The MAPK (RAS-RAF-MEK-ERK) pathway is activated in many cancers, and the clinical efficacy of BRAF and MEK inhibitors in melanoma confirms that targeting the MAPK pathway has therapeutic potential. Unfortunately, intrinsic and acquired drug resistance limits use of MAPK-directed therapies, and resistance is often associated with activated ERK signaling. Here, we report characterization of BVD-523 (ulixertinib), a novel small-molecule ERK1/2 kinase inhibitor currently under investigation in Phase 1 clinical trials. BVD-523 potently and selectively inhibits ERK1 and ERK2 kinases in a reversible, ATP-competitive fashion. Consistent with its mechanism of action, BVD-523 inhibits signal transduction, cell proliferation, and cell survival, most potently in cell lines bearing mutations that activate MAPK pathway signaling. Similarly, single-agent BVD-523 inhibits tumor growth in vivo in BRAF-mutant melanoma and colorectal xenografts as well as in KRAS-mutant colorectal and pancreatic models. Combination treatment with BVD-523 and dabrafenib inhibits tumor growth in a BRAF-mutant melanoma model.

Importantly, BVD-523 is effective in several models that show intrinsic or acquired resistance to other MAPK pathway inhibitors. BVD-523 inhibits with equivalent potency the growth of parental cells or those cultured for resistance to dabrafenib, trametinib, or the combination of both drugs. Additionally, BVD-523 inhibits growth in wild-type cells and a RAF/MEK cross-resistant cell line bearing a MEK1 Q56P mutation with similar potency. Lastly, single-agent BVD-523 inhibits the growth of a patient-derived tumor xenograft harboring cross-resistance to dabrafenib, trametinib, and the combination treatment following clinical progression on a MEK inhibitor.

Phase 1 trials of BVD-523 are currently recruiting patients with advanced solid tumors (NCT0178429) or hematologic malignancies (NCT02296242). Eligibility criteria include diagnosis according to certain genetic features, and treatment in backgrounds including progression following prior MAPK targeted therapy. The primary objective of these studies is to identify the recommended Phase 2 dose(s) for single-agent BVD-523 treatment. Additional objectives include pharmacokinetic and pharmacodynamic assessments, and preliminary measures of efficacy. The solid tumor protocol has met its study objectives in Part 1 (defining the safety profile and maximum tolerated dose), and will be reported separately; findings appear consistent with the activity profile defined in preclinical studies.

In total, preclinical and clinical studies will help elucidate how BVD-523 (ulixertinib) may be used as a novel agent in MAPK-directed therapeutic strategies, including for patients that have failed treatment due to intrinsic or acquired resistance and active signaling through ERK.

Citation Format: Ursula Germann, Brinley Furey, Jeff Roix, William Markland, Russell Hoover, Alex Aronov, Michael Hale, Guanjing Chen, Gabriel Martinez-Botella, Rossitza Alargova, Bin Fan, David Sorrell, Kay Meshaw, Paul Shapiro, Michael J. Wick, Cyril Benes, Mathew Garnett, Gary DeCrescenzo, Mark Namchuk, Saurabh Saha, Dean J. Welsch. The selective ERK inhibitor BVD-523 is active in models of MAPK pathway-dependent cancers, including those with intrinsic and acquired drug resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4693. doi:10.1158/1538-7445.AM2015-4693