Effect of Food on Selumetinib Dosing for Adolescent Patients With Neurofibromatosis Type 1 With Plexiform Neurofibromas

According to a phase 1 study, the dosing of selumetinib with a low-fat meal, instead of the previously advised fasted state, had no clinically relevant impact on selumetinib exposure or gastrointestinal (GI) tolerability among adolescent patients with neurofibromatosis type 1 with plexiform neurofibromas (NF1-PN).

The potent, highly selective MEK1/2 inhibitor selumetinib is FDA-approved for the treatment of patients aged ≥ 2 years. Initially, the approved label required selumetinib to be taken on an empty stomach, with no food at least 2 hours prior and 1 hour after each dose. Previous food effect studies have shown that while consumption of a high-fat meal may reduce the rate of absorption of selumetinib, the amount of reduction was not clinically relevant. Additionally, previous studies have shown GI adverse events are commonly associated with selumetinib, most frequently including vomiting, abdominal pain, diarrhea, and nausea.

This single-arm phase 1 study analysis includes 24 patients aged ≥12 to <18 years with NF1-PN. After an initial 28-day screening period, patients received 25 mg/m2 selumetinib twice daily, with approximately 12 hours between each dose. For 28 days, patients received selumetinib with a meal consisting of approximately 500 calories with <15g of fat (fed treatment period). After a 7-day washout period, patients received selumetinib in a fasted state, wherein patients did not eat or drink (excluding water) for 2 hours before the dose and for 1 hour after the dose (fasted treatment period). The primary objectives were evaluation of the effect of the low-fat meal on the absorption of selumetinib and of GI tolerability after multiple selumetinib doses.

There were no notable differences in the area under the curve from 0 to 12 hours after selumetinib administration at steady-state (AUC0-12,SS) in the fed or fasted treatment period. The incidence of GI adverse events was similar in both treatment periods. There were 7 participants who reported any GI adverse events in the fed treatment period, 3 of whom also reported GI adverse events during the fasted treatment period. There were 8 patients who reported ≥ 1 GI adverse event in the fasted treatment period. No grade ≥3 GI adverse events occurred during this study, and there were no serious GI adverse events or GI adverse events which led to treatment interruption, discontinuation, or dose reduction. The most common GI adverse events of any grade, occurring in >5%, of patients were vomiting (12.5% in both fed and fasted periods), nausea (8.3% in fed, 12.5% in fasted), and diarrhea (8.3% in fed, 4.2% in fasted).

Study authors concluded, “Based on the contribution of these data, patients can now take selumetinib with or without food, without compromising [pharmacokinetics] or GI tolerability,” adding that this flexibility could improve adherence to treatment “as fasting can be burdensome for young patients.”

Source:

Viskochil D, Wysocki M, Learoyd M, et al. Effect on food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas. Neuro-Oncology Advances. 2024;6(1). doi:10.1093/noajnl/vdae100