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Ref Type abstract
Authors E.J. Sherman, F. Tsai, F. Janku, C. Allen, R. Yaeger, N. Ammakkanavar, N. Butowski, G. Michelson, M. Paz, A. Tussay-Lindenberg, K. Wang, S. Shepherd, E. Dehan, M. de la Fuente, J. Rodon
Title 466P Efficacy of BRAF inhibitor FORE8394 in BRAF V600+ patients
Journal Ann Oncol
Vol 33
Issue suppl_7
Date 2022
Abstract Text Abstract 466P Background 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. Methods 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. Results 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 naive 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 naive/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 naive/V600E HGG had cPR. Conclusions 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600X Advanced Solid Tumor predicted - sensitive PLX8394 Phase Ib/II Actionable In a Phase I/IIa trial, PLX8394 resulted in an objective response rate of 20.8% and a clinical benefit rate (CBR) of 35.4% at 24 weeks in advanced solid tumor patients harboring BRAF V600X, and in patients with no prior BRAF/MEK inhibitor therapy (excluding colorectal cancer), resulted in 31.6% (6/19) confirmed partial responses, a CBR of 63.2% (12/19), a median response time of 12.1 weeks, and a median response duration of 13.5 mo (Ann Oncol (2022) 33 (suppl_7): S197-S224; NCT02428712). detail...