New Drugs on the Horizon

Abstract title:

Interim results from a phase 1/2 precision medicine study of PLX8394- a next generation BRAF inhibitor
F. Janku1 , E. Sherman J. , A.R. Parikh , L. Feun G. , F. Tsai , C. Allen E , C. Zhang , P. Severson , K. Inokuchi , J. Walling , S. Averbuch , G. Tarcic , G. Bollag .
The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Huston, USA.
MSKCC, Department of Medical Oncology, New York, USA.
Massachusetts General Hospital, Department of Medicine, Boston, USA.
Sylvester Comprehensive Cancer Center- University of Miami, Department of Medicine, Miami, USA.
Honor Health, Department of Medicine, Scottsdale, USA.
Texas Children’s Cancer Center- Baylor College of Medicine, Department of Pediatrics, Huston, USA.
Plexxikon, Plexxikon, Berkeley, USA.
Novellus Bio, Novellus, Jerusalem, Israel.

Background: BRAF inhibition with 1 generation BRAF inhibitors (BRAFi) has provided remarkable clinical benefit in several tumor types; however, paradoxical re-activation of the MAPK pathway contributes to therapeutic resistance. PLX8394 is a next-generation, orally available small-molecule BRAFi that does not induce MAPK paradoxical activation and blocks signaling from both monomeric BRAF and dimeric BRAF mutated protein.

Materials and Methods: This is an ongoing phase 1/2 study of PLX8394 with or without cobicistat (cobi), a CYP3A4 inhibitor to enhance PLX8394 exposure, to determine the safety, PK, tolerability, and efficacy in patients (pts) with refractory solid tumors (NCT02428712). Results are reported as of July 31, 2020.

Results: 75 pts were treated with PLX8394 (450 mg BID, 450 mg TID, and 900mg BID) with (N=56) or without cobi (n=19). Pts had BRAF V600 (n=49), BRAF non-V600 (n=17) or non-BRAF mutated (n=9) tumors. The use of cobi resulted in 2-3-fold increase of PLX8394 exposure, demonstrating a non-saturating dose proportional increase in exposure. Grade 3 (G3) AST elevation and Grade 3 (G3) blood bilirubin increase were the only DLTs and PLX8394 900 mg BID with cobi was declared as RP2D. Other ≥G3 toxicities in ≥2 pts included increased ALT (4), increased AST (3), blood bilirubin increase (4), and diarrhea (2).

Of 45 evaluable pts with BRAF-mutations, who received a median of 3 prior therapies, including 12 pts (27%) which received prior MAPK pathway targeted therapies, 10 pts (22%) achieved confirmed and mostly durable partial responses (gliomas (3), ovarian (2), and 1 each for papillary thyroid cancer, small bowel, colorectal carcinoma, anaplastic thyroid carcinoma, and melanoma). At time of analysis 10 pts remain on study for ≥24 months (range, 24-59 months) providing encouraging long-term safety data including lack of secondary skin lesions observed with Class 1 BRAF inhibitors.

Conclusions: PLX8394 + cobi demonstrated favorable safety profile and encouraging activity in refractory solid tumors with BRAF mutations including BRAF fusion. Further studies to refine the RP2D with a modified tablet formulation to reduce dose burden and improve dose linearity are ongoing.

Conflict of interest:
Conflict of interest:
Other Substantive Relationships:
Chao Zhang, Paul Severson, Kerry Inokuchi, Jackie Walling, Gideon Bollag are employees of Plexxikon.
Steven Averbuch, Gabi Tarcic are employees of Novellus