Phase Ⅱ trial of CDK4/6 inhibitor palbociclib in advanced sarcoma based on mRNA expression of CDK4/CDKN2A
作者机构：Health Research Institute-Fundación Jiménez Díaz University HospitalUniversidad Autónoma de Madrid(IIS-FJDUAM)28040MadridSpain Medical Oncology DepartmentFundación Jimenez Diaz University Hospital28040MadridSpain General de Villalba University Hospital28400MadridSpain Medical Oncology DepartmentUniversity Hospital Virgen de la Arrixaca30120MurciaSpain Department of Medical OncologyHospital Universitario La Paz-IdiPAZP.Castellana26128046MadridSpain Hematology DepartmentUniversity Hospital Son Espases07120MallorcaSpain Medical Oncology DepartmentSant Pau Hospital08025BarcelonaSpain Medical Oncology DepartmentUniversity Hospital Miguel Servet50009ZaragozaSpain Investigación Clínica y Traslacional en Cáncer/Instituto de Investigaciones Biomédicas de Malaga(IBIMA)/Hospitales Universitarios Regional y Virgen de la Victoria de MalagaMalagaSpain Medical Oncology DepartmentHospital Universitari i Politècnic La Fe46026ValenciaSpain Medical Oncology DepartmentCentral University Hospital of Asturias33011OviedoSpain Instituto de Biomedicina de Sevilla(IBiSHUVRCSICUS)41013SevillaSpain Pathology DepartmentVirgen del Rocio University Hospital41013SevillaSpain Radiology DepartmentFundación Jimenez Diaz University Hospital28040MadridSpain Computational Medicine PlatformFundación progreso y salud(FPS)Hospital Virgen del Rocío41013SevilleSpain Bioinformatics in Rare Diseases(BiER).Centro de Investigación Biomédica en Red de Enfermedades Raras(CIBERER)FPSHospital Virgen del RocioSevillaSpain Universitat de València-ERI-CES46010ValenciaSpain
出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)
年 卷 期：2023年第8卷第11期
页 面：5518-5527页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
摘 要：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.
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