Regorafenib Produces High Response and Durable Disease Control in KIT-Mutant Advanced Melanoma

Clinical Summary: 

• Design/Population: The single-center, phase 2 RegoMel trial evaluated continuous daily regorafenib in heavily pretreated patients with advanced melanoma regardless of driver mutation, with an additional KIT-mutant expansion cohort.
• Key Outcomes: Regorafenib met its primary end point, demonstrating clinically meaningful antitumor activity in advanced melanoma. The greatest activity was observed in KIT-mutant melanoma, with high objective response and disease control rates. Regorafenib plus BRAF/MEK inhibitors also demonstrated activity in patients with BRAFV600-mutant melanoma following progression on prior BRAF/MEK inhibitors.
• Clinical Relevance: These findings support further investigation of regorafenib-based strategies in molecularly selected melanoma, particularly KIT-mutant disease and BRAFV600-mutant melanoma with acquired resistance to BRAF/MEK inhibitors.

Results from the phase 2 RegoMel trial demonstrated that continuous daily regorafenib produced clinically meaningful antitumor activity with manageable toxicity in heavily pretreated patients with advanced melanoma.

“Most patients with advanced melanoma progress despite standard-of-care treatments,” stated Iris Dirven, MD, PhD, Vrije Universiteit Brussels, Belgium, and coauthors. “Regorafenib, 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.” 

In this single-center, investigator-initiated trial, 16 patients with advanced melanoma received continuous daily regorafenib at doses ranging from 40 mg to 120 mg. Patients with BRAFV600-mutant melanoma were permitted to add BRAF/MEK inhibitors at disease progression on regorafenib monotherapy. Following early efficacy signals, investigators enrolled an additional KIT-mutant expansion cohort (n = 9). The primary end point was the confirmed objective response rate (ORR). Secondary end points included disease control rate, duration of response, progression-free survival (PFS), overall survival (OS), and safety.

In the initial cohort, regorafenib achieved an ORR of 37.5%, including 1 complete response and 5 partial responses. The disease control rate was 56%, median duration of response was 37.4 weeks, median PFS was 12.1 weeks, and median OS was 75.8 weeks.

The greatest activity was observed in the KIT-mutant expansion cohort, where the ORR was 78% and the disease control rate was 100%. Median PFS was 43.4 weeks, and median OS was not reached.

Among the 6 patients with BRAFV600-mutant melanoma who received regorafenib plus BRAF/MEK inhibitors after progression on regorafenib monotherapy, the ORR was 33% and the disease control rate was 83%. Median PFS was 20.4 weeks, and median OS was 62.1 weeks.

Grade 3 treatment-related adverse events occurred in 59% of patients receiving regorafenib monotherapy and 50% of those receiving regorafenib plus BRAF/MEK inhibitors. The most common treatment-related adverse events included hand-foot skin reaction, hypertension, and diarrhea. No grade 4 or 5 treatment-related adverse events were reported, and all treatment-related serious adverse events resolved following treatment interruption.

“This prospective phase 2 clinical trial evaluating [regorafenib] monotherapy in advanced pretreated melanoma met its primary end point and demonstrated high antitumor activity,” concluded Dr Dirven et al. “A phase 2 clinical trial evaluating [regorafenib] BRAF/MEKi in BRAFV600-mutant melanoma and a prospective phase 2 clinical trial in KIT-mutant melanoma have been initiated to confirm these findings.”

Source: 

Dirven I, Bertels C, Moreels Y, et al. Efficacy and safety of regorafenib in patients with advanced pretreated melanoma: results of the RegoMel phase II clinical trial. ESMO Open. Published online: April 9, 2026. doi: 10.1016/j.esmoop.2026.106941