Abstract 2693: Combining ulixertinib (ERK1/2 Inhibitor) with EGFR and BRAF inhibition yields significant efficacy in preclinical BRAFV600E mutant colorectal cancer models

Abstract

Abstract The BRAFV600E mutation occurs in approximately 7% of colorectal cancer (CRC). BRAF plus EGFR inhibition (encorafenib with cetuximab) is an FDA approved treatment option for adult patients with metastatic CRC. Ultimately, patients develop resistance leading to disease progression. The addition of a MEK inhibitor, binimetinib, did not confer overall survival benefit. We hypothesized that addition of ERK inhibition would increase magnitude and duration of response to BRAF plus EGFR inhibition by overcoming MAPK-related acquired resistance mechanisms. ERK is the terminal master regulator kinase of the RAS-MAPK pathway, therefore, targeting this node is likely to be effective in the context of numerous mechanisms of acquired resistance that reactivate the MAPK pathway. Ulixertinib (BVD-523) is a first-in-class and best-in-class small molecule inhibitor of ERK1/2 currently being investigated in several oncology clinical trials, both as a single agent and in combination with other therapeutics. Ulixertinib has demonstrated efficacy in patients with tumors harboring alterations within the RAS-MAPK pathway. The efficacy of ulixertinib, in combination with EGFR inhibition (cetuximab), plus BRAF inhibition (encorafenib), was assessed in CRC cell line derived xenograft models harboring BRAFV600E mutations. The triple combination resulted in superior tumor growth inhibition compared to dosing of any single agent or doublet. RNA sequencing was performed on treated tumor samples. Expression of the mutant BRAF allele was readily confirmed from RNA sequencing data. Gene expression analysis showed differential expression of MAPK pathway genes in triple combination treated groups versus single or doublet therapy. A complete response to ulixertinib in combination with cetuximab and encorafenib for the treatment of a patient with metastatic CRC has been reported (Stuhlmiller, Timothy Joseph, et al. "Updated clinical outcomes from ULI-EAP-100, an intermediate expanded access program for ulixertinib (BVD-523)." (2022): e15101-e15101). The patient was treated under the Expanded Access Protocol (NCT04566393) for compassionate use access to ulixertinib. Preclinical data and clinical complete response warrants further investigation of ulixertinib plus BRAF and EGFR inhibition. Citation Format: Deborah Knoerzer, Anupama Reddy, Jessica A. Box, Anna Groover, Brent Kreider, Martin Teresk, Caroline M. Emery. Combining ulixertinib (ERK1/2 Inhibitor) with EGFR and BRAF inhibition yields significant efficacy in preclinical BRAFV600E mutant colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2693.