Reference Detail

Ref Type

PMID

Authors

Karyn Bouhana; Deborah Anderson; Walter DeWolf; Suzy Brown; Lance Williams; Li Ren; David Moreno; Ross Wallace; Jay Brad Fell; Dylan Hartley; Patrice Lee

Title

Nonclinical development of PF-07284890 (ARRY-461), a potent, brain-penetrant, small molecule inhibitor of BRAF V600-mutation-driven tumors in vitro and in vivo

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	81	Issue 13_Supplement	July 01 2021

URL

https://aacrjournals.org/cancerres/article/81/13_Supplement/1473/667351/Abstract-1473-Nonclinical-development-of-PF

Abstract Text

Although approved BRAF inhibitors have transformed the treatment of patients with certain BRAF V600 mutant cancers, their long-term efficacy is thought to be limited by poor brain penetration. As a result, disease progression in the brain is a significant cause of morbidity and mortality. PF-07284890 (ARRY-461) is an orally bioavailable, brain penetrant, potent, small molecule inhibitor targeting BRAF V600 mutant tumors and is in clinical development in patients with BRAF V600 metastatic melanoma with progression to the brain. In biochemical in vitro studies, PF-07284890 inhibits BRAF and CRAF with IC50's of 5.8 and 4.1 nM, respectively. Additionally, PF-07284890 inhibits the clinically relevant kinase domain BRAF V600 mutants (V600E and V600K) (IC50 = 24-25 nM). In cell-based systems, PF-07284890 potently inhibits phosphorylation of ERK, a downstream marker of BRAF inhibition, and potently inhibits proliferation of BRAF V600E/K mutant melanoma cell lines (IC50 18-38 nM). PF-07284890 was designed to distribute to the brain and, as such, in vitro experiments indicate that PF-07284890 has high cellular membrane permeability and is not a substrate for human P glycoprotein (P-gp). After oral administration of PF-07284890 to mice and rats, PF-07284890 distributes to the brain where the free fraction adjusted exposure in the brain was approximately proportional to the free fraction adjusted exposure in plasma (i.e., Cbrain,u/Cplasma,u approaches 1.0). In vivo, PF-07284890 inhibits phosphorylation of ERK in A375 BRAF V600E tumors, achieving maximal target inhibitions at a dose of 10 mg/kg. PF-07284890 has been evaluated for its ability to control BRAF V600E cell line and patient-derived melanoma xenograft tumor growth in nude mice when implanted both subcutaneously and intracranially. Dose-related tumor growth inhibition was demonstrated at dose levels ranging from 1 to 30 mg/kg, BID in both subcutaneous and intracranial xenograft models. In all models, regardless of tumor location, maximal efficacy was observed in dose ranges of 10-30 mg/kg BID. In the intracranial A375-luc BRAF V600E melanoma xenograft model, significant and durable tumor regressions were seen at doses of 10 and 30 mg/kg/day which translated to a profound survival benefit in animals receiving PF-07284890 (median survival > 55 days post-implantation) compared to control animals (median survival = 15 days). GLP safety studies demonstrated a good safety profile for PF-07284890. PF-07284890 is fully brain penetrant, with the potential to address this key unmet medical need and thereby defines a new class of brain penetrant, potent and selective BRAF inhibitors.

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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
PF-07284890	PF-07284890	1	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PF-07284890		PF07284890\|PF 07284890\|ARRY-461\|ARRY461\|ARRY 461	BRAF Inhibitor 25	PF-07284890 inhibits BRAF, potentially leading to inhibition of tumor growth and tumor regression (Cancer Res 2021;81(13_Suppl):Abstract nr 1473).

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
BRAF V600E	melanoma	predicted - sensitive	PF-07284890	Preclinical - Cell line xenograft	Actionable	In a preclinical study, PF-07284890 treatment led to inhibition of tumor growth, tumor regression, and survival benefit in an intracranial model, and tumor growth inhibition in a subcutaneous cell line xenograft model of melanoma harboring BRAF V600E (Cancer Res 2021;81(13_Suppl):Abstract nr 1473).	detail...