Mosperafenib, a Novel Paradox-Breaker BRAF Inhibitor with Potent Preclinical Activity in BRAF-Mutated Colorectal
Florian Renner1, Jan Eckmann2, Cornelia Handl1
1Roche Innovation Center Basel, F. Hoffmann-La Roche, Basel, Switzerland.
Abstract:
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.
Insights
Mosperafenib, a next-generation BRAF inhibitor, shows superior preclinical activity in BRAF-mutated colorectal cancer models compared to encorafenib. It demonstrates potential as both a monotherapy and a backbone agent for combination treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- First-generation BRAF inhibitors (BRAFi) like encorafenib combined with cetuximab offer limited benefit in BRAF V600E-mutated metastatic colorectal cancer (CRC).
- There is a need for more effective BRAF-targeted therapies in CRC, particularly those with improved safety and efficacy profiles.
Purpose of the Study:
- To evaluate the preclinical efficacy of mosperafenib, a next-generation BRAF inhibitor designed as a MAPK paradox breaker, in colorectal cancer models.
- To assess mosperafenib's potential as a monotherapy and in combination regimens for BRAF-mutated CRC.
Main Methods:
- Preclinical characterization of mosperafenib in BRAF-mutated CRC models, including in vivo xenograft and patient-derived xenograft (PDX) models.
- Comparison of mosperafenib (as monotherapy and in combination with cetuximab or FOLFOX) against encorafenib/cetuximab and encorafenib/FOLFOX.
Main Results:
- Mosperafenib monotherapy demonstrated higher activity than encorafenib/cetuximab in BRAFi-naïve xenograft models.
- Mosperafenib plus cetuximab showed significant tumor regression and long survival benefits in both BRAFi-naïve and BRAFi-experienced models.
- Mosperafenib combined with FOLFOX exhibited superior activity compared to encorafenib/FOLFOX.
Conclusions:
- Mosperafenib exhibits potent preclinical activity in BRAF-mutated CRC, outperforming current standards of care.
- Mosperafenib demonstrates efficacy in both BRAFi-naïve and BRAFi-experienced settings, suggesting a broad therapeutic window.
- Mosperafenib represents a promising candidate for monotherapy and a preferred backbone BRAFi for combination therapies in BRAF-mutated CRC.
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