Combination therapy

Abstract

Reversing resistance to a B-Raf inhibitor for the treatment of a proliferative disease by obtaining a tumor sample from the patient and testing it for genetic alterations in a panel of genes comprising BRAF, CRAF, CCND1, CDK4, HER2, IGF-1R, cMET, FGFR1, FGFR2, FGFR3, EGFR, MAP2K1, MAP2K2, NRAS, KRAS, HRAS, PTEN, PIK3CA, and P16 and administering a drug combination therapy comprising the B-Raf inhibitor and a second inhibitor which overcomes resistance to the B-Raf inhibitor, which second inhibitor is selected based on genetic alterations discovered in the tumor sample.

1 . A method for treating a patient suffering from a proliferative disease characterized by a mutation in B-Raf, particularly a V600 mutation in B-Raf, very particularly a melanoma characterized by a V600 mutation in B-Raf, which comprises:
 (a) obtaining a tumor sample from the patient and testing for a genetic alteration in a gene selected from the group comprising BRAF, CRAF, CCND1, CDK4, HER2, IGF-1R, cMET, FGFR1, FGFR2, FGFR3 EGFR, MAP2K1, MAP2K2, NRAS, KRAS HRAS, PTEN, PIK3CA, and P16,   (b) administering a drug combination therapy comprising a B-Raf inhibitor and a second inhibitor, which second inhibitor is selected based on genetic alterations discovered in the tumor sample, wherein,
 (i) the second inhibitor is a Mek 1/2 inhibitor when the tumor sample has a genetic alteration in BRAF, CRAF, MAP2K1, MAPK2, NRAS, KRAS HRAS or EGFR, or 
 (ii) the second inhibitor is a CDK 4 inhibitor when the tumor sample has a genetic alteration in CCND1, CDK4 or P16, or 
 (iii) the second inhibitor is a PI3 Kinase inhibitor when the tumor sample has a genetic alteration in HER2, IGF-1R, PTEN or PIK3CA, or 
 (iv) the second inhibitor is a c-Met receptor tyrosine kinase inhibitor when the tumor sample has a genetic alteration in cMET, 
 (v) the second inhibitor is a FGFR kinase inhibitor when the tumor sample has a genetic alteration in FGFR1, FGFR2 or FGFR3.