PLX8394, a second generation BRAF inhibitor, does not induce paradoxical activation and blocks signaling from both monomeric BRAFV600 and dimeric BRAFnon-V600 alterations.
A phase I/II study of oral PLX8394 with or without an oral CYP3A4 inhibitor, cobicistat (150 mg daily) to enhance systemic exposure, enrolled patients (pts) with advanced solid tumours to establish recommended phase II dose (R2PD) and dose-limiting toxicities (DLT). Dynamic changes in plasma ctDNA using droplet digital PCR (ddPCR) and targeted next-generation sequencing (NGS) were compared to treatment outcomes.
69 pts (BRAFV600, 43; BRAFnon-V600, 17; non-BRAF, 9; colorectal cancer, 30%; melanoma, 14%) were treated with escalating doses of PLX8394 (450-1,800 mg BID) with or without cobicistat. Grade 3 (G3) AST elevation (900 mg BID) was the only DLT. Other
PLX8394 and cobicistat demonstrated a favorable safety profile and encouraging activity in patients with advanced cancers with BRAF class I and II alterations. Dynamic changes in ctDNA were predictive of clinical outcomes.
NCT02428712.
Plexxikon.
Plexxikon.
E.J. Sherman: Advisory/Consultancy, Research grant/Funding (institution): Regeneron; Advisory/Consultancy: Eisai; Advisory/Consultancy: Novartis; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Lilly. A. Parikh: Advisory/Consultancy: Natera; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy: Puretech; Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Guardant Health; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Array; Research grant/Funding (institution): Tesaro. S. Kummar: Advisory/Consultancy: Bayer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: HarbourBioMed; Advisory/Consultancy: Genome & Company; Advisory/Consultancy: Springworks Therapeutics; Advisory/Consultancy: Corvus Pharmaceuticals; Advisory/Consultancy: Varian; Leadership role, Co-Founder: PathomIQ . C. Zhang: Leadership role, Full/Part-time employment: Plexxikon. P. Severson: Full/Part-time employment: Plexxikon. K. Inokuchi: Full/Part-time employment: Plexxikon. M. Silverman: Advisory/Consultancy: Plexxikon. G. Bollag: Leadership role, Full/Part-time employment: Plexxikon. F. Janku: Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): BioMed Valley Discoveries; Research grant/Funding (institution): Plexxikon; Research grant/Funding (institution): Deciphera; Research grant/Funding (institution): Piqur; Research grant/Funding (institution): Symphogen; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): FujiFilm Corporation; Research grant/Funding (institution): Astex; Research grant/Funding (institution): Asana; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Agios; Research grant/Funding (institution): Proximagen; Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: Asana; Advisory/Consultancy: Deciphera; Advisory/Consultancy: IFM Therapeutics; Advisory/Consultancy: Synlogic; Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Ideaya; Advisory/Consultancy: PureTech Health; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Cardiff Oncology; Advisory/Consultancy: Immunomet; Advisory/Consultancy: Jazz Pharmaceuticals; Advisory/Consultancy: Sotio. All other authors have declared no conflicts of interest.