Table 2.

Mechanism of action and results of the clinical trials with targeted agents for the treatment of progressive plexiform neurofibromas

Drug	Mechanism of action	Results
Tipifarnib	Farnesyltransferase inhibitor	Patient: 31 patients (median age, 9.7 years; range, 3–21.5 years) treated with tipifarnib, 29 patients treated with placebo (median age, 8.2 years; range, 3–17.7 years)
	- Prevent RAS from binding to the membrane	Treatment: Tipifarnib/placebo administered orally 200 mg/m2/dose after a meal every 12 hours for 21 days followed by a 7-day rest period for 28-day treatment cycles
		Result: The median TTP was 10.6 months on the placebo arm and 19.2 months on the tipifarnib arm (P=0.12; 1-sided).
Pirfenidone	5methyl‐1‐phenyl‐2‐(1H)‐pyridone	Patient: 36 patients (median age, 8.9 years; range, 3–18.8 years), placebo arm from the tipifarnib trial
	- Modulates the expression of growth factors and cytokines that are relevant to fibrosis	Treatment: 500 mg/m2/dose every 8 hours on a continuous dosing schedule for 28‐day treatment cycles
		Result: The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group (2-tailed P=0.92; 1-tailed P=0.46)
Sirolimus	Mammalian target of rapamycin (mTOR) inhibitor	Patient: 29 patients treated with sirolimus (median age, 8.2 years; range, 3–17.7 years), 46 patients treated with placebo (median age, 7.9 years; range, 3–45.4 years)
	- Neurofibromin controls cell growth by negatively regulating mTOR pathway activity	Treatment: Starting dose of sirolimus was 0.8 mg/m2 body-surface area by mouth twice daily for a 28-day course, achieve a trough blood concentration of 10–15 ng/mL
		Result: The estimated median TPP of subjects receiving sirolimus was 15.4 months (95% CI, 14.3–23.7), which was significantly longer than 11.9 months (P<0.001), the median TTP of the placebo
Pegylated interferon α-2b	Type 1 interferons	Patient: 82 patients (median age, 10 years; range, 1.6–21.4 years)
	- have antiproliferative, antiviral, immunoregulatory, and antitumor activities	Treatment: Weekly subcutaneous injection at a dose of 1.0 μg/kg/wk
		Result: Imaging responses (≥20% decrease in volume) in 4 patients (5%)
Imatinib	Tyrosine kinase inhibitor	Patients: 36 patients (median age, 13 years; interquartile range, 7.5–23 years)
	- targeting cellular phosphosignaling cascades in the tumor microenvironment	Treatment: Daily oral imatinib mesylate at 220 mg/m2 twice a day for children and 400 mg twice a day for adults for 6 months
		Results: Six of 36 patients (17%) with a 20% or more decrease in tumor volume.
Selumetinib	Selective mitogen-activated protein kinase kinase inhibitor	Patients: 24 patients (median age, 10.9 years; range, 3.0–18.5 years)
	- targeted inhibition of RAS pathway	Treatment: Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles)
		Result: Partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%)

TPP, time to progression; CI, confidence interval.