O'Hara Mark H, Jegede Opeyemi, Dickson Mark A, DeMichele Angela M, Piekarz Richard, Gray Robert J, Wang Victoria, McShane Lisa M, Rubinstein Lawrence V, Patton David R, Williams P Mickey, Hamilton Stanley R, Onitilo Adedayo, Tricoli James V, Conley Barbara A, Arteaga Carlos L, Harris Lyndsay N, O'Dwyer Peter J, Chen Alice P, Flaherty Keith T
Abramson Cancer Center at the University of Pennsylvania, Philadelphia, Pennsylvania.
Dana Farber Cancer Institute - ECOG-ACRIN Biostatistics Center, Boston, Massachusetts.
Clin Cancer Res. 2025 Jan 6;31(1):56-64. doi: 10.1158/1078-0432.CCR-24-0036.
Amplification of cyclin-dependent kinase 4 (CDK4) and CDK6 is a feature of a variety of malignancies, and preclinical evidence suggests that inhibition of CDK4/6 is a plausible treatment strategy in these tumors. Subprotocol Z1C of the NCI-Molecular Analysis for Therapy Choice trial was designed to evaluate the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors.
Patients had a solid malignancy or lymphoma with progression on at least one systemic therapy for advanced disease or with no standard-of-care therapy available. Tumors with ≥7 copies of CDK4 or CDK6 were considered amplified and molecularly eligible. Enrolled patients were treated with palbociclib 125 mg daily on days 1 to 21 of a 28-day cycle. The primary endpoint was objective response rate.
Forty-three patients were enrolled on subprotocol Z1C, and 38 patients were deemed eligible, treated, and included in analyses; 25 patients were eligible, treated, and centrally confirmed to have CDK4 or CDK6 amplification and comprised the primary analysis cohort for objective response rate endpoint. Among the 25 patients in the primary cohort, one patient had a partial response, 4 patients had stable disease, and 16 patients had progressive disease as best response. Four patients were not evaluable due to lack of follow-up scans. Among the 38 evaluable patients, one patient had a partial response, 10 patients had stable disease, and 21 patients had progressive disease as best response. Partial response and stable disease were seen only in patients with CDK4 amplification. Median progression-free survival was 2.0 months, and median overall survival was 8.8 months.
Palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, although central nervous system tumors may be worthy of future investigation.
细胞周期蛋白依赖性激酶4（CDK4）和CDK6的扩增是多种恶性肿瘤的一个特征，临床前证据表明，抑制CDK4/6在这些肿瘤中是一种可行的治疗策略。美国国立癌症研究所（NCI）治疗选择分子分析试验的子方案Z1C旨在评估CDK4/6抑制剂帕博西尼在CDK4或CDK6扩增肿瘤中的疗效。
患者患有实体恶性肿瘤或淋巴瘤，至少接受过一种晚期疾病的全身治疗后病情进展，或无标准治疗方案可用。CDK4或CDK6拷贝数≥7的肿瘤被认为是扩增的且符合分子入选标准。入组患者在28天周期的第1至21天每天接受125 mg帕博西尼治疗。主要终点是客观缓解率。
43例患者入组子方案Z1C，38例患者被认为符合条件、接受了治疗并纳入分析；25例患者符合条件、接受了治疗并经中心确认有CDK4或CDK6扩增，构成客观缓解率终点的主要分析队列。在主要队列的25例患者中，1例患者部分缓解，4例患者病情稳定，16例患者病情进展为最佳反应。4例患者因缺乏随访扫描而无法评估。在38例可评估患者中，1例患者部分缓解，10例患者病情稳定，21例患者病情进展为最佳反应。仅在CDK4扩增的患者中观察到部分缓解和病情稳定。无进展生存期的中位数为2.0个月，总生存期的中位数为8.8个月。
帕博西尼在组织学类型不限的CDK4或CDK6扩增肿瘤中显示出有限的活性，尽管中枢神经系统肿瘤可能值得未来进一步研究。
