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 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.
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.
Clinical trial identification
Protocol # PLX120-03, 25 March 2019 NCT02428712.
Editorial acknowledgement
Guissou Dabiri, PhD GD Scientific & Medical Writing, LLC Wynnewood, Pennsylvania USA.
Legal entity responsible for the study
Fore Biotherapeutics, Inc.
Funding
1.
Disclosure
E.J. Sherman: Financial Interests, Personal, Advisory Board: Eisai, Roche, Regeneron, Exelixis, Bayer; Financial Interests, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Regeneron; Financial Interests, Institutional, Invited Speaker, Also Local PI: Eli Lilly; Non-Financial Interests, Principal Investigator, PI of randomized study in thyroid cancer: novartis. F. Tsai: Financial Interests, Personal, Advisory Board: Aptitude; Financial Interests, Personal, Stocks/Shares: Salarius; Other, Co-Founder: Caremission LLC. F. Janku: Financial Interests, Personal, Advisory Board: Cardiff Oncology, Immunomet, MedinCell, Mersana Therapeutics, Synlogic, Fore Bio, Crown Bioscience; Financial Interests, Personal, Full or part-time Employment: Monte Rosa Therapeutics; Financial Interests, Personal, Stocks/Shares: Monte Rosa Therapeutics, Cardiff Oncology, Moderna, Pfizer, Globus Med Inc. C. Allen: Financial Interests, Personal, Advisory Board, Participation in Scientific Steering Committee and Advisory Boards for emapalumab trials and related studies.: Sobi; Financial Interests, Personal, Advisory Board: Atara; Financial Interests, Invited Speaker, Support for Investigator Initiated Trial.: Genentech; Financial Interests, Invited Speaker, Local PI for study on which abstract is based.: Fore Bio. R. Yaeger: Financial Interests, Personal, Advisory Board: Pfizer, Natera, Mirati Therapeutics; Financial Interests, Institutional, Invited Speaker: Mirati Therapeutics, Boehringer Ingelheim, Pfizer. N. Ammakkanavar: Financial Interests, Institutional, Invited Speaker: Bristol Myer Squibb; Financial Interests, Institutional, Advisory Board: AstraZeneca, Sanofi. G. Michelson: Financial Interests, Invited Speaker: fore; Financial Interests, Personal, Other, medical consultant: Fore Biotherapeutic; Non-Financial Interests, Other, medical consultant: Fore Biotherapeutics. M. Paz: Financial Interests, Personal, Full or part-time Employment: FORE Biotherapeutics; Financial Interests, Personal, Stocks/Shares: FORE Biotherapeutics. A. Tussay-Lindenberg: Financial Interests, Personal, Full or part-time Employment, AD, Clinical Data Management: Fore Bio; Non-Financial Interests, Project Lead, AD, Clinical Data Management: Fore Bio; Non-Financial Interests, Personal, Proprietary Information, AD, Clinical Data Management: Fore Bio. K. Wang: Financial Interests, Personal, Full or part-time Employment: Fore Bio; Financial Interests, Personal, Stocks/Shares: Fore Bio. S. Shepherd: Financial Interests, Personal, Full or part-time Employment: QED Therapeutics / BridgeBio; Financial Interests, Personal, Full or part-time Employment, Chief Medical Officer: Fore Biotherapeutics; Financial Interests, Personal, Stocks/Shares: Abbott, AbbVie, BridgeBio, Fore BIotherapeutics. E. Dehan: Financial Interests, Personal, Full or part-time Employment: Fore Biotherapeutics. M. de la Fuente: Financial Interests, Personal, Advisory Board: Forma Therapeutics, Agios; Non-Financial Interests, Other, Co-Chair, WDC: Society for Neuro-Oncology. J. Rodon: Financial Interests, Personal, Advisory Board: Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners, IONCTURA SA; Financial Interests, Institutional, Other, Clinical Research: Bayer, Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GlaxoSmithKline; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics; Other, Other: VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC; Other, Travel Reimbursement: European Society for Medical Oncology. All other authors have declared no conflicts of interest.