CTP-08. Efficacy and tolerability of mirdametinib (PD-0325901) in children, adolescents, and young adults with recurrent/progressive low-grade glioma: update from the SJ901 (NCT04923126) phase 1/2 clinical trial

Abstract BACKGROUND SJ901 trial was designed to determine the recommended Phase 2 dose (RP2D), safety, and efficacy of mirdametinib, an oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration, in patients with pediatric low-grade glioma (pLGG). METHODS Participants were ≥2 and <25 years, MEKi-naive with recurrent/progressive pLGG and biopsy-proven MAPK pathway activation (excluding BRAF V600). Three dose levels (2.0, 2.5, and 3.0 mg/m2/dose) of mirdametinib given twice daily on a continuous schedule over 24 months were evaluated in a rolling-six design. An expansion at the highest tolerated dose level was used to define the RP2D in 12 patients and, once declared, an additional 12 patients were evaluated to determine efficacy in a total of 24 patients. Efficacy was defined as ≥ 50% reduction (partial response) sustained over 8 weeks observed anytime on active treatment. RESULTS Between June 2021 and December 2024, 35 patients were enrolled: 5 on 2.0mg/m2, 6 on 2.5mg/m2 and 24 on 3.0mg/m2. The median age was 8.4 years (2.4-21.9). Alterations were seen in BRAF (n=23;66%), FGFR1 (n=6;17%), NF1 (n=3;8%), RAF1 (n=2;6%), and MYB (n=1;3%). As of May 2025, data cutoff, 15(43%) remain on-therapy, 14(40%) completed therapy, and 6(17%) stopped prematurely (4 progressions, 2 toxicity). One DLT was observed (grade-3 thrombocytopenia). Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity occurred. To date, 26(74%) achieved objective responses per RAPNO-LGG criteria (2 complete, 3 major, 10 partial, 11 minor) with a median time to response of 5.4 months (1.7-24.1). Efficacy was demonstrated in 4(36%) of the 11 patients treated with 2.0 and 2.5 mg/m2/dose and 9(38%) of 24 patients treated with 3.0mg/m2 (declared RP2D). Eleven (79%) of 14 patients who have completed therapy remain off therapy. CONCLUSIONS Mirdametinib in patients with pLGG shows promising clinical activity and is well tolerated. Greater than one-third of patients treated at 3mg/m2/dose (declared RP2D) have already met efficacy criteria.