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Ref Type Journal Article
PMID (40627883)
Authors Teleanu MV, Heilig CE, Pirmann S, Hamacher R, Bauer S, Gaidzik VI, Mayer-Steinacker R, Al-Sabah J, Roldan Pinzon SSL, 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 TFE, Fröhling S, Schlenk RF
Title CDK4/6 inhibition in advanced chordoma: final results of the NCT PMO-1601 trial.
Journal Vol Issue Date Pages Journal Short Title
ESMO open 10 7 2025 Jul 07 105498 ESMO Open
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CDKN2A loss chordoma sensitive Palbociclib Phase II Actionable In a Phase II trial (NCT PMO-1601), Ibrance (palbociclib) treatment resulted in modest activity with a disease control rate of 39% (11/28, all stable disease), median progression-free survival of 5.6 months, median overall survival of 24.6 months in patients with chordoma with CDKN2A or p16 loss (PMID: 40627883; NCT03110744). 40627883