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- Title
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.
- Authors
Shi, Chaoji; Ju, Houyu; Zhou, Rong; Xu, Shengming; Wu, Yunteng; Gu, Ziyue; Wang, Ying; Chen, Wanling; Huang, Xinyi; Han, Yong; Sun, Shuyang; Li, Chuwen; Wang, Min; Zhou, Guoyu; Zhang, Zhiyuan; Li, Jiang; Ren, Guoxin
- 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.
- Subjects
BRAF genes; CYCLIN-dependent kinase inhibitors; CYCLIN-dependent kinases; DACARBAZINE; LEUKOCYTE count; MELANOMA
- Publication
BMC Medicine, 2024, Vol 22, Issue 1, p1
- ISSN
1741-7015
- Publication type
Article
- DOI
10.1186/s12916-024-03431-x