# KRAS G12C-mutant colorectal cancer

Source: https://onco.cc/cancers/kras-g12c-colorectal/  
OnCo record `kras-g12c-colorectal` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: KRAS G12C colorectal cancer; G12C-mutant bowel cancer; RAS-mutant colorectal cancer (G12C subset)
- Tags: subtype-page
- Group: gastrointestinal
- Burden: 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.
- Subtypes: KRAS G12C with an anti-EGFR combination (sotorasib-panitumumab, adagrasib-cetuximab); Other KRAS mutations (G12D, G12V, G13D): RAS(ON) and pan-RAS inhibitors in trials; RAS-mutant colorectal cancer, left-sided or right-sided, in which anti-EGFR antibodies do not work; NRAS-mutant colorectal cancer (about 4 percent; no targeted therapy)
- Biomarkers: KRAS G12C by tumour or circulating tumour DNA sequencing; Extended RAS testing (KRAS and NRAS exons 2, 3 and 4) before any anti-EGFR antibody; Co-mutations (TP53, APC, PIK3CA) and acquired RAS or MAPK alterations at progression; Mismatch repair status

## Standard of care

- Metastatic, previously treated: Sotorasib plus panitumumab (CodeBreaK 300) or adagrasib plus cetuximab (KRYSTAL-1) after fluoropyrimidine, oxaliplatin and irinotecan. ([CodeBreaK 300](https://onco.cc/trials/codebreak-300/), [Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1](https://onco.cc/trials/nct03785249/), [Sotorasib](https://onco.cc/drugs/sotorasib/), [Panitumumab](https://onco.cc/drugs/panitumumab/), [Adagrasib](https://onco.cc/drugs/adagrasib/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/))
- 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). ([FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [FOLFIRI (5-FU, leucovorin, irinotecan)](https://onco.cc/drugs/folfiri/), [CAPOX (capecitabine, oxaliplatin)](https://onco.cc/drugs/capox/), [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [Study of Sotorasib, Panitumumab and FOLFIRI Versus FOLFIRI With or Without Bevacizumab-awwb in Treatment-naïve Participants With Metastatic Colorectal](https://onco.cc/trials/nct06252649/))
- Later lines: Trifluridine-tipiracil with bevacizumab (SUNLIGHT), fruquintinib (FRESCO-2) or regorafenib; clinical trials of next-generation RAS inhibitors. ([SUNLIGHT](https://onco.cc/trials/sunlight/), [FRESCO-2](https://onco.cc/trials/fresco-2/), [Trifluridine/tipiracil](https://onco.cc/drugs/trifluridine-tipiracil/), [Fruquintinib](https://onco.cc/drugs/fruquintinib/), [Regorafenib](https://onco.cc/drugs/regorafenib/))

## State of the art

- Two approved KRAS G12C plus anti-EGFR combinations after chemotherapy (2024 and 2025).
- The EGFR-feedback lesson from BRAF-mutant disease was reused to make KRAS inhibitors work in the bowel.
- Pan-RAS and RAS(ON) inhibitors are the first drugs to reach the far commoner G12D and G12V mutations.

## Open problems

- Responses last months, not years; acquired RAS and MAPK alterations drive resistance.
- G12D, the commonest colorectal KRAS allele, has no approved drug.
- First-line use of the combinations awaits CodeBreaK 301 and KRYSTAL-10.
- Anti-EGFR skin and magnesium toxicity limits the combinations for some patients.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/KRAS
- Wikipedia: https://en.wikipedia.org/wiki/KRAS
- NCCN Guidelines: Colon Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428

## Connected records

- technologies: [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [Adagrasib](https://onco.cc/drugs/adagrasib/), [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [CAPOX (capecitabine, oxaliplatin)](https://onco.cc/drugs/capox/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/), [Divarasib](https://onco.cc/drugs/divarasib/), [Elironrasib](https://onco.cc/drugs/elironrasib/), [FOLFIRI (5-FU, leucovorin, irinotecan)](https://onco.cc/drugs/folfiri/), [FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [Fruquintinib](https://onco.cc/drugs/fruquintinib/), [Glecirasib](https://onco.cc/drugs/glecirasib/), [Olomorasib](https://onco.cc/drugs/olomorasib/), [Panitumumab](https://onco.cc/drugs/panitumumab/), [Regorafenib](https://onco.cc/drugs/regorafenib/), [Sotorasib](https://onco.cc/drugs/sotorasib/), [Trifluridine/tipiracil](https://onco.cc/drugs/trifluridine-tipiracil/), [VS-7375](https://onco.cc/drugs/vs-7375/), [Zoldonrasib](https://onco.cc/drugs/zoldonrasib/)
- pathways: [Colorectal cancer (KEGG map)](https://onco.cc/pathways/colorectal-cancer-signalling/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [Sidedness (left vs right colon)](https://onco.cc/terms/sidedness/)
- trials: [A Study of GFH375 Combined With Cetuximab or Chemotherapy in Participants With Solid Tumors Harboring KRAS G12D Mutation](https://onco.cc/trials/nct07259590/), [CodeBreaK 300](https://onco.cc/trials/codebreak-300/), [FRESCO-2](https://onco.cc/trials/fresco-2/), [JAB-21822 in Combination With Cetuximab in Patients With Advanced CRC and Other Solid Tumors With KRAS G12C Mutation](https://onco.cc/trials/nct05194995/), [Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1](https://onco.cc/trials/nct03785249/), [Phase 3 Study of MRTX849 With Cetuximab vs Chemotherapy in Patients With Advanced Colorectal Cancer With KRAS G12C Mutation (KRYSTAL-10)](https://onco.cc/trials/nct04793958/), [Study of Sotorasib, Panitumumab and FOLFIRI Versus FOLFIRI With or Without Bevacizumab-awwb in Treatment-naïve Participants With Metastatic Colorectal](https://onco.cc/trials/nct06252649/), [SUNLIGHT](https://onco.cc/trials/sunlight/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)

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