Phase II trial of CDK4/6 inhibitor palbociclib in advanced sarcoma based on mRNA expression of CDK4/CDKN2A

• Published in: Signal transduction and targeted therapy 2023-10, Vol.8 (1), p.405-405, Article 405
• Main Authors: Martin-Broto, Javier, Martinez-Garcia, Jeronimo, Moura, David S., Redondo, Andres, Gutierrez, Antonio, Lopez-Pousa, Antonio, Martinez-Trufero, Javier, Sevilla, Isabel, Diaz-Beveridge, Roberto, Solis-Hernandez, Maria Pilar, Carnero, Amancio, Perez, Marco, Marcilla, David, Garcia-Foncillas, Jesus, Romero, Pablo, Fernandez-Jara, Javier, Lopez-Lopez, Daniel, Arribas, Ivan, Hindi, Nadia
• Format: Article
• Language: English
• Subjects: 692/308/575; 692/4028/67/1798; 692/53/2423; Adult; Biopsy; Bone tumors; Cancer Research; Cell Biology; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-dependent kinases; Gene expression; Humans; Internal Medicine; Kinases; Lipopolysaccharides; Medicine; Medicine & Public Health; Oncology; Oral administration; Pathology; Piperazines - pharmacology; Piperazines - therapeutic use; RNA, Messenger; Sarcoma; Sarcoma - genetics; Survival
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-023-01661-8

Cyclin-dependent kinases 4 and 6 ( CDK4/6 ) inhibitors demonstrated activity in terms of progression-free survival (PFS) in advanced dedifferentiated liposarcoma (DD-LPS), a sarcoma with CDK4 amplification. CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors. Preclinical investigators of this study found that CDK4 overexpression, while not of CDKN2A , was the most consistent predictive factor for palbociclib efficacy in sarcomas. Advanced adult-type soft-tissue sarcoma, excluding DD-LPS, or bone sarcoma patients, progressing after at least one systemic line, whose tumors overexpressed CDK4 , but not CDKN2A at baseline biopsy, were accrued in this single-arm phase II trial (EudraCT number: 2016-004039-19). With the main endpoint of a 6-month PFS rate, 40% was considered promising in this population. Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles. A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening, archival material (141), and screening, baseline biopsy (95). There were 28 (29%) with favorable mRNA profiles from 95 screened patients at baseline. From 23 enrolled patients, 21 evaluable, the 6-month PFS rate was 29% (95% CI 9–48), and there were 6 patients out of 21 with a PFS longer than 6 months. The median PFS and overall survival were 4.2 (95% CI 3.6–4.8) and 12 (95% CI 8.7–15.4) months, respectively. Translational research showed a significant correlation between CDK4 mRNA and protein expression. Palbociclib was active in a variety of sarcoma subtypes, selected by CDK4/CDKN2A, and deserves further investigation in the sarcoma context.