Selumetinib in adults with NF1 and inoperable plexiform neurofibroma: a phase 2 trial

Abstract

The MEK inhibitor selumetinib induces objective responses and provides clinical benefit in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). To evaluate whether similar outcomes were possible in adult patients, in whom PN growth is generally slower than in pediatric patients, we conducted an open-label phase 2 study of selumetinib in adults with NF1 PNs. The study was designed to evaluate objective response rate (primary objective), tumor volumetric responses, patient reported outcomes, and pharmacodynamic effects in PN biopsies. The objective response rate was 63.6% (21/33 participants). Median maximal PN volume decrease was 23.6% (range: −48.1%-5.5%). No disease progression relative to baseline PN volumes occurred prior to data cut-off with a median of 28 cycles completed (range: 1–78, 28 days/cycle). Participants experienced decreased tumor pain intensity and pain interference. Adverse events (AEs) were similar to those of the pediatric trial; acneiform rash was the most prevalent AE. Phosphorylation ratios of ERK1/2 decreased significantly (ERK1 median change: −64.6% [range: −99.5%-104.3%], ERK2 median change: − 57.7% [range: −99.9%-84.6%]) in paired PN biopsies (P≤0.001 for both isoforms) without compensatory phosphorylation of AKT1/2/3. The sustained PN volume decreases, associated improvement in pain, and manageable AE profile indicate selumetinib provides benefit to adults with NF1 and inoperable PNs.