TRAM-01: A phase 2 study of trametinib for pediatric patients with neurofibromatosis type 1 and plexiform neurofibromas

BACKGROUND: Plexiform neurofibromas (PNs) are observed in up to 50% of patients with neurofibromatosis type 1 (NF1). Trametinib has been used widely to treat PNs but limited data has been reported on its efficacy within a clinical trial. We conducted a phase 2 trial with trametinib for patients with NF1 and inoperable PNs. METHODS: Patients with NF1 and inoperable PNs aged ≥1 month to ≤25 years when starting trametinib were eligible. Patients received trametinib once daily orally continuously for a maximum of 18 cycles of 28 days. Patients completed patient-reported outcome measures. Response evaluations were performed after cycle 3, 6, 12 and at the end of treatment and then every 6 months. The PN volumes were centrally quantified using a semi-automatic 3D segmentation method. RESULTS: Forty-six patients were recruited. The median age was 11.1 years (range 0.7-19.8). The median baseline tumor volume was 104.6 ml (range 16.3 to 650.1 ml). Volumetric assessment demonstrated an overall response rate (volume decrease of ≥20%) in 47.8% (22/46) of patients. Median volume change was -19.3% (range -80.5 to 3.5). Forty-one patients (89.1%) completed the planned treatment. The 3 years progression free survival and the event free survival were respectively 73.1% (95% CI 53.3%-85.5%) and 47.1% (95% CI 28.8-63.5). CONCLUSIONS: We report outcomes and volumetric response of PNs treated with trametinib within a phase 2 trial. Based on these results, trametinib is effective and overall well tolerated.