Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen - European Metropolitan Region of Nuremberg, Erlangen, Germany.
Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.
Eur J Cancer. 2021 Nov;157:348-357. doi: 10.1016/j.ejca.2021.08.015. Epub 2021 Sep 22.
Activating genomic alterations of the receptor tyrosine kinase KIT are found preferentially in certain melanoma subtypes such as acral and mucosal melanoma or melanoma arising in chronically sun-damaged skin. However, the therapeutic value of c-Kit inhibitors for these subtypes currently remains unclear.
The objective of this study was to summarise the efficacy and safety of c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma.
We performed a systematic literature research in MEDLINE, Embase and CENTRAL and hand searched pertinent trial registers and conference abstracts for eligible trials until 23rd June 2020. Results were pooled using a random-effects model to calculate pooled proportions of objective response rates (ORRs) and severe adverse events (sAEs) from unselected KIT mutant or amplified cohorts.
Nineteen single-arm studies with an overall sample size of 601 patients were included. The studies investigated imatinib (n = 8), nilotinib (n = 7), dasatinib (n = 3) and sunitinib (n = 1). The pooled ORR for all inhibitors was 15% (95% confidence interval [CI]: 12-18%). Subgroup analysis revealed the highest ORR (20%; 95% CI: 14-26%) for nilotinib. The ORR for mucosal melanoma was 14% (95% CI: 6-24%) and 22% for acral lentiginous melanoma (95% CI: 14-30%). At least one sAE was reported in 42% of patients (95% CI: 34-50%).
c-Kit inhibitors represent a valuable treatment option for patients with KIT-mutant melanoma, in particular for mutations of exons 11 and 13. Furthermore, high-quality trials are urgently needed to investigate putative combinations of specific targeted therapies with immunotherapy.
受体酪氨酸激酶 KIT 的激活基因改变主要存在于某些黑色素瘤亚型中，如肢端和黏膜黑色素瘤，或发生于慢性日光损伤皮肤的黑色素瘤。然而，目前 c-Kit 抑制剂对这些亚型的治疗价值尚不清楚。
本研究旨在总结 c-Kit 抑制剂在不可切除或转移性黏膜、肢端或慢性日光损伤黑色素瘤中的疗效和安全性。
我们在 MEDLINE、Embase 和 CENTRAL 进行了系统的文献检索，并对手头的试验登记册和会议摘要进行了手工搜索，以获取合格试验的相关信息，检索截止日期为 2020 年 6 月 23 日。我们使用随机效应模型汇总结果，以计算来自未选择 KIT 突变或扩增队列的客观缓解率（ORR）和严重不良事件（sAE）的汇总比例。
纳入了 19 项单臂研究，共 601 例患者。这些研究分别考察了伊马替尼（n = 8）、尼洛替尼（n = 7）、达沙替尼（n = 3）和舒尼替尼（n = 1）。所有抑制剂的汇总 ORR 为 15%（95%置信区间 [CI]：12-18%）。亚组分析显示，尼洛替尼的 ORR 最高（20%；95% CI：14-26%）。黏膜黑色素瘤的 ORR 为 14%（95% CI：6-24%），肢端黑色素瘤为 22%（95% CI：14-30%）。至少有 1 例 sAE 报告发生在 42%的患者中（95% CI：34-50%）。
c-Kit 抑制剂是 KIT 突变黑色素瘤患者的一种有价值的治疗选择，尤其是对外显子 11 和 13 的突变。此外，迫切需要高质量的试验来研究特定靶向治疗与免疫治疗的潜在联合应用。
