Phase II trial of CDK4/6 inhibitor palbociclib in advanced sarcoma based on mRNA expression of CDK4/CDKN2A
Martín-Broto, Javier (Hospital Universitario General de Villalba)
Martinez-Garcia, Jeronimo (Hospital Universitario Virgen de la Arrixaca (Múrcia))
Moura, David S. (Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz)
Redondo, Andres (Hospital Universitario La Paz (Madrid))
Gutierrez, Antonio (Hospital Universitari Son Espases (Palma de Mallorca, Balears))
López Pousa, Antonio (Institut d'Investigació Biomèdica Sant Pau)
Martínez-Trufero, Javier (Hospital Universitari Miguel Servet)
Sevilla, Isabel (Instituto de Investigación Biomédica de Málaga)
Diaz-Beveridge, Roberto (Hospital Universitari i Politècnic La Fe (València))
Solis-Hernandez, Maria Pilar (Hospital Universitario Central de Asturias)
Carnero, Amancio (Instituto de Biomedicina de Sevilla)
Perez, Marco (Hospital Universitario Virgen del Rocío)
Marcilla, David (Hospital Universitario Virgen del Rocío)
Garcia-Foncillas, Jesus (Hospital Universitario Fundación Jiménez Díaz)
Romero, Pablo (Universidad Autónoma de Madrid)
Fernandez-Jara, Javier (Hospital Universitario Fundación Jiménez Díaz)
López López, Daniel (Hospital Virgen del Rocio)
Arribas, Ivan (Universitat de València)
Hindi, Nadia (Hospital Universitario General de Villalba)
Universitat Autònoma de Barcelona

Fecha:	2023
Resumen:	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.
Ayudas:	European Commission. Horizon 2020 825806
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Predictive markers ; Sarcoma ; Translational research
Publicado en:	Signal Transduction and Targeted Therapy, Vol. 8 (october 2023) , ISSN 2059-3635

DOI: 10.1038/s41392-023-01661-8
PMID: 37875500

10 p, 1.3 MB

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