Teleanu M-V, Heilig C E, Pirmann S, Hamacher R, Bauer S, Gaidzik V I, Mayer-Steinacker R, Al-Sabah J, Roldan Pinzon S S L, Süße H, Freitag A, Horak P, Kreutzfeldt S, Hutter B, Hüllein J, Sedlaczek O, Lehner B, Egerer G, Jäger D, Müller-Tidow C, Hübschmann D, von Kalle C, Barth T F E, Fröhling S, Schlenk R F
Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
ESMO Open. 2025 Jul;10(7):105498. doi: 10.1016/j.esmoop.2025.105498. Epub 2025 Jul 7.
This study aims to evaluate antitumor response of palbociclib in patients with advanced chordoma, an ultra-rare cancer without approved systemic therapy. Previous data showed that palbociclib reduced cell viability and proliferation in CDKN2A-deficient chordoma cell lines.
We conducted a phase II single-arm, open-labeled trial on palbociclib in adult patients with advanced chordomas with p16 (by immunohistochemistry) or CDKN2A (by genomic analysis) loss along with retained CDK4/6 and RB1 expression (by immunohistochemistry or RNA sequencing). Based on CDK4/6/pRB (S780) immunohistochemical expression patterns, a responder versus non-responder signature was assigned. The study used a Simon optimal two-stage design with the primary endpoint of disease control rate (DCR) by RECISTv1.1 after six cycles. Secondary endpoints included progression-free survival, overall survival, and biomarker analysis. The study was considered positive if 25% of patients reached the primary endpoint.
Twenty-eight patients with a median age of 59 years were assessed for the primary endpoint. After a median follow-up of 28 months, the DCR was 39%, with 11 patients achieving stable diseases. No objective responses were obtained. The median progression-free survival was 5.6 months, and the median overall survival was 24.6 months. Treatment was well tolerated without new safety signals. There was no correlation between immunohistochemical responder phenotypes and outcome. Biomarker analysis identified additional clinically actionable alterations affecting PIK3CA, PTEN, MTAP, or MET genes, and druggable pathways by transcriptomic analysis.
Although antitumor activity was modest, the trial met its primary endpoint. Molecularly tailored combination therapies should be considered in the future to improve efficacy.
本研究旨在评估哌柏西利对晚期脊索瘤患者的抗肿瘤反应，脊索瘤是一种极为罕见的癌症，尚无获批的全身治疗方法。既往数据显示，哌柏西利可降低CDKN2A缺陷型脊索瘤细胞系的细胞活力和增殖。
我们对成年晚期脊索瘤患者开展了一项II期单臂、开放标签试验，这些患者的p16（通过免疫组织化学检测）或CDKN2A（通过基因组分析）缺失，同时保留CDK4/6和RB1表达（通过免疫组织化学或RNA测序）。根据CDK4/6/pRB（S780）免疫组织化学表达模式，确定反应者与无反应者特征。该研究采用西蒙最优两阶段设计，主要终点为6个周期后依据RECISTv1.1标准评估的疾病控制率（DCR）。次要终点包括无进展生存期、总生存期和生物标志物分析。如果25%的患者达到主要终点，则认为该研究为阳性。
对28例中位年龄为59岁的患者进行了主要终点评估。中位随访28个月后，DCR为39%，11例患者病情稳定。未观察到客观缓解。中位无进展生存期为5.6个月，中位总生存期为24.6个月。治疗耐受性良好，未出现新的安全信号。免疫组织化学反应者表型与结局之间无相关性。生物标志物分析确定了影响PIK3CA、PTEN、MTAP或MET基因的其他具有临床可操作性的改变，以及通过转录组分析确定的可用药途径。
尽管抗肿瘤活性一般，但该试验达到了主要终点。未来应考虑采用分子靶向联合疗法以提高疗效。
