Retrospective Study of Trametinib in Patients With Advanced <i>NF1</i>-Mutant Melanoma.

Abstract

Neurofibromin 1 (<i>NF1</i>) mutations, the third most common driver mutation in melanoma, occur in approximately 15% of cases and lead to the constitutive activation of the RAF/MAPK pathway, resulting in cell proliferation and survival. MEK inhibitors can inhibit the RAF/MAPK pathway and potentially induce tumor regression. We conducted a retrospective study to evaluate the clinical benefit of trametinib in patients with metastatic melanoma harboring an <i>NF1</i> mutation, using the Institutional Tumor Registry and Melanoma Database. We reviewed the records of all patients with metastatic melanoma whose tumor specimens were analyzed by next-generation sequencing. Among 231 patients whose melanoma was analyzed by next-generation sequencing, 34 (14.7%) had an <i>NF1</i> mutation and four were treated with trametinib. The median age was 77 years; two patients had mucosal melanoma, and two had cutaneous melanoma. Three patients had stage IV disease. All four patients were previously treated with anti-PD1 antibodies, and three were also treated with anti-CTLA4 antibodies. Three (75%) patients experienced initial tumor regression, including one prolonged partial response with a progression-free survival (PFS) duration of 18 months. The other two patients discontinued treatment because of intolerable adverse events, and their tumors subsequently progressed on treatment discontinuation. The median PFS duration was 6 months. Interestingly, the patient with the longest response had the highest variant allele frequency (VAF) of <i>NF1</i>, whereas the early progressor had the lowest VAF. Two of the responders had a primary mucosal melanoma. Despite the small number of patients in our study, our findings suggest the promising activity of trametinib in patients with <i>NF1</i>-mutant melanoma, supporting a rationale for prospective studies of MEK inhibitor therapy.