Abstract
BACKGROUND: Selumetinib is approved in children aged ≥ 2 years (USA) with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN) based on data from SPRINT (NCT01362803). This analysis estimated PN progression risk with selumetinib in SPRINT versus age-matched patients from the National Cancer Institute NF1 Natural History (NH) study (NCT00924196), accounting for differences in baseline characteristics using propensity score (PS) methods. METHODS: Differences in baseline characteristics between the cohorts were assessed. PSs based on age, sex, race, weight, height, and PN (location, volume, and progression status) were used in 1:1 PS matching without replacement, stabilized inverse probability of treatment weighting (sIPTW), and 1:2 PS matching with replacement as sensitivity analyses. The effect of selumetinib (maximum follow-up 5.6 years) on progression risk was evaluated using univariate and multivariable Cox models (adjusted for baseline characteristics) of progression-free survival. RESULTS: Before PS matching, patient baseline characteristics (n = 50 SPRINT; n = 75 NH) were generally balanced (standardized difference ≤ 0.2), except PN location (0.51) and PN status (0.60). Following 1:1 PS matching (n = 37), all characteristics were balanced except PN status (standardized difference 0.25). Balance was achieved with sIPTW and 1:2 PS matching (n = 46:43). Progression-free survival hazard ratios (95% confidence interval) were 0.11 (0.05-0.25), 0.11 (0.04-0.29), 0.12 (0.06-0.25), and 0.11 (0.06-0.24) (all P < .001) for direct comparison, 1:1 PS matching, sIPTW, and 1:2 PS matching, respectively. CONCLUSIONS: Reduction in risk of NF1-related PN progression with selumetinib was consistent with direct comparison and statistically significant, robust, and comparable across PS methods. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01362803. Registered May 27, 2011, https://clinicaltrials.gov/study/NCT01362803.