Efficacy and safety of regorafenib in patients with advanced pretreated melanoma: results of the RegoMel phase II clinical trial

Abstract

Background Most patients with advanced melanoma progress despite standard-of-care treatments. Regorafenib (REGO), an oral multikinase inhibitor with RAF-dimer activity, demonstrated clinical activity in melanoma in retrospective case series and preclinical efficacy in overcoming resistance to BRAF/MEK inhibitors (BRAF/MEKi). This study prospectively evaluated REGO in heavily pretreated advanced melanoma patients. Patients and methods This single-center, phase II clinical trial (RegoMel, NCT05370807) assessed the objective response rate (ORR) upon continuous REGO dosing (40-120 mg daily) in 16 patients with advanced pretreated melanoma, regardless of the melanoma driver mutation. In BRAFV600-mutant patients, BRAF/MEKi addition was permitted upon progression on REGO monotherapy. Based on early efficacy signs, a KIT-mutant expansion cohort was also recruited and analyzed. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results There was one complete (BRAFV600-mutant) and five partial responses [KIT- (n = 3), BRAFV600-mutant (n = 2); ORR 37.5%; disease control rate (DCR) 56%]. Median duration of response was 37.4 weeks with median PFS (mPFS) and mOS of 12.1 weeks and 75.8 weeks, respectively. In the KIT-mutant expansion cohort (N = 9), ORR and DCR were 78% and 100%, respectively, and mPFS 43.4 weeks; mOS was not reached. Six BRAFV600-mutant patients received REGO + BRAF/MEKi at first progression (ORR 33%, DCR 83%, mPFS 20.4 weeks, mOS 62.1 weeks). Grade 3 treatment-related adverse events (TRAEs) occurred in 59% of patients on REGO monotherapy and 50% on REGO + BRAF/MEKi. The most common TRAEs were hand-foot-skin reaction, hypertension, and diarrhea. All TRAEs were reversible. Conclusion This phase II clinical trial met its primary endpoint, demonstrating clinically meaningful antitumor activity and manageable toxicity with continuous daily REGO in advanced pretreated melanoma. The unprecedented high response rates in KIT-mutant melanoma and encouraging activity in BRAFV600-mutant patients receiving REGO + BRAF/MEKi support further investigation of REGO-based regimens in these subpopulations of melanoma patients.