Abstract 4022: ERK1/2 inhibitor ulixertinib demonstrates activity in atypical (non-V600) BRAF mutant models

Abstract

Abstract Atypical BRAF (non-V600) alterations comprise approximately half of all BRAF mutations in cancer and can be categorized according to characteristics of molecular signaling (either Class II or III). Atypical BRAF alterations are rare (approximately 3% across all human cancers) and there are currently no approved therapies for this indication. As next-generation sequencing becomes standard clinical practice, oncologists are frequently identifying atypical BRAF alterations in their patients’ tumors. The efficacy of the first-in-class ERK1/2 inhibitor, ulixertinib (BVD-523), was assessed across 10 patient-derived xenograft (PDX) models, which harbored class II or III BRAF alterations (5 models with type II alterations, 4 models with class III, and 1 model with both class II and III). Responses ranging from robust regression to moderate tumor growth delay were observed in 9/10 models. RNA sequencing was performed on tumors from the vehicle-treated and ulixertinib-treated groups with three replicates per PDX model. The samples were collected 2 hours after the last dose of treatment. Expression of the mutant BRAF alleles was readily confirmed from RNA-seq data in all PDX models. In addition, gene expression analysis showed differential expression of MAPK pathway genes in responders compared to the non-responders. In summary, ulixertinib has exhibited strong pre-clinical activity in a variety of patient-derived xenograft models with atypical BRAF alterations. Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, harboring specific BRAF mutations (G469A, L485W, or L597Q) and is currently under clinical evaluation in patients with tumors harboring any atypical BRAF alteration (NCT04488003). Citation Format: Deborah Knoerzer, Anupama Reddy, Adnan Derti, Caroline M. Emery. ERK1/2 inhibitor ulixertinib demonstrates activity in atypical (non-V600) BRAF mutant models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4022.