Original Research Palbociclib in advanced acral melanoma with genetic aberrations in the cyclin-dependent kinase 4 pathway
Original Research Palbociclib in advanced acral melanoma with genetic aberrations in the cyclin-dependent kinase 4 pathway
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DOI：
10.1016/j.ejca.2021.02.021
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发表时间：
2021-03-23
影响因子：
8.4
通讯作者：
Guo, Jun
中科院分区：
文献类型：
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作者：
Mao, Lili;Dai, Jie;Guo, Jun
背景：82% 的肢端黑色素瘤 (AM) 患者存在细胞周期蛋白依赖性激酶 (CDK)4 通路的遗传畸变，AM 是中国黑色素瘤的主要亚型。我们的目的是评估帕博西尼（一种选择性 CDK4/6 抑制剂）对患有 CDK4 通路基因畸变的晚期 AM 患者的抗肿瘤活性。 方法：在这项 II 期试验中，患有 CDK4 或/和 CCND1 增加或/和 CDKN2A 缺失的晚期 AM 患者在 28 天周期的第 1-21 天接受口服帕博西尼（125 mg）治疗。主要终点是总体缓解率（ORR）。次要终点是无进展生存期（PFS）、总生存期（OS）和治疗相关不良事件（TRAE）。对 9 名患者的可用福尔马林固定、石蜡包埋样本进行全外显子组测序和多重免疫组织化学分析，以探索哌柏西利反应的预测生物标志物。 结果：15 名患者入组。三名 (20.0%) 患者在 8 周时实现肿瘤缩小，其中一名患者已确认部分缓解。截至数据截止日期，一名患者的治疗正在进行中。中位 PFS 为 2.2 个月（范围：1.5-13.3 个月；95% 置信区间 [CI]：1.9-2.5），中位 OS 为 9.5 个月（范围：2.6-14.1 个月，95% CI：5.7-13.4）。八名患者因疾病进展而死亡。最常见的 TRAE 是白细胞减少症（87%；III/IV 级，27%）、中性粒细胞减少症（80%；III/IV 级，27%）和疲劳（53%；III/IV 级，7%）。在接受哌柏西利治疗未获得任何临床获益 (CB) 的患者中观察到显着的 JAK2 缺失和 SH2B3 扩增。研究发现 MCM7 扩增或蛋白表达水平与 CB 相关。结论：Palbociclib 单药疗法在患有 CDK4 通路畸变的晚期 AM 患者中显示出初步疗效和可接受的安全性。 MCM7 扩增或蛋白水平高的患者更容易从 Palbociclib 中受益。 JAK-STAT 通路可能在 Palbociclib 在 AM 中的作用机制中发挥作用。试用注册号：NCT03454919。注册日期：2018年3月6日。(c) 2021 Elsevier Ltd.保留所有权利。
Background: Genetic aberrations in the cyclin-dependent kinase (CDK)4 pathway occur in 82% of patients with acral melanoma (AM), which is the predominant subtype of melanoma in China. We aimed to evaluate the anti-tumour activity of palbociclib, a selective CDK4/6 inhibitor, in patients with advanced AM with CDK4 pathway gene aberrations.Methods: In this phase II trial, patients with advanced AM with CDK4 or/and CCND1 gain or/and CDKN2A loss were treated with oral palbociclib (125 mg) on days 1-21 of a 28-day cycle. The primary end-point was overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Whole-exome sequencing and multiplex immunohistochemistry of the available formalin-fixed, paraffin-embedded samples of nine patients were analysed to explore the predictive biomarkers of palbociclib response.Results: Fifteen patients were enrolled. Three (20.0%) patients achieved tumour shrinkage at 8 weeks, including one with confirmed partial response. At data cut-off date, treatment was ongoing for one patient. The median PFS was 2.2 mo (range: 1.5-13.3 mo; 95% confidence interval [CI]: 1.9-2.5), and the median OS was 9.5 mo (range: 2.6-14.1 mo, 95% CI: 5.7-13.4). Eight patients died due to disease progression. The most common TRAEs were leukopenia (87%; Grade III/IV, 27%), neutropenia (80%; grade III/IV, 27%), and fatigue (53%; grade III/IV, 7%). Significant JAK2 deletions and SH2B3 amplifications were observed in patients who did not achieve any clinical benefit (CB) with palbociclib treatment. MCM7 amplification or protein expression level was found to be associated with CB.Conclusions: Palbociclib monotherapy demonstrated preliminary efficacy and an acceptable safety profile in advanced AM patients with CDK4 pathway aberrations. Patients with amplification or high protein levels of MCM7 were more prone to benefit from palbociclib. The JAK-STAT pathway might play a role in the mechanism of action of palbociclib in AM. Trial registration number: NCT03454919. The date of registration: March 6, 2018.(c) 2021 Elsevier Ltd. All rights reserved.