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 BRAFi encorafenib and the EGFR blocking antibody cetuximab in second line metastatic colorectal cancers (CRC) harboring BRAF V600E mutations remains limited and short lived. Here, we present the preclinical characterization of the next generation BRAF inhibitor mosperafenib (RG6344/RO7276389) in colorectal cancer (CRC) models. Mosperafenib was designed as a MAPK paradox breaker. Since it does not trigger P-ERK over-activation in BRAF WT 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. Combination of mosperafenib and cetuximab demonstrated potent activity with tumor regression and long survival benefits in BRAFi naïve models and in PDX models derived from patients that 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 to 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 CRC.