Reference Detail

Ref Type

abstract

PMID

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	Vol	Issue	Date	Pages	Journal Short Title
Ann Oncol	33	suppl_7	2022

URL

https://www.annalsofoncology.org/article/S0923-7534(22)02446-2/fulltext#relatedArticles

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