Biomarkers

A plasma cfDNA mutation on PI3KCA could help predict resistance to combined inhibition of MEK, CDK4 and CDK6 in NRAS-mutant melanoma. In samples from a patient with metastatic NRAS-mutant melanoma treated with binimetinib and Kisqali ribociclib, high frequencies in plasma cfDNA of a known E545K oncogenic mutant on PI3KCA were associated with acquired drug resistance. In two NRAS-mutant human melanoma cell lines, overexpression of the E545K mutant PI3KCA variant decreased sensitivity to binimetinib and Kisqali compared with wild-type PI3KCA. Next steps include evaluating the effect of the mutation on treatment resistance to other combinations of MEK, CDK4 and CDK6 inhibitors and in additional cancer types treated with the combination therapy.

Array BioPharma Inc., Laboratoires Pierre Fabre S.A. and Ono Pharmaceutical Co. Ltd. have binimetinib (MEK162, ONO-7703), a small molecule selective inhibitor of MAP kinase kinase 1 (MAP2K1; MEK1) and MAP2K2, in registration to treat melanoma, Phase III testing to treat ovarian and colorectal cancers, Phase II testing to treat cardiomyopathy and solid tumors, and Phase I/II testing to treat gastrointestinal and biliary cancers...