粘膜黑色素瘤（MM）是一种罕见但具有破坏性的黑色素瘤亚型。我们之前的研究表明，细胞周期蛋白依赖性激酶 4/6 (CDK 4/6) 抑制剂在具有 CDK4 扩增的头颈 MM (HNMM) 患者来源的异种移植模型中具有强大的抗肿瘤作用。在此，我们旨在研究 dalpiciclib (SHR6390)（一种 CDK4/6 抑制剂）在携带 CDK4 扩增的 HNMM 患者中的疗效和安全性。通过 HNMM 患者来源的异种移植（PDX）模型和患者评估 dalpiciclib 的抗肿瘤功效体内和体外衍生的肿瘤细胞（PDC）。然后进行免疫组织化学分析和蛋白质印迹来评估细胞增殖和CDK4/6信号通路的标志物。在临床试验中，CDK4 扩增的晚期复发性和/或转移性 HNMM 患者接受 dalpiciclib 125 mg 每日一次治疗，连续 21 天，以 28 天为一个周期。主要终点是疾病控制率（DCR）。次要终点包括安全性、客观缓解率 (ORR)、无进展生存期 (PFS) 和总生存期 (OS)。Dalpiciclib 深度抑制 CDK4 扩增的 HNMM-PDX 和 PDC 的生长，而在 CDK4 扩增的患者中表现出相对较弱的抑制作用。 CDK4野生型与媒介物比较。与对照组相比，dalpiciclib导致Ki-67和磷酸化Rb的表达水平显着降低。在临床试验中，共有17名患者入组，其中16名患者可评估。 ORR 为 6.3%，DCR 为 81.3%。估计中位 PFS 为 9.9 个月（95% CI，4.8-NA），但未达到中位 OS。 12 个月和 24 个月的 OS 率分别为 68.8%（95% CI，0.494-0.957）和 51.6%（95% CI，0.307-0.866）。最常见的不良事件是中性粒细胞计数减少、白细胞计数减少和疲劳。在本研究中，Dalpiciclib 耐受性良好，对 CDK4 扩增的 HNMM 患者显示出持久的益处。关于CDK4抑制剂及其针对MM的联合策略的进一步研究值得进一步探索。ChiCTR2000031608.© 2024。作者。

Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification.The anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).Dalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494-0.957) and 51.6% (95% CI, 0.307-0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue.Dalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration.ChiCTR2000031608.© 2024. The Author(s).