KRAS G12C-mutant colorectal cancer

KRAS was the first human oncogene identified in colorectal cancer, and RAS mutations, found in about 45 percent of tumours, predict failure of cetuximab and panitumumab, which is why RAS testing precedes any anti-EGFR therapy. G12C is a minority RAS allele in the bowel (3 to 4 percent, against 13 percent for G12D) but it was the first to be drugged, because the mutant cysteine can be trapped covalently by inhibitors of the inactive GDP-bound state, a chemistry described by Ostrem and Shokat in 2013.

Sotorasib and adagrasib alone produced responses in only about a fifth of colorectal patients, far fewer than in lung cancer, because inhibition triggers rapid EGFR-driven reactivation of the pathway. Combining with an anti-EGFR antibody fixed this: in KRYSTAL-1 adagrasib plus cetuximab produced a response rate of 34 percent with median progression-free survival of 6.9 months and overall survival of 15.9 months, leading to FDA accelerated approval in June 2024; in the randomised CodeBreaK 300 trial sotorasib 960 mg plus panitumumab lengthened progression-free survival to 5.6 months against 2.2 months with trifluridine-tipiracil or regorafenib, with a response rate of 26 percent against none, and the FDA approved the combination in January 2025.

CodeBreaK 301 (sotorasib, panitumumab and FOLFIRI first line) and KRYSTAL-10 (adagrasib plus cetuximab against chemotherapy in second line) are the phase 3 trials that will decide when the combinations are given. Next-generation G12C inhibitors (divarasib, olomorasib, glecirasib), G12D inhibitors and the pan-RAS and RAS(ON) inhibitors such as daraxonrasib aim at the far larger group of other RAS-mutant colorectal cancers.