Trametinib in Adults with Neurofibromatosis Type 1-Related Symptomatic Plexiform Neurofibromas.
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OBJECTIVE: Mitogen-activated protein kinase kinase inhibitors have shown promising results in treatment of plexiform neurofibromas in neurofibromatosis type 1 patients, but data in adults are limited. The aim of this phase 2 study was to investigate the efficacy and safety of trametinib in adults with neurofibromatosis type 1. METHODS: Thirty patients with a diagnosis of generalized or mosaic neurofibromatosis type 1 and a symptomatic inoperable plexiform neurofibroma were treated with 2mg trametinib per day. Primary outcome measures were partial response rate on tumor volume at cycle 12 and overall partial response rate. Partial response was defined as ≥20% decrease in tumor volume compared to baseline as measured with 3-dimensional volumetric analysis on magnetic resonance imaging every sixth cycle. Secondary outcome measures were pain, pain interference, quality of life, and toxicity. RESULTS: Partial response rate after cycle 12 was 47% (n = 14/30). Overall partial response rate was 50% (n = 15/30). Median best response was -22% decrease of tumor volume (range: -63 to +7%), and median time until best response was 12 cycles (range: 6-42 cycles). Pain score and pain interference were significantly decreased after 12 cycles of treatment. No change in quality of life was reported. Acneiform rash and fatigue were the most reported adverse events. Overall rate of treatment discontinuation because of adverse events was 40%. INTERPRETATION: We observed a positive effect of trametinib on tumor volume and significant pain reduction in adults with plexiform neurofibromas. However, adverse events are common and frequently led to early termination of treatment. ANN NEUROL 2026;99:73-83.