Abdul Razak Albiruni R, Bauer Sebastian, Suarez Cristina, Lin Chia-Chi, Quek Richard, Hütter-Krönke Marie Luise, Cubedo Ricardo, Ferretti Stephane, Guerreiro Nelson, Jullion Astrid, Orlando Elena J, Clementi Giorgia, Sand Dejmek Janna, Halilovic Ensar, Fabre Claire, Blay Jean-Yves, Italiano Antoine
Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Universitätsklinikum Essen Klinik für Innere Medizin, Essen, Germany.
Clin Cancer Res. 2022 Mar 15;28(6):1087-1097. doi: 10.1158/1078-0432.CCR-21-1291.
Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are characterized by co-amplification of the murine double minute-2 (MDM2) and cyclin-dependent kinase-4 (CDK4) oncogenes. Siremadlin, a p53-MDM2 inhibitor, was combined with ribociclib, a CDK4/6 inhibitor, in patients with locally advanced/metastatic WDLPS or DDLPS who had radiologically progressed on, or despite, prior systemic therapy.
In this proof-of-concept, phase Ib, dose-escalation study, patients received siremadlin and ribociclib across different regimens until unacceptable toxicity, disease progression, and/or treatment discontinuation: Regimen A [4-week cycle: siremadlin once daily (QD) and ribociclib QD (2 weeks on, 2 weeks off)], Regimen B [3-week cycle: siremadlin once every 3 weeks; ribociclib QD (2 weeks on, 1 week off)], and Regimen C [4-week cycle: siremadlin once every 4 weeks; ribociclib QD (2 weeks on, 2 weeks off)]. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of siremadlin plus ribociclib in one or more regimens.
As of October 16, 2019 (last patient last visit), 74 patients had enrolled. Median duration of exposure was 13 (range, 1-174) weeks. Dose-limiting toxicities occurred in 10 patients, most of which were Grade 3/4 hematologic events. The RDE was siremadlin 120 mg every 3 weeks plus ribociclib 200 mg QD (Regimen B). Three patients achieved a partial response, and 38 achieved stable disease. One patient (Regimen C) died as a result of treatment-related hematotoxicity.
Siremadlin plus ribociclib demonstrated manageable toxicity and early signs of antitumor activity in patients with advanced WDLPS or DDLPS.
高分化（WDLPS）和去分化（DDLPS）脂肪肉瘤的特征是鼠双微体2（MDM2）和细胞周期蛋白依赖性激酶4（CDK4）致癌基因的共同扩增。西瑞马德林是一种p53-MDM2抑制剂，与CDK4/6抑制剂瑞博西尼联合用于局部晚期/转移性WDLPS或DDLPS患者，这些患者在接受过先前的全身治疗后出现了影像学进展或尽管接受了治疗仍出现进展。
在这项概念验证的Ib期剂量递增研究中，患者接受不同方案的西瑞马德林和瑞博西尼治疗，直至出现不可接受的毒性、疾病进展和/或治疗中断：方案A[4周周期：西瑞马德林每日一次（QD），瑞博西尼QD（2周用药，2周停药）]，方案B[3周周期：西瑞马德林每3周一次；瑞博西尼QD（2周用药，1周停药）]，方案C[4周周期：西瑞马德林每4周一次；瑞博西尼QD（2周用药，2周停药）]。主要目标是确定西瑞马德林加瑞博西尼在一种或多种方案中的最大耐受剂量（MTD）和/或推荐扩展剂量（RDE）。
截至2019年10月16日（最后一名患者最后一次访视），74名患者入组。中位暴露持续时间为13（范围1-174）周。10名患者出现剂量限制性毒性，其中大多数为3/4级血液学事件。RDE为西瑞马德林每3周120 mg加瑞博西尼200 mg QD（方案B）。3名患者获得部分缓解，38名患者病情稳定。1名患者（方案C）因治疗相关的血液毒性死亡。
西瑞马德林加瑞博西尼在晚期WDLPS或DDLPS患者中显示出可管理的毒性和早期抗肿瘤活性迹象。
