Efficacy of braf inhibitor plixorafenib (fore8394) in recurrent, primary central nervous system tumors (pcnst)

Abstract Plixorafenib, a selective potent BRAFi, is uniquely designed to disrupt BRAF dimers and evade paradoxical MAPK pathway activation. Thus, it inhibits both V600 and non-V600 BRAF alterations and may be less prone to toxicities and resistance typical of approved BRAFi. An approved BRAFi, when used with MEKi, has ORR 33% with mDOR 13.6=months and ORR=50% with DOR of 6-29 months in V600+ HGG and LGG, respectively (dabrafenib US Prescribing Information, 2023). Phase 1/2a is a single-arm study (NCT02428712) in patients (n=113) with BRAF-altered advanced tumors to assess safety, PK, and efficacy of oral plixorafenib 900-3600 mg/day alone or with cobicistat (CYP3A4/P-gp inhibitor). Symptomatic TEAEs (rash, pyrexia, myalgia) were low grade and infrequent relative to approved BRAFi. This pre-specified analysis (31Mar2023) was in MAPKi-naïve adults with BRAFV600+ PCNST. 22 patients with PCNST received plixorafenib: 9 LGG, 1 glioneuronal tumor (LGG/GNT; 5 V600+), 12 HGG (10 V600+). Treatment-emergent AEs (TEAEs, ≥ 20%) were limited to LFT changes, G1 increased creatinine, fatigue, headache, and nausea. Only one G3 event (increased ALT) occurred at the RP2D (n=7) showing better tolerability than dabrafenib. 10 BRAFV600+ MAPKi-naïve adults with PCNST (median age 45 yrs, 6 females, 9 non-Hispanic) were efficacy evaluable: 6 HGG (4 glioblastoma, 1 epithelioid glioblastoma, 1 anaplastic astrocytoma); 4 LGG/GNT (1 each: ganglioglioma, pilocytic astrocytoma, xanthoastrocytoma, neuroepithelial tumor). Prior anti-cancer treatments included surgery (8/10), radiotherapy (8/10), and systemic therapy (8/10, including temozolomide [n=8], bevacizumab [n=2], carboplatin [n=1], dendritic cell vaccine [n=1]). 1 was treatment-naïve (unresectable; declined radiation/chemotherapy). ORR=60% (6/10) including HGG=67% (4/6), LGG/GNT=50% (2/4); median time to response=1.94 months; 4/6 responders with DOR > 9 months; mPFS=34.1 months; median follow-up=10.3 months; 4/10 ongoing. Plixorafenib has a benign safety profile and leads to a high ORR and durable response in MAPKi-naïve BRAFV600+ PCNST. A phase 2 study is ongoing to confirm these findings (NCT05503797).