A multicenter, open-label, single-arm, phase 1 dose-escalation and phase 2 dose-expansion study to evaluate the safety, tolerability, and anti-tumor activity of FCN-159 in adults with neurofibromatosis type 1.

3011 Background: Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic disease that increases susceptibility to malignant tumors. Up to 50% of patients with NF1 present with plexiform neurofibroma (PN). Surgery, a common treatment strategy for patients with PN, has limited efficacy. NF1 is caused by mutations in the gene that encodes neurofibromin; the NF1 mutation then leads to tumorigenesis via dysregulation of the Ras/Raf/MEK/ERK pathway. FCN-159 is anti-tumorigenic via highly potent, selective inhibition of MEK1/2. This study aims to assess the safety of FCN-159 in patients with NF1-related PN. Methods: This is a multicenter, open-label, single-arm, phase 1 dose-escalation and phase 2 dose-expansion study (NCT04954001). Patients with NF1-related PN that was not completely resectable or not suitable for surgery were enrolled in the study; they received FCN-159 monotherapy continuously in 28-day cycles. Here, we report safety and clinical efficacy data from adults enrolled in phase 1. Results: As of the data cutoff of December 1, 2021, 19 adults from 3 hospitals in China have been enrolled in the phase 1 dose-escalation study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. The most common neurofibroma-related complications were disfigurement and pain, occurring in 10 patients (52.6%) and 4 patients (21.1%) at baseline, respectively. Four patients experienced dose-limiting toxicity; G3 folliculitis was reported in 1 patient (16.7%) receiving the 8-mg dose and 3 (100%) patients receiving the 12-mg dose. The maximum tolerated dose was determined to be 8 mg. Study-drug-related treatment-emergent adverse events (TEAEs) were observed in all 19 patients (100%); the majority were grade 1 or 2 in severity. Nine (47.4%) patients reported grade 3 study drug-related TEAEs; 4 patients experienced paronychia and 5 experienced folliculitis, which were the most common causes of dose reduction (42.1%) and drug interruption (21.2%). One patient experienced a serious adverse event of rhegmatogenous retinal detachment, but this was considered unrelated to the study drug as it was preexisting at baseline. Of the 16 patients with at least 1 post-baseline tumor assessment, all (100%) had reduced tumor size and 6 (37.5%) had a reduction in tumor size of > 20%. Three out of 6 patients with a second tumor assessment result had further tumor shrinkage; tumor volumes in the remaining 3 patients were similar to those at first assessment. The largest reduction in tumor size was 84.2%. Conclusions: Overall, FCN-159 at 8 mg is well tolerated, with easy to manage adverse events, and showed promising anti-neurofibroma activity in phase 1; this warrants further investigation in a phase 2 study on efficacy and safety in this indication. Clinical trial information: NCT04954001.