实验室肌钙蛋白升高发生率高和总体反应率低有关。
