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Abstract：
BACKGROUND: 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.
METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: ChiCTR2000031608.
METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: ChiCTR2000031608.
摘要：
背景：粘膜黑色素瘤（MM）是一种罕见但破坏性的黑色素瘤亚型。我们先前的研究已经证明了细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂在具有CDK4扩增的头颈部MM（HNMM）患者来源的异种移植模型中的强大抗肿瘤作用。在这里，我们旨在研究dalpiciclib（SHR6390）的疗效和安全性，CDK4/6抑制剂，在携带CDK4扩增的HNMM患者中。
方法：通过HNMM患者来源的异种移植（PDX）模型和患者来源的肿瘤细胞（PDC）在体内和体外评估dalpiciciclib的抗肿瘤功效。然后进行免疫组织化学分析和蛋白质印迹以评估细胞增殖和CDK4/6信号通路的标志物。对于临床试验，CDK4扩增的晚期复发和/或转移性HNMM患者接受dalpiciclib125mg治疗,每天1次,连续21天,共28天.主要终点是疾病控制率（DCR）。次要终点包括安全性，客观反应率（ORR），无进展生存期（PFS），总生存率（OS）。
结果：Dalpiciclib通过CDK4扩增，极大地抑制了HNMM-PDX和PDC的生长，而与载体相比，CDK4野生型的抑制相对较弱。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,共纳入17名患者,16例患者可评估。ORR为6.3%，DCR为81.3%。估计的中位PFS为9.9个月(95%CI，4.8-NA)，未达到中位OS。12个月和24个月的总有效率分别为68.8%(95%CI,0.494-0.957)和51.6%(95%CI,0.307-0.866),分别。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。
结论：Dalpiciclib在本研究中对CDK4扩增的HNMM患者具有良好的耐受性，并显示出持久的益处。CDK4抑制剂及其联合治疗MM的研究值得进一步探索。
背景：ChiCTR2000031608。
方法：通过HNMM患者来源的异种移植（PDX）模型和患者来源的肿瘤细胞（PDC）在体内和体外评估dalpiciciclib的抗肿瘤功效。然后进行免疫组织化学分析和蛋白质印迹以评估细胞增殖和CDK4/6信号通路的标志物。对于临床试验，CDK4扩增的晚期复发和/或转移性HNMM患者接受dalpiciclib125mg治疗,每天1次,连续21天,共28天.主要终点是疾病控制率（DCR）。次要终点包括安全性，客观反应率（ORR），无进展生存期（PFS），总生存率（OS）。
结果：Dalpiciclib通过CDK4扩增，极大地抑制了HNMM-PDX和PDC的生长，而与载体相比，CDK4野生型的抑制相对较弱。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,共纳入17名患者,16例患者可评估。ORR为6.3%，DCR为81.3%。估计的中位PFS为9.9个月(95%CI，4.8-NA)，未达到中位OS。12个月和24个月的总有效率分别为68.8%(95%CI,0.494-0.957)和51.6%(95%CI,0.307-0.866),分别。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。
结论：Dalpiciclib在本研究中对CDK4扩增的HNMM患者具有良好的耐受性，并显示出持久的益处。CDK4抑制剂及其联合治疗MM的研究值得进一步探索。
背景：ChiCTR2000031608。
