# 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

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/kras-g12c-colorectal/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/kras-g12c-colorectal/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/kras-g12c-colorectal/#what-it-is [4 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/kras-g12c-colorectal/#finding-it [4 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/kras-g12c-colorectal/#treating-it [3 settings, 3 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/kras-g12c-colorectal/#evidence [21 trials, 3 key papers, 7 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/kras-g12c-colorectal/#science [5 targets, 2 pathways]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/kras-g12c-colorectal/where-you-are/ [29 UK centres]
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/kras-g12c-colorectal/#living-with-it [18 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/kras-g12c-colorectal/coming/ [18 medicines, 19 trials, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/kras-g12c-colorectal/data/ [77 connected records]

## 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

- cancers: [BRAF V600E-mutant colorectal cancer](https://onco.cc/cancers/braf-v600e-colorectal/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Early-onset colorectal cancer (under 50)](https://onco.cc/cancers/early-onset-colorectal/), [HER2-amplified colorectal cancer](https://onco.cc/cancers/her2-amplified-colorectal/), [KRAS G12C-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-g12c-pdac/), [Mismatch-repair deficient (MSI-high) colorectal cancer](https://onco.cc/cancers/msi-high-colorectal/), [Rectal cancer](https://onco.cc/cancers/rectal-cancer/)
- 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/), [Extended RAS testing](https://onco.cc/terms/extended-ras-testing/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [Sidedness (left vs right colon)](https://onco.cc/terms/sidedness/)
- trials: [5-fluorouracil Plus Panitumumab (Anti-EGFR) and Sotorasib (KRAS G12C Inhibitor) in First-line Treatment of Patients Non-eligible for a Doublet/Triplet Chemother](https://onco.cc/trials/nct07124884/), [A Clinical Study of Calderasib (MK-1084) With Targeted Therapy and Chemotherapy in People With Colorectal Cancer (MK-1084-012/KANDLELIT-012)](https://onco.cc/trials/nct06997497/), [A Multicenter Phase 1b/2 Study of Adagrasib, Cetuximab, and Cemiplimab for Metastatic Colorectal Cancer Harboring KRAS G12C Mutations](https://onco.cc/trials/nct06412198/), [A Study Evaluating FMC-376 in Participants With KRAS G12C Mutated Solid Tumors](https://onco.cc/trials/nct06244771/), [A Study of GFH375 Combined With Cetuximab or Chemotherapy in Participants With Solid Tumors Harboring KRAS G12D Mutation](https://onco.cc/trials/nct07259590/), [A Study of Olomorasib (LY3537982) in Participants With Advanced Colorectal Cancer and a KRAS G12C Mutation](https://onco.cc/trials/nct07814417/), [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/), [Neoadjuvant Treatment of Fulzerasib Plus Cetuximab N01 in KRAS G12C Mutated Locally Advanced Colorectal Cancer With or Without Resectable Metastases](https://onco.cc/trials/nct07581912/), [Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1](https://onco.cc/trials/nct03785249/), [Phase 1/2 Trial of S241656 in Selected RAS/MAPK Mutation- Positive Malignancies](https://onco.cc/trials/nct05786924/), [Phase 1/2a Study of JAB-21822 Plus JAB-3312 in Patients With Advanced Solid Tumors Harboring KRAS p.G12C Mutation](https://onco.cc/trials/nct05288205/), [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/), [Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation](https://onco.cc/trials/nct05358249/), [Study of Elironrasib and Daraxonrasib as Monotherapies and Combination Therapy in Participants With Advanced KRAS G12C Mutant Solid Tumors](https://onco.cc/trials/nct06128551/), [Study of JDQ443 in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation](https://onco.cc/trials/nct04699188/), [Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C)](https://onco.cc/trials/nct04956640/), [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/), [The Efficacy and Safety of IBI351, Cetuximab β Combined With FOLFIRI as First-line /IBI351, Cetuximab β as Second-line in the Treatment of KRAS G12C-mutated Met](https://onco.cc/trials/nct06959589/)
- key papers: [CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer](https://onco.cc/key-papers/paper-codebreak-300-nejm-2023/), [KRYSTAL-1: adagrasib with or without cetuximab in KRAS G12C-mutated colorectal cancer](https://onco.cc/key-papers/paper-krystal-1-crc-yaeger-nejm-2023/), [Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer (SUNLIGHT)](https://onco.cc/key-papers/paper-prager-sunlight-trifluridine-tipiracil-bevacizumab-nejm-2023/)
- roadmaps: [Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation](https://onco.cc/roadmaps/colorectal-roadmap/)
- people: [Gerald W. Prager](https://onco.cc/people/gerald-prager/), [Rona Yaeger](https://onco.cc/people/rona-yaeger/)

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JSON: https://onco.cc/api/v1/entities/kras-g12c-colorectal.json