466P Efficacy of BRAF Inhibitor FORE8394 in BRAF V600+ Patients

FORE8394 is a selective, potent BRAFi (class 1, 2 including fusions). By disrupting BRAF dimers, FORE8394 evades paradoxical MAPK pathway activation and may be less prone to toxicities & resistance typical of 1st generation BRAFi. This is an ongoing phase I/IIa single-arm, open label study in patients (pts) with advanced tumors with activating BRAF alterations to assess safety, PK, & efficacy in pts with ≥1 post baseline assessment (mITT). Pts received oral FORE8394 900-3600 mg/day alone or with cobicistat (CYP3A4/P-gp inhibitor) to increase exposure. The majority of FORE8394 doses were 450-900 mg BID. This interim analysis was in adults (≥18 yrs) with V600+ advanced solid & central nervous system (CNS) tumors. To date, 94 pts received ≥1 dose of FORE8394 (median age [range] 58 yr [4,86]). Median lines of therapy were 2 (0, 9). 10/94 have been on treatment for >2 yrs. Clinically relevant exposures were achieved, suggesting a wide therapeutic window. Symptomatic adverse events (AEs) were low grade. AEs (≥20%) were reversible hepatic lab changes (mainly in first 2 cycles), fatigue, nausea, diarrhea, & vomiting. AEs ≥Grade 3 (≥5%) were increased ALT (10.6%), increased bilirubin (6.4%), hyponatraemia (5.3%), with no secondary skin malignancies or acanthomas. 48 pts were V600+ (mITT), including 14 (29%) with colorectal cancer (CRC, 1 confirmed partial response [cPR]); 4/48 V600 K/M (0 cPR). Objective response rate (ORR) = 20.8%; clinical benefit rate (CBR) = 35.4% at 24 weeks. 19 pts with no prior BRAFi/MAPKi (excluding CRC) included: 6 papillary thyroid cancer (PTC), 4 anaplastic thyroid cancer (ATC), 3 high grade glioma (HGG), and others; 2/19 V600K/M (ATC, pancreas). cPR = 31.6% (6/19), CBR = 63.2% (12/19), median response time = 12.1 wks; median response duration = 13.5 mo. Of 6 BRAFi/MAPKi naïve pts with V600+ PTC, median progression free survival (PFS) not reached (median follow-up 4.9 yrs); 4 received FORE8934 ≥2 yrs, including 1 cPR (PFS 6.3+ years). 2/3 ATC pts (BRAFi naïve/V600E) were on FORE8394 >2 yrs: PFS 2.4 yrs (cPR, SOD -63%) & PFS 3.4 yrs (SD, SOD -28%). 3/3 pt with BRAFi naïve/V600E HGG had cPR. FORE8394 achieved clinically relevant exposures, low rate of symptomatic AEs, and high ORR & durable PFS in BRAFi/MAPKi naïve pts with BRAFV600 solid & CNS tumors. NCT02428712.