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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.
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.
About 3 to 4 percent of colorectal cancers carry KRAS G12C, a small slice of the 45 percent that are RAS-mutant; they behave like other RAS-mutant tumours, resistant to anti-EGFR antibodies, with a somewhat worse outlook.
Right-sided tumours behave differently from left-sided and rectal ones; the colon drains along its mesenteric vessels, the rectum into the mesorectum and pelvic side wall.
Same organ: Colon cancer (adenocarcinoma of the colon), Micropapillary adenocarcinoma of the colon and rectum, Adenoma-like adenocarcinoma of the colon and rectum, Lynch syndrome-associated colorectal cancer, Familial adenomatous polyposis-associated colorectal cancer, Mucinous adenocarcinoma of the colon and rectum, Signet ring cell carcinoma of the colon and rectum, Medullary carcinoma of the colon, Serrated adenocarcinoma of the colon and rectum, Peritoneal mesothelioma, Colorectal cancer, Rectal cancer, Mismatch-repair deficient (MSI-high) colorectal cancer, BRAF V600E-mutant colorectal cancer, HER2-amplified colorectal cancer, Early-onset colorectal cancer (under 50), Anal cancer (squamous cell carcinoma), Appendiceal cancer and pseudomyxoma peritonei, Small intestine cancer (small bowel adenocarcinoma), Small intestinal neuroendocrine tumours, Anal high-grade squamous intraepithelial lesions (precursor), Localised anal squamous cell carcinoma (stage I to III), Metastatic and recurrent anal squamous cell carcinoma, Low-grade appendiceal mucinous neoplasm and pseudomyxoma peritonei, Appendiceal adenocarcinoma (mucinous and non-mucinous, including signet ring cell), Goblet cell adenocarcinoma of the appendix, Localised small bowel adenocarcinoma (stage I to III, resected), Advanced and metastatic small bowel adenocarcinoma
Nothing recorded yet.
Also on OnCo: Symptoms and red flags · Early detection roadmap.
Sotorasib plus panitumumab (CodeBreaK 300) or adagrasib plus cetuximab (KRYSTAL-1) after fluoropyrimidine, oxaliplatin and irinotecan.
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).
Trifluridine-tipiracil with bevacizumab (SUNLIGHT), fruquintinib (FRESCO-2) or regorafenib; clinical trials of next-generation RAS inhibitors.
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Patients with metastatic colorectal cancer carrying a KRAS G12C mutation (about 3-4% of cases) who have exhausted standard chemotherapy now have a targeted option that works far better than trifluridine-tipiracil or regorafenib. The higher sotorasib dose is clearly superior, and the EGFR antibody is essential because KRAS inhibition alone has little effect in bowel cancer. Responses are still modest and short-lived compared with EGFR or ALK inhibitors in lung cancer.
Adagrasib plus cetuximab is an approved option for previously treated KRAS G12C colorectal cancer, alongside sotorasib plus panitumumab; monotherapy is not enough because EGFR signalling reactivates the pathway.
Trifluridine-tipiracil with bevacizumab is the refractory-line standard, and a reminder that combining two drugs already on the shelf can beat anything new in the same line.
Query for this cancer: (TITLE:"KRAS G12C-mutant colorectal cancer" OR ABSTRACT:"KRAS G12C-mutant colorectal cancer" OR TITLE:"KRAS G12C colorectal cancer" OR ABSTRACT:"KRAS G12C colorectal cancer" OR TITLE:"G12C-mutant bowel cancer" OR ABSTRACT:"G12C-mutant bowel cancer" OR TITLE:"RAS-mutant colorectal cancer G12C subset" OR ABSTRACT:"RAS-mutant colorectal cancer G12C subset") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about KRAS G12C-mutant colorectal cancer, not a curated reading list.
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Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
Take with a low-fat breakfast (under 30% fat).
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
Not recommended in severe impairment; hepatotoxicity is a boxed warning.
See all on the product pages:AdagrasibBevacizumabCAPOX (capecitabine, oxaliplatin)FOLFIRI (5-FU, leucovorin, irinotecan)FOLFOX (5-FU, leucovorin, oxaliplatin)FruquintinibRegorafenibSotorasibTrifluridine/tipiracil·Printable cards in the navigator
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