c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma: a systematic review and one-arm meta-analysis

• Published in: European Journal of Cancer Vol. 157; pp. 348 - 357
• Main Authors: Steeb, Theresa, Wessely, Anja, Petzold, Anne, Kohl, Christoph, Erdmann, Michael, Berking, Carola, Heppt, Markus V.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2021; Elsevier BV; Elsevier Science Ltd
• Subjects: Acral lentiginous melanoma; Adverse events; c-Kit protein; Clinical trials; Confidence intervals; Dasatinib; Dasatinib - administration & dosage; Exons; Exons - genetics; Genomic analysis; Humans; Imatinib; Imatinib Mesylate; Imatinib Mesylate - administration & dosage; Immunotherapy; Inhibitor drugs; Inhibitors; Kinases; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - mortality; Melanoma - pathology; Meta-analysis; Metastases; Metastasis; Mucosa; Mucosal melanoma; Mucous Membrane; Mucous Membrane - pathology; Mutants; Mutation; Nilotinib; Patients; Progression-Free Survival; Protein Kinase Inhibitors; Protein Kinase Inhibitors - administration & dosage; Protein-tyrosine kinase receptors; Proto-Oncogene Proteins c-kit; Proto-Oncogene Proteins c-kit - antagonists & inhibitors; Proto-Oncogene Proteins c-kit - genetics; Pyrimidines; Pyrimidines - administration & dosage; Skin; Skin - pathology; Skin - radiation effects; Skin Neoplasms; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - mortality; Skin Neoplasms - pathology; Subgroups; Sunitinib; Sunitinib - administration & dosage; Sunlight; Sunlight - adverse effects; Tyrosine; Acral lentiginous melanoma; Nilotinib; Dasatinib; Imatinib; Sunitinib; KIT; Mucosal melanoma; Meta-analysis
• ISSN: 0959-8049; 1879-0852; 1879-0852
• DOI: 10.1016/j.ejca.2021.08.015

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. •The therapeutic value of c-Kit inhibitors in rare melanoma subtypes is unclear.•Twenty-one studies with n = 649 patients were identified in a systematic literature research.•Pooled objective response rate was 15% (95% confidence interval: 11–20%) for all c-Kit inhibitors.•Combination of c-Kit inhibitors with immunotherapy should be further investigated.