SAR-096: Phase II clinical trial of ribociclib in combination with everolimus in advanced dedifferentiated liposarcoma (DDL), and leiomyosarcoma (LMS)

Purpose: DDL and LMS are two common subtypes of soft tissue sarcoma, a rare group of diseases for which new treatments are needed. Chemotherapy remains the standard option for advanced disease. Targeting CDK4/6 in DDL and mTOR in LMS is of biologic interest. When combined, the CDK4 inhibitor ribociclib and the mTOR inhibitor everolimus, have shown synergistic growth inhibition in multiple tumor models, suggesting that this combination could be beneficial in patients.Methods: This was a single arm, open label, multi-center phase II study of the combination of ribociclib and everolimus. Patients were enrolled into one of two cohorts: DDL or LMS with intact Rb. The primary endpoint was progression free rate (PFR) at 16 weeks. Secondary endpoints included progression free (PFS) and overall survival, safety and biomarker analyses. Results: In the DDL cohort, 33.3% (95% CI 15.6%-55.3%) of patients were progression free at 16 weeks. Median PFS in this cohort was 15.4 weeks (95% CI, 8-36 weeks) with 2 partial responses. In the LMS cohort the PFR at 16 weeks was 29.2% (95% CI 12.6%-51.1%). Median PFS in this cohort was 15.7 weeks (95% CI 7.7-NA). Most common toxicities included fatigue (66.7%), anorexia (43.8%) and hyperglycemia (43.8%). Concordance between Rb testing methodologies was poor.Conclusions: The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (=16 weeks) meeting the primary endpoint. Notably partial responses were observed. The primary endpoint was not reached in the LMS cohort. The combination was well tolerated with expected side effects. Overall design: We have collected total RNAs of sarcoma patient samples which are either responders or non-responders. We want to study the gene expression changes between the two groups.

研究背景：去分化脂肪肉瘤（DDL）和平滑肌肉瘤（LMS）是两种常见的软组织肉瘤（soft tissue sarcoma）亚型，这类疾病属于罕见病群体，亟需开发新型治疗手段。目前化疗仍是晚期软组织肉瘤的标准治疗方案。针对DDL靶向CDK4/6（细胞周期蛋白依赖性激酶4/6）、针对LMS靶向mTOR（哺乳动物雷帕霉素靶蛋白）具有明确的生物学研究价值。既往研究显示，CDK4抑制剂瑞博西尼（ribociclib）与mTOR抑制剂依维莫司（everolimus）联合使用，在多种肿瘤模型中可产生协同生长抑制效应，提示该联合疗法或可使患者获益。

研究方法：本研究为一项单臂、开放标签、多中心II期临床试验，评估瑞博西尼联合依维莫司的疗效。入组患者被分为两个队列：DDL队列，以及RB（视网膜母细胞瘤蛋白）状态完整的LMS队列。本研究的主要终点为16周无进展率（PFR, progression free rate）；次要终点包括无进展生存期（PFS, progression free survival）、总生存期、安全性评价及生物标志物分析。

研究结果：在DDL队列中，33.3%（95%置信区间：15.6%~55.3%）的患者在16周时仍处于无进展状态。该队列的中位PFS为15.4周（95%置信区间：8~36周），且观察到2例部分缓解病例。LMS队列的16周PFR为29.2%（95%置信区间：12.6%~51.1%），该队列的中位PFS为15.7周（95%置信区间：7.7~未达到）。本研究中最常见的不良事件包括疲劳（66.7%）、食欲减退（43.8%）及高血糖（43.8%）。不同RB检测方法之间的一致性较差。

研究结论：瑞博西尼联合依维莫司在DDL队列中展现出明确的抗肿瘤活性，患者16周无进展疾病比例达标，达成主要研究终点，且观察到部分缓解病例。LMS队列未达成主要研究终点。该联合疗法耐受性良好，不良事件均为预期内反应。

研究设计：本研究收集了存在应答者与非应答者的肉瘤患者样本的总RNA，旨在探究两组之间的基因表达差异。