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Background c-KIT mutations are found in approximately 15% of the patients with malignant melanoma; agents such as imatinib have previously shown high response rates. Regorafenib, an oral multikinase inhibitor, acts against wild-type and mutant KIT. This multi-institutional phase II single-arm study aimed to evaluate the efficacy of regorafenib against metastatic malignant melanoma harboring the c-KIT mutation.Methods Patients with recurrent/metastatic melanoma positive for c-KIT mutations, whose disease progressed after at least one line of systemic treatment, were eligible. The patients received oral regorafenib 160 mg once daily for 3 weeks (4-week cycle). The primary endpoint was the disease control rate (DCR), and the secondary endpoints were safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results In all, 153 patients were screened for c-KIT mutations and 23 patients were enrolled (December 2014–January 2022). c-KIT mutations were frequently reported in exon 11 (14/23, 60.9%), followed by exons 13, 17, and 9 in 5 (21.7%), 5 (21.7%), and 2 (8.7%) patients, respectively. The DCR at 8 weeks was 73.9%, with 2 patients (8.7%) achieving CR, 5 (21.7%) achieving PR, and 10 (43.5%) showing stable disease. The ORR was 30.4% (7/23). The median follow-up period was 15.2 months (95% confidence interval [CI], 10.0–21.5), and median OS and PFS were 21.5 months (95% CI, 15.1–27.9) and 7.1 months (95% CI, 5.0–9.2), respectively. Circulating tumor DNA (ctDNA) analysis in selected patients showed high c-KIT correlation (85.7%) with tissue-based tumor mutational profiles. Skin reactions, including Palmar-plantar erythrodysesthesia (52.2%) and skin rash (30.4%) were the most common adverse events (AEs). Grade 3 AEs, including infection, rash, mucositis, and marrow suppression, occurred in 9 patients (39.1%).Conclusion Regorafenib in second- or later-line settings demonstrated significant activity in patients with metastatic melanoma harboring c-KIT mutations, with an ORR of 30.4% and DCR of 73.9%.Trial registration ClinicalTrials.gov NCT02501551, registered Jul 17, 2015. |
