Efficacy and Safety of Tunlametinib in Adults with Inoperable Neurofibromatosis Type 1–Associated Plexiform Neurofibromas: Phase IIa Trial and Biomarker Research

PURPOSE: Plexiform neurofibromas (PN) present a significant clinical challenge, with a notable unmet need for effective and well-tolerated therapies, particularly for the adult population. PATIENTS AND METHODS: A single-arm, open-label, phase IIa trial of tunlametinib was conducted to assess its efficacy and safety in adults with inoperable, radiologically measurable PN. Patients received tunlametinib at a dose of 9 mg twice daily, following a continuous 21-day cycle regimen. The primary endpoint was the confirmed objective response rate (ORR), and secondary endpoints included disease control rate, duration of response, progression-free survival, and improvements in patient-reported outcomes (PRO) compared with baseline. Exploratory analyses integrating clinical variables and single-cell transcriptomic profiles were performed to explore response heterogeneity. RESULTS: Of 15 adults (10 males and five females; median age, 27 years; range, 18-45), eight patients achieved a confirmed partial response, with an ORR of 53.3% (95% confidence interval, 26.69-78.73) and a median neurofibroma volume reduction of -23.5% (range, 1.6% to -49.1%). Significant improvements in multiple PRO domains were observed, including Patients' Global Impression of Change and the Plexiform Neurofibromas Quality of Life scale. Regarding safety, all patients experienced at least one treatment-related adverse event, the majority of which were grade 1 or 2. Single-cell RNA sequencing profiling of pretreatment biopsies from one rapid responder and two gradual responders revealed substantial microenvironmental heterogeneity. CONCLUSIONS: Tunlametinib demonstrated promising efficacy and an acceptable safety profile in adults with PN, broadly aligning with the prior PN trials, including selumetinib and mirdametinib.