Outcomes of patients with advanced NF1-mutant melanoma treated with MEK inhibitors.

Abstract

e21513 Background: Mutations in neurofibromin 1 ( NF1) constitute the third most frequent driver mutation in melanoma, occurring in approximately 15% of patients. NF1 is a tumor suppressor gene that negatively regulates the MAPK pathway by inactivating RAS through the hydrolysis of RAS-GTP to the inactive form, RAS-GDP. Preclinical studies have demonstrated that NF1 mutations induce the activation of the MAPK pathway through constitutively maintaining the active form of RAS protein, and that MEK inhibitors cause growth arrest of NF1-mutant melanoma in vitro and tumor regressions in vivo. Methods: We conducted a retrospective analysis to evaluate the outcomes of patients with NF1-mutant melanoma who were treated with MEK inhibitors using our institutional melanoma database. We searched for all melanoma patients whose melanoma was analyzed with next generation sequencing (NGS), and their clinical, pathological and molecular characteristics were examined along with the details of MEK inhibitor treatment and clinical outcomes. Results: Among 229 patients whose melanoma was analyzed with the NGS, we identified 32 patients whose melanoma harbored a pathogenic or likely pathogenic NF1 mutation, of which four were treated with trametinib. The clinical, molecular characteristics and the outcomes of the 4 patients are summarized in the table. All had previously experienced disease progression following anti-PD1 antibody therapy. One patient with metastatic mucosal melanoma had a confirmed partial response to trametinib treatment with time to progression of 18 months. Two patients had regression of the metastatic lesions at the initial tumor response evaluation, but due to significant toxicity, treatment was discontinued. Their disease progressed within 3 months after treatment discontinuation. Two patients with initial tumor regression had a mucosal primary melanoma. Interestingly, the patient with a prolonged response had the highest variant allele frequency (VAF) of NF1 whereas the early progressor had the lowest VAF (Table). All responders (including the unconfirmed responders) had a VAF of >35%. Conclusions: Despite the small sample size, our findings suggest a potential promising efficacy of trametinib in the setting of NF1-mutant melanoma, particularly those with high allelic frequency, thereby providing a strong rationale for a prospective study to evaluate the clinical efficacy of MEK inhibitors in this molecular subtype of melanoma. [Table: see text]