BRAF Class II and NRAS-Targeting Drug Shows Promising Efficacy, Safety, and Tolerability in Early Phase I Data

Source: Genome Web, July 2023

Exarafenib, a pan-RAF inhibitor being investigated as a monotherapy in BRAF and NRAS-driven solid tumors by Kinnate Biopharma, was well-tolerated and demonstrated early signs of activity with durable responses in various patient populations, including those with BRAF Class II and NRAS-mutant melanoma, according to early Phase I trial results. The investigational agent could potentially contribute to meeting the significant medical need posed by patients whose tumors harbor alterations such as BRAF Class II and NRAS.

BRAF alterations play a significant role in the development of various cancers, like lung, skin, colorectal, ovarian, and thyroid cancers. These alterations are grouped into three classes. Class I alterations involve BRAF acting as an activated individual molecule, or monomer. Class II alterations occur when two BRAF molecules combine to form a pair — or homodimer — independent of RAS and activate the MAPK pathway. This often happens due to mutations, gene fusions, or genetic changes by which the kinase domain of BRAF is abnormally joined to another gene. Class III alterations involve BRAF with low kinase activity and lead to its pairing with other members of the RAF kinase family, such as ARAF or CRAF. This heterodimerization results in increased interaction with activated RAS, enhanced enzymatic activity, and subsequent signaling.

Currently, there are approved drugs that specifically target the Class I alteration of BRAF, which is a well-known and actionable target in cancer treatment. However, targeting Class II and Class III alterations has been more difficult, and there are no approved therapies available for these alterations. Class II and III alterations make up more than half of all BRAF alterations and are found in approximately 2.1 percent of solid tumors. Patients with Class II and III alterations have shown shorter overall survival compared to those with Class I alterations, particularly in non-small cell lung cancer and melanoma.