529MO - Activity, safety and circulating tumour DNA (ctDNA) dynamics of paradox breaker BRAF inhibitor PLX8394 in patients with advanced cancer

Background

PLX8394, a second generation BRAF inhibitor, does not induce paradoxical activation and blocks signaling from both monomeric BRAF^V600 and dimeric BRAF^non-V600 alterations.

Methods

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.

Results

69 pts (BRAF^V600, 43; BRAF^non-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 >G3 toxicities occuring in more than 1 pt included ALT (4), AST (2), bilirubin (3), and diarrhea (2). The RP2D was declared at 900 mg BID. Coadministration of cobicistat resulted in 2-3-fold increase in PLX8394 systemic exposure, with dose dependent increase. Partial responses (-32% to -100%) lasting up to 56 months were observed in 10 pts (BRAF^V600, 9; BRAF fusion, 1; prior BRAF and MEK inhibitors, 2) of 46 pts with BRAF alterations. Dynamic changes in BRAF^V600-mutant ctDNA in 11 pts with available serial samples for ddPCR testing demonstrated that the median variant allele frequency (VAF) was lower at baseline, on day 21 of cycle 1 and at the first restaging in pts without progression vs. those with progression (p=0.02, p=0.05, p=0.02, respectively). Pts with detectable ctDNA at any timepoint had a shorter median progression-free survival (p<0.04). Increase in ctDNA VAF preceded or co-occurred with progression in 6 pts (67%). Targeted NGS of serially collected ctDNA samples from 16 pts detected broad spectrum somatic alterations in 14 samples and clonal evolution corresponded with the clinical course.

Conclusions

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.

Clinical trial identification

NCT02428712.

Editorial acknowledgement

Legal entity responsible for the study

Plexxikon.

Funding

Plexxikon.

Disclosure

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.