The efficacy and safety of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor, in patients with advanced head and neck mucosal melanoma harboring CDK4 amplification
Chaoji Shi,
Houyu Ju,
Rong Zhou,
Shengming Xu,
Yunteng Wu,
Ziyue Gu,
Ying Wang,
Wanling Chen,
Xinyi Huang,
Yong Han,
Shuyang Sun,
Chuwen Li,
Min Wang,
Guoyu Zhou,
Zhiyuan Zhang,
Jiang Li,
Guoxin Ren
Affiliations
Chaoji Shi
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Houyu Ju
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Rong Zhou
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Shengming Xu
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Yunteng Wu
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Ziyue Gu
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Ying Wang
Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd
Wanling Chen
National Clinical Research Center for Oral Diseases, National Center for Stomatology
Xinyi Huang
National Clinical Research Center for Oral Diseases, National Center for Stomatology
Yong Han
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Shuyang Sun
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Chuwen Li
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Min Wang
National Clinical Research Center for Oral Diseases, National Center for Stomatology
Guoyu Zhou
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Zhiyuan Zhang
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Jiang Li
National Clinical Research Center for Oral Diseases, National Center for Stomatology
Guoxin Ren
Department of Oral and Maxillofacial-Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
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. Trial registration ChiCTR2000031608.
