Mosperafenib, a Novel Paradox-Breaker BRAF Inhibitor with Potent Preclinical Activity in BRAF-Mutated Colorectal Cancer.

The therapeutic benefit of the combination of the first-generation BRAF inhibitor (BRAFi) encorafenib and the EGFR-blocking antibody cetuximab in second-line metastatic colorectal cancers harboring BRAFV600E mutations remains limited and short lived. In this study, we present the preclinical characterization of the next-generation BRAFi mosperafenib (RG6344/RO7276389) in colorectal cancer models. Mosperafenib was designed as an MAPK paradox breaker. As it does not trigger phosphorylated ERK overactivation in BRAF wild-type contexts, we hypothesized that it may lead to an improved safety profile while reaching higher target coverage in the clinic. In in vivo experiments conducted in BRAFi-naïve xenograft models, mosperafenib monotherapy outperformed encorafenib/cetuximab at clinically relevant doses, indicating higher activity of mosperafenib. The combination of mosperafenib and cetuximab demonstrated potent activity with tumor regression and long survival benefits in BRAFi-naïve models and in patient-derived xenograft models derived from patients who progressed to encorafenib/cetuximab therapy, supporting the activity of mosperafenib even in BRAFi-experienced patients. Additional combination studies of mosperafenib with FOLFOX resulted in tumor regression and superior activity compared with the same combination with encorafenib. Collectively, these data provide a strong preclinical rationale for the potentially transformative activity of mosperafenib as monotherapy and as a preferred backbone BRAFi for combinatorial regimen for BRAF-mutated colorectal cancer.