A Phase 2 Clinical Trial of Trametinib and Low-Dose Dabrafenib in Patients with Advanced Pretreated NRAS(Q61R/K/L) Mutant Melanoma (TraMel-WT)

SIMPLE SUMMARY: MEK-inhibitor monotherapy has activity in advanced NRAS(Q61R/K/L) mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAF(V600E/K) mutant melanoma) has low cutaneous toxicity. We hypothesized that a low dose of the BRAF-inhibitor dabrafenib can mitigate the skin toxicity associated with a full dose of the MEK-inhibitor trametinib in patients with advanced NRAS(Q61R/K/L) mutant melanoma who progressed after treatment with immune checkpoint inhibitors. The results of this two-stage phase 2 trial show that addition of a low dose of dabrafenib effectively mitigates the skin toxicity associated with trametinib. This combination is, however, insufficiently active in patients with advanced NRAS(Q61R/K/L) mutant melanoma. The combination of low-dose dabrafenib plus full-dose trametinib can be of further interest for the treatment of MEK-inhibitor-sensitive tumors. ABSTRACT: Background: MEK-inhibitor monotherapy has activity in advanced NRAS(Q61R/K/L) mutant melanoma but is associated with dose-limiting cutaneous toxicity. The combination of a BRAF- with a MEK-inhibitor at their full dose (as in BRAF(V600E/K) mutant melanoma) has low cutaneous toxicity. It is unknown whether a low dose of BRAF-inhibitor can mitigate the skin toxicity associated with full-dose MEK-inhibitor treatment in patients with advanced NRAS(Q61R/K/L) mutant melanoma. Methods: This two-stage phase 2 clinical trial investigated trametinib 2 mg once daily in patients with advanced NRAS(Q61R/K/L) mutant melanoma who were pretreated with immune checkpoint inhibitors. In case of trametinib-related cutaneous toxicity, low-dose dabrafenib (50 mg twice daily) was added to prevent recurrent cutaneous toxicity (pre-amendment). Following an amendment, trametinib was combined upfront with low-dose dabrafenib (post-amendment). Objective response rate (ORR) served as the primary endpoint. Results: All 6 patients enrolled pre-amendment developed trametinib-related cutaneous toxicity, necessitating treatment interruption. Combining trametinib with low-dose dabrafenib prevented recurrent skin toxicity thereafter. Trametinib-related skin toxicity was effectively mitigated in all 10 patients post-amendment. In all 16 included patients, the ORR and disease control rate was 6.3% (1 partial response) and 50.0%, respectively. The trial was halted after the first stage. Conclusions: Combining full-dose trametinib with low-dose dabrafenib can mitigate MEK-inhibitor-related skin toxicity but was insufficiently active in this patient population. This combination can be of further interest for the treatment of MEK-inhibitor-sensitive tumors.