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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
KRAS G12C bowel cancer carries a mutation that was undruggable for forty years. The first KRAS drugs work only weakly on their own in the bowel, because the tumour switches EGFR back on, so they are given with an anti-EGFR antibody: sotorasib with panitumumab and adagrasib with cetuximab are both approved after chemotherapy.
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.
| Setting | Approach | Guideline |
|---|---|---|
| Metastatic, previously treated | Sotorasib plus panitumumab (CodeBreaK 300) or adagrasib plus cetuximab (KRYSTAL-1) after fluoropyrimidine, oxaliplatin and irinotecan. | not mapped |
| Metastatic, first line | FOLFOX, FOLFIRI or CAPOX with bevacizumab, as for any RAS-mutant colorectal cancer; anti-EGFR antibodies are not used; KRAS G12C combinations are under test first line (CodeBreaK 301). | not mapped |
| Later lines | Trifluridine-tipiracil with bevacizumab (SUNLIGHT), fruquintinib (FRESCO-2) or regorafenib; clinical trials of next-generation RAS inhibitors. | not mapped |