Wagner Andrew J, Banerji Udai, Mahipal Amit, Somaiah Neeta, Hirsch Heather, Fancourt Craig, Johnson-Levonas Amy O, Lam Raymond, Meister Amy K, Russo Giuseppe, Knox Clayton D, Rose Shelonitda, Hong David S
Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ.
J Clin Oncol. 2017 Apr 20;35(12):1304-1311. doi: 10.1200/JCO.2016.70.7117. Epub 2017 Feb 27.
Purpose To evaluate MK-8242 in patients with wild-type TP53 advanced solid tumors. Patients and Methods MK-8242 was administered orally twice a day on days 1 to 7 in 21-day cycles. The recommended phase II dose (RP2D) was determined on the basis of safety, tolerability, pharmacokinetics (PK), and by mRNA expression of the p53 target gene pleckstrin homology-like domain, family A, member 3 ( PHLDA3). Other objectives were to characterize the PK/pharmacodynamic (PD) relationship, correlate biomarkers with response, and assess tumor response. Results Forty-seven patients received MK-8242 across eight doses that ranged from 60 to 500 mg. Initially, six patients developed dose-limiting toxicities (DLTs): grade (G) 2 nausea at 120 mg; G3 fatigue at 250 mg; G2 nausea and G4 thrombocytopenia at 350 mg; and G3 vomiting and G3 diarrhea at 500 mg. DLT criteria were revised to permit management of GI toxicities. Dosing was resumed at 400 mg, and four additional DLTs were observed: G4 neutropenia and G4 thrombocytopenia at 400 mg and G4 thrombocytopenia (two patients) at 500 mg. Other drug-related G3 and G4 events included anemia, leukopenia, pancytopenia, nausea, hyperbilirubinemia, hypophosphatemia, and anorexia. On the basis of safety, tolerability, PK, and PD, the RP2D was established at 400 mg (15 evaluable patients experienced two DLTs). PK for 400 mg (day 7) showed Cmax 3.07 μM, Tmax 3.0 hours, t1/2 (half-life) 6.6 hours, CL/F (apparent clearance) 28.9 L/h, and Vd/F (apparent volume) 274 L. Blood PHLDA3 mRNA expression correlated with drug exposure ( R = 0.68; P < .001). In 41 patients with postbaseline scans, three patients with liposarcoma achieved a partial response (at 250, 400, and 500 mg), 31 showed stable disease, and eight had progressive disease. In total, 27 patients with liposarcoma had a median progression-free survival of 237 days. Conclusion At the RP2D of 400 mg twice a day, MK-8242 activated the p53 pathway with an acceptable safety and tolerability profile. The observed clinical activity (partial response and prolonged progression-free survival) provides an impetus for further study of HDM2 inhibitors in liposarcoma.
目的 评估MK-8242在野生型TP53晚期实体瘤患者中的疗效。患者与方法 MK-8242于第1至7天每天口服两次，每21天为一个周期。基于安全性、耐受性、药代动力学（PK）以及p53靶基因普列克底物蛋白同源样结构域家族A成员3（PHLDA3）的mRNA表达来确定推荐的II期剂量（RP2D）。其他目标是表征PK/药效学（PD）关系、将生物标志物与反应相关联以及评估肿瘤反应。结果 47例患者接受了剂量范围为60至500 mg的8种剂量的MK-8242治疗。最初，6例患者出现剂量限制性毒性（DLT）：120 mg时出现2级恶心；250 mg时出现3级疲劳；350 mg时出现2级恶心和4级血小板减少；500 mg时出现3级呕吐和3级腹泻。DLT标准进行了修订以允许对胃肠道毒性进行管理。在400 mg时恢复给药，并观察到另外4例DLT：400 mg时出现4级中性粒细胞减少和4级血小板减少，500 mg时出现4级血小板减少（2例患者）。其他与药物相关的3级和4级事件包括贫血、白细胞减少、全血细胞减少、恶心、高胆红素血症、低磷血症和厌食。基于安全性、耐受性、PK和PD，RP2D确定为400 mg（15例可评估患者经历了2例DLT）。400 mg（第7天）的PK显示Cmax为3.07 μM，Tmax为3.0小时，t1/2（半衰期）为6.6小时，CL/F（表观清除率）为28.9 L/h，Vd/F（表观容积）为274 L。血液PHLDA3 mRNA表达与药物暴露相关（R = 0.68；P <.001）。在41例进行基线后扫描的患者中，3例脂肪肉瘤患者获得部分缓解（分别在250、400和500 mg剂量下），31例疾病稳定，8例疾病进展。总体而言，27例脂肪肉瘤患者的无进展生存期中位数为237天。结论 在每天两次400 mg的RP2D剂量下，MK-8242激活了p53通路，具有可接受的安全性和耐受性。观察到的临床活性（部分缓解和延长的无进展生存期）为进一步研究HDM2抑制剂在脂肪肉瘤中的应用提供了动力。
