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.
Authors: Hu Xiaojie , Zeng Kang , Li Wenbin , Li Yanling , Tao Juan , Xu Zhongyuan , Li Changxing , Kang Zhuang , Ma Yaohui , Yang Liu , Wu Zhuli , Han Pu , Lin Hongmei , Zhong Wen , Hui Ai-Min , Wang Xingli , Lin Xiaoxi 
Published: June 2023

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Background: Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disease characterized by elevated RAS-mitogen activated protein kinase (MAPK) signaling that causes tumors to grow along the nerves. There is currently no medical cure for adult patients (pts). Plexiform neurofibromas (PN) is present in 20-50% of NF1 pts and may cause serious complications. FCN-159 is a highly potent anti-tumorigenic agent that functions via selective inhibition of MEK1/2. This study assessed the safety and efficacy of FCN-159 in adult NF1 pts with PN. Methods: This was a multi-center, open-label, single-arm phase 1 dose-escalation (data have been published in ASCO 2022, abstract no. 3011) and phase 2 dose-expansion study. Participants with NF1-related PN that was not completely resectable or not suitable for surgery were enrolled in the study to receive FCN-159 monotherapy continuously on a 28-day cycles. Herein, we report the safety and clinical efficacy of adult participants in both phase 1 and phase 2. Results: As of November 21, 2022, 82 pts were enrolled, including 19 pts in phase 1 and 63 pts in phase 2. The median follow-up was 10.2 months (range 9.4-11.0 months) at the data cut-off. All pts received more than one dose of FCN-159 and 78 had at least one tumor assessment based on REiNS critiera. A total of 26 (33%) pts had achieved partial response (PR) as best response, 51 (65%) pts had stable disease (SD), and only one pt was not evaluable for not meeting the minimum SD requirement of at least 16 weeks. The overall response rate (ORR) was 31.7% (95% CI: 21.9-42.9%). After 6-8 cycles of treatment, 68.2% (15/22) of pts with definite tumor pain (NRS-11 score≥2 points) at baseline had a decrease in pain intensity of at least 2 points at C7/C9 assessment. Pain scores decreased by an average of 2.7 points across all 22 pts. A total of 82 (100%) pts experienced treatment emergent adverse events (TEAEs). The most common TEAEs (≥ 20%) included folliculitis (69.5%), mouth ulcer (47.6%), diarrhea (41.5%), paronychia (41.5%), alopecia (32.9%), elevated lactate dehydrogenase (30.5%), elevated alkaline phosphatase (29.3%), tricuspid insufficiency (26.8%), and mitral insufficiency (26.8%). The most common grade ≥3 TEAEs were folliculitis (25.6%), paronychia (4.9%). There were no grade ≥ 4 treatment-related adverse events. One pt (1.2%) experienced a serious adverse event (duodenal ulcer) considered related to the study drug. 9.8% reported TEAEs leading to dose reductions, and 12.2% reported TEAEs leading to discontinuation. No death occurred during the study. Conclusions: Overall, FCN-159 has a manageable safety profile and demonstrated evidence of anti-tumor activity in the adult population with NF1-related PN. These promising findings warrant further investigation with long-time follow-up. Clinical trial information: NCT04954001 .