Melanoma and Sarcoma Medical Oncology Unit, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou.
Melanoma and Sarcoma Medical Oncology Unit, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou.
ESMO Open. 2024 Aug;9(8):103636. doi: 10.1016/j.esmoop.2024.103636. Epub 2024 Jul 13.
The mouse double minute 2 homolog (MDM2) oncogene exerts oncogenic activities in many cancers and represents a potential therapeutic target. This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of alrizomadlin (APG-115), a novel MDM2/p53 inhibitor, in patients with advanced solid tumors.
Patients with histologically confirmed advanced solid tumors who had progressed to standard treatment or lacked effective therapies were recruited. Alrizomadlin was administered once daily every other day for 21 days of a 28-day cycle until disease progression or intolerable toxicity.
A total of 21 patients were enrolled and treated with alrizomadlin; 57.1% were male and the median age was 47 (25-60) years. The maximum tolerated dose of alrizomadlin was 150 mg and the recommended phase II dose was 100 mg. One patient in the 200-mg cohort experienced dose-limiting toxicity of thrombocytopenia and febrile neutropenia. The most common grade 3/4 treatment-related adverse events were thrombocytopenia (33.3%), lymphocytopenia (33.3%), neutropenia (23.8%), and anemia (23.8%). Alrizomadlin demonstrated approximately linear pharmacokinetics (dose range 100-200 mg) and was associated with increased plasma macrophage inhibitory cytokine-1, indicative of p53 pathway activation. Of the 20 assessable patients, 2 [10%, 95% confidence interval (CI) 1.2% to 31.7%] patients achieved partial response and 10 (50%, 95% CI 27.2% to 72.8%) showed stable disease. The median progression-free survival was 6.1 (95% CI 1.7-10.4) months, which was significantly longer in patients with wild-type versus mutant TP53 (7.9 versus 2.2 months, respectively; P < 0.001). Among patients with MDM2 amplification and wild-type TP53, the overall response rate was 25% (2/8) and the disease control rate was 100% (8/8).
Alrizomadlin had an acceptable safety profile and demonstrated promising antitumor activity in MDM2-amplified and TP53 wild-type tumors. This study supports further exploration of alrizomadlin with recommended doses of 100 mg q.o.d. in 21 days on and 7 days off regimen.
鼠双微体 2 同源物（MDM2）癌基因在许多癌症中具有致癌活性，是潜在的治疗靶点。本试验评估了新型 MDM2/p53 抑制剂 alrizomadlin（APG-115）在晚期实体瘤患者中的安全性、药代动力学、药效学和初步疗效。
入组经组织学证实的晚期实体瘤患者，这些患者在标准治疗后进展或缺乏有效治疗。alrizomadlin 每 28 天周期的第 1 至 21 天，每 2 天给药 1 次，直至疾病进展或出现不可耐受的毒性。
共 21 例患者接受 alrizomadlin 治疗；57.1%为男性，中位年龄为 47（25-60）岁。alrizomadlin 的最大耐受剂量为 150mg，推荐的 II 期剂量为 100mg。200mg 队列中有 1 例患者出现血小板减少症和发热性中性粒细胞减少症的剂量限制毒性。最常见的 3/4 级治疗相关不良事件是血小板减少症（33.3%）、淋巴细胞减少症（33.3%）、中性粒细胞减少症（23.8%）和贫血症（23.8%）。Alrizomadlin 表现出近似线性的药代动力学（剂量范围 100-200mg），并与血浆巨噬细胞抑制细胞因子-1 的增加相关，提示 p53 通路的激活。在 20 例可评估的患者中，2 例（10%，95%置信区间 [CI]1.2%至 31.7%）患者部分缓解，10 例（50%，95%CI27.2%至 72.8%）患者疾病稳定。中位无进展生存期为 6.1 个月（95%CI1.7-10.4），野生型 TP53 患者的无进展生存期明显长于突变型 TP53 患者（分别为 7.9 个月和 2.2 个月；P<0.001）。在 MDM2 扩增且 TP53 野生型的患者中，总体缓解率为 25%（2/8），疾病控制率为 100%（8/8）。
Alrizomadlin 具有可接受的安全性，并在 MDM2 扩增和 TP53 野生型肿瘤中显示出有希望的抗肿瘤活性。本研究支持进一步探索 alrizomadlin，推荐剂量为 100mg，每 2 天给药 1 次，21 天为 1 个周期，停药 7 天。
