A phase II study to evaluate the efficacy of regorafenib in C-KIT mutated metastatic malignant melanoma patients who have progressed on first-line treatment: A Multicenter Trial of Korean Cancer Study Group (UN-14–13)

Abstract

Background: C-KIT mutation is a therapeutic target for malignant melanoma, and C-KIT inhibitors such as imatinib have previously shown clinical efficacy. Regorafenib is a 3rd generation inhibitor of C-KIT and demonstrates high response rate in C-KIT mutated gastrointestinal stromal tumor. We evaluated the anti-tumor activity and safety of regorafenib in C-KIT mutated metastatic malignant melanoma patients who have progressed on first-line treatment. Material and methods: We conducted a multicenter phase II clinical trial of regorafenib in patients with metastatic melanoma positive for C-KIT mutations whose disease progressed after at least one line of systemic treatment. C-KIT mutations were analyzed either by quantitative PCR (qPCR) method or next-generation sequencing (NGS). Patients enrolled received oral regorafenib 160 mg once daily for the 3 weeks of each 4-week cycle. The primary endpoint was disease control rate (DCR), and the secondary endpoint was safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Between December 2014 and January 2022, 153 patients were screened for C-KIT mutation and ultimately 23 patients were enrolled and started treatment. Median age was 68 (range, 31–86), with 11 male (47.8%) and 12 female (52.2%) patients. Occurrences in melanoma subtypes included 9 (39.1%) acral, 6 (26.1%) mucosal, and 3 (13.0%) chronic sun-damaged melanomas. The DCR was 73.9%, with 2 patients (8.7%) showing complete response, 5 patients (21.7%) partial response, and 10 patients (43.5%) showing stable disease, and ORR was 30.4% (7/23 patients). Median follow-up duration was 15.2 months (95% confidential interval [CI], 10.0–21.5), and median PFS and OS were 7.0 months (95% CI, 1.5–12.5) and 16.3 months (95% CI, 12.6–19.9), respectively. Screening for C-KIT mutations found exon 11 to be the most common site (14 patients, 60.9%), with other sites including exon 13, 17, and 9 in 5 (21.7%), 5 (21.7%), 2 (8.7%) patients, respectively, and there was no difference of ORR according to the mutation site. Skin reactions including hand-foot syndrome were the most commonly reported adverse event (All grade 60.9%, G3 13.0%). Grade 3 adverse events occurred in 9 patients (39.1%), which included infection, rash, mucositis, and bone marrow suppression, and none of grade 4 toxicities nor treatment-related deaths were observed. Conclusion: In metastatic malignant melanoma harboring C-KIT mutations, regorafenib in second or later line setting demonstrated significant clinical activity in patients, with ORR of 30.4% and DCR of 73.9%. Further biomarker studies with circulating tumor DNA analysis are currently underway.