Systemic Therapy in Metastatic Melanoma

Selumetinib is a MEK inhibitor that has been compared with dacarbazine and temozolomide with no significant OS advantage. A novel highly specific inhibitor of MEK, cobimetinib, is currently being studied in combination with BRAF inhibitors.

Combined BRAF and MEK Inhibition

A randomized, double-blind, phase 3 study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo in patients with advanced melanoma with a BRAF V600E mutation was presented at the 2014 American Society of Clinical Oncology meeting. Researchers found that after a median follow-up period of 9 months, there was a significant improvement with the combination in the PFS (9.3 months vs 8.8 months) and the ORR (67% vs 51%), with a similar incidence of AEs. ⁵⁶ The combination therapy group had fewer incidences of SCC of the skin but more incidence of pyrexia.

The combination of dabrafenib and trametinib was compared with vemurafenib monotherapy in a recent randomized phase 3 trial among 704 metastatic melanoma patients with a BRAF V600 mutation. Median PFS and ORR were significantly better with combination therapy compared with vemurafenib alone (11.4 months vs 7.3 months, 64% vs 51%, respectively). Overall survival rate at 1 year was significantly improved in the combination group as well (72% vs 65%). ⁵⁷ The incidence of SCC and keratoacanthoma was less in the combination (1%) compared with vemurafenib alone (18%). Another study investigating the coadministration and sequential administration of vemurafenib and trametinib is underway. ⁵⁸

The vemurafenib and cobimetinib combination was studied in a phase 3 trial of previously untreated unresectable locally advanced or metastatic BRAF V600
mutation-positive melanoma. The median PFS was 9.9 months in the combination group and 6.2 months in the control group. The interim analysis showed a 9-month survival rate of 81% in the combination group and 73% in the control group, with no significantly higher incidence of AEs in either arm. ⁵⁹ A longer follow-up will be needed to assess the OS benefit with the combination.

Encorafenib, a selective BRAF inhibitor, has been studied in a phase 1 trial in combination with binimetinib. ⁶⁰ This trial has paved the way to the initiation of a currently ongoing phase 3 trial (NCT01909453) comparing the combination with vemurafenib or encorafenib alone.

C-KIT Inhibitors

Mutations of c-KIT are seen more commonly in chronic sun damage-induced cutaneous melanomas, along with acral and mucosal melanomas. ^61,62 Earlier trials involving patients without selection for c-KIT mutation positivity failed to show benefit with imatinib. A single-arm, phase 2 trial of imatinib mesylate in patients with metastatic melanoma harboring the c-KIT mutation, an ORR of 23% was achieved, with a median PFS of 3.5 months. ⁶³ Imatinib showed an ORR of 29% in a phase 2 trial of mucosal, acral, and in chronic sun damage-induced melanoma patients with c-KIT amplifications and/or mutations. It was demonstrated that c-KIT amplification alone is not as responsive to imatinib compared with c-KIT mutation, suggesting that all patients with these specific melanomas should be tested for KIT mutation status. ⁶⁴

A second-generation c-KIT inhibitor, nilotinib, has shown some promising results with a favorable AE profile in small phase 2 trials.65,66 However, more clinical research will be needed before definite recommendations on its use in cutaneous melanomas can be made. Currently, its role seems to be limited to the management of acral, mucosal, and chronic sun damage-related melanomas with c-KIT mutations.