# KRAS G12C-mutant pancreatic ductal adenocarcinoma

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

## TL;DR

KRAS G12C pancreatic cancer is the small slice of pancreatic cancer whose KRAS mutation happens to be the one that the first KRAS drugs were built for. Sotorasib and adagrasib, approved for lung cancer, shrink a share of these tumours after chemotherapy and are listed as options, and newer inhibitors such as elironrasib, olomorasib and the pan-RAS drug daraxonrasib are being tested in this group.

## Summary

KRAS is mutated in more than nine out of ten pancreatic ductal adenocarcinomas, but the covalent inhibitors that reached the clinic first bind only the cysteine of the G12C variant, which is rare in the pancreas. The G12C subgroup otherwise resembles other KRAS-mutant pancreatic cancers in its presentation, its TP53, CDKN2A and SMAD4 co-alterations and its response to chemotherapy; it is found only by tumour or plasma sequencing, which is why guidelines ask for it at diagnosis in advanced disease.

Sotorasib in the pancreatic cohort of CodeBreaK 100 (2023) and adagrasib in KRYSTAL-1 (2023) produced responses in a minority of previously treated patients with disease control in most, durable for some months. Both are NCCN-listed options after first-line chemotherapy and are used off label or through access schemes, since neither has a pancreatic indication. Resistance arises through secondary KRAS mutations, amplification and bypass through receptor tyrosine kinases, and pancreatic tumours appear to depend more on wild-type RAS and on EGFR-family signalling than lung tumours do, which is the rationale for combining G12C inhibitors with EGFR antibodies or with pan-RAS drugs.

The pan-RAS inhibitor daraxonrasib, active against G12C alongside the other variants, lengthened survival in RASolute 302 and is approved after first-line chemotherapy regardless of KRAS subtype, so G12C-mutant patients now have a RAS inhibitor with pancreatic-specific evidence. Elironrasib (a RAS(ON) G12C-selective inhibitor) is being combined with daraxonrasib, olomorasib is in a pancreatic cohort, glecirasib has a pancreatic phase 2 in China, and divarasib, garsorasib and FMC-376 are in earlier studies. Open questions are whether a G12C-selective drug adds anything to a pan-RAS inhibitor, how to sequence them with chemotherapy, and whether responses in the pancreas can be made as deep as in the lung.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: KRAS G12C pancreatic cancer; KRAS p.G12C PDAC; G12C-mutant pancreatic adenocarcinoma
- Tags: subtype-page; gastrointestinal
- Group: gastrointestinal
- Burden: About 1 to 2 percent of pancreatic ductal adenocarcinomas carry KRAS G12C, far fewer than the G12D, G12V and G12R mutations that make up most of the rest, so it is a small group even in a common cancer.
- Subtypes: KRAS G12C PDAC after first-line chemotherapy (sotorasib or adagrasib listed; daraxonrasib approved); KRAS G12C PDAC in trials of G12C-selective inhibitors (elironrasib, olomorasib, glecirasib, divarasib); KRAS G12C PDAC with acquired resistance (secondary KRAS mutations, bypass signalling); KRAS G12C PDAC treated first line with chemotherapy as for other KRAS-mutant disease
- Biomarkers: KRAS G12C by tissue or plasma next-generation sequencing (about 1 to 2 percent of pancreatic adenocarcinomas); Co-alterations in TP53, CDKN2A and SMAD4; Acquired KRAS mutations, KRAS amplification or receptor tyrosine kinase bypass at progression; CA 19-9 for response monitoring; Liver enzymes on a G12C inhibitor

## 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-pdac/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-pdac/#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-pdac/#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-pdac/#finding-it [5 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-pdac/#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-pdac/#evidence [9 trials, 4 key papers, 5 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-pdac/#science [2 targets, 3 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-pdac/where-you-are/ [32 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-pdac/#living-with-it [17 questions, 5 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-pdac/coming/ [11 medicines, 7 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-pdac/data/ [56 connected records]

## Standard of care

- First line: Chemotherapy as for other pancreatic adenocarcinoma: modified FOLFIRINOX, NALIRIFOX or gemcitabine plus nab-paclitaxel; G12C inhibitors are not approved first line. ([FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/), [NALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV)](https://onco.cc/drugs/nalirifox/), [Gemcitabine + nab-paclitaxel](https://onco.cc/drugs/gemcitabine-nab-paclitaxel/), [KRAS mutation subtypes (G12C, G12D, G12V)](https://onco.cc/terms/kras-mutation-subtypes/))
- After first-line chemotherapy: Daraxonrasib (RASolute 302, approved for pancreatic cancer irrespective of KRAS subtype); sotorasib or adagrasib as NCCN-listed options on the CodeBreaK 100 and KRYSTAL-1 cohorts. ([Daraxonrasib](https://onco.cc/drugs/daraxonrasib/), [RASolute 302](https://onco.cc/trials/rasolute-302/), [Sotorasib](https://onco.cc/drugs/sotorasib/), [Adagrasib](https://onco.cc/drugs/adagrasib/), [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/))
- Clinical trials: Elironrasib with daraxonrasib, olomorasib, glecirasib and other G12C-selective inhibitors alone or with chemotherapy or EGFR antibodies. ([Elironrasib](https://onco.cc/drugs/elironrasib/), [Study of Elironrasib and Daraxonrasib as Monotherapies and Combination Therapy in Participants With Advanced KRAS G12C Mutant Solid Tumors](https://onco.cc/trials/nct06128551/), [Olomorasib](https://onco.cc/drugs/olomorasib/), [Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C)](https://onco.cc/trials/nct04956640/), [Glecirasib](https://onco.cc/drugs/glecirasib/), [A Phase II Study Evaluating JAB-21822 Monotherapy in Adult Patients With Pancreatic Cancer and Other Solid Tumors Harboring the KRAS p.G12C Mutation.](https://onco.cc/trials/nct06008288/))

## State of the art

- Sotorasib and adagrasib give responses in a minority and disease control in most previously treated patients, and are guideline-listed options.
- Daraxonrasib gives the G12C group, like every other KRAS subgroup, an approved RAS inhibitor with pancreatic phase 3 evidence.
- RAS(ON) G12C-selective inhibitors such as elironrasib are being combined with pan-RAS inhibition to deepen responses.

## Open problems

- Responses to G12C-selective inhibitors are shallower and shorter in the pancreas than in the lung.
- Neither sotorasib nor adagrasib has a pancreatic indication, so access depends on off-label use and trials.
- Whether adding a G12C-selective drug to a pan-RAS inhibitor improves on the pan-RAS drug alone is untested.
- The group is too small for large randomised trials of its own.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/KRAS
- Wikipedia: https://en.wikipedia.org/wiki/KRAS
- NCCN Guidelines: Pancreatic Adenocarcinoma: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455

## Connected records

- cancers: [Borderline resectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/borderline-resectable-pdac/), [BRCA or PALB2-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/brca-palb2-pdac/), [KRAS G12C-mutant colorectal cancer](https://onco.cc/cancers/kras-g12c-colorectal/), [KRAS G12C-mutant non-small-cell lung cancer](https://onco.cc/cancers/kras-g12c-nsclc/), [KRAS wild-type pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-wild-type-pdac/), [Locally advanced unresectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/locally-advanced-pdac/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma](https://onco.cc/cancers/msi-high-pdac/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- roadmaps: [KRAS roadmap: undruggable → G12C → pan-RAS](https://onco.cc/roadmaps/kras-roadmap/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/)
- drugs: [Adagrasib](https://onco.cc/drugs/adagrasib/), [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/), [Divarasib](https://onco.cc/drugs/divarasib/), [Elironrasib](https://onco.cc/drugs/elironrasib/), [FOLFIRINOX / mFOLFIRINOX](https://onco.cc/drugs/folfirinox/), [Garsorasib](https://onco.cc/drugs/garsorasib/), [Gemcitabine + nab-paclitaxel](https://onco.cc/drugs/gemcitabine-nab-paclitaxel/), [Glecirasib](https://onco.cc/drugs/glecirasib/), [NALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV)](https://onco.cc/drugs/nalirifox/), [Olomorasib](https://onco.cc/drugs/olomorasib/), [Sotorasib](https://onco.cc/drugs/sotorasib/)
- companies: [Amgen](https://onco.cc/companies/amgen/), [Bristol Myers Squibb](https://onco.cc/companies/bms/), [Eli Lilly (incl. Loxo)](https://onco.cc/companies/eli-lilly/), [Jacobio Pharmaceuticals](https://onco.cc/companies/jacobio-pharmaceuticals/), [Revolution Medicines](https://onco.cc/companies/revolution-medicines/), [Roche / Genentech](https://onco.cc/companies/roche-genentech/)
- pathways: [Pancreatic cancer (KEGG map)](https://onco.cc/pathways/pancreatic-cancer-signalling/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [CA 19-9](https://onco.cc/terms/ca19-9/), [Driver mutation](https://onco.cc/terms/driver-mutation/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [KRAS mutation subtypes (G12C, G12D, G12V)](https://onco.cc/terms/kras-mutation-subtypes/), [Oncogene](https://onco.cc/terms/oncogene/)
- trials: [A Phase II Study Evaluating JAB-21822 Monotherapy in Adult Patients With Pancreatic Cancer and Other Solid Tumors Harboring the KRAS p.G12C Mutation.](https://onco.cc/trials/nct06008288/), [A Study Evaluating FMC-376 in Participants With KRAS G12C Mutated Solid Tumors](https://onco.cc/trials/nct06244771/), [An Open-label, Multicenter, Phase II Clinical Study to Evaluate HRS-7058 in Patients With Pancreatic Cancer](https://onco.cc/trials/nct07589569/), [CodeBreaK 100 (pancreatic cancer cohort)](https://onco.cc/trials/codebreak-100/), [Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1](https://onco.cc/trials/nct03785249/), [RASolute 302](https://onco.cc/trials/rasolute-302/), [Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma](https://onco.cc/trials/nct07491445/), [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 LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C)](https://onco.cc/trials/nct04956640/)
- people: [Andrew J. Aguirre](https://onco.cc/people/andrew-aguirre/), [Eileen M. O'Reilly](https://onco.cc/people/eileen-oreilly/), [Frank McCormick](https://onco.cc/people/frank-mccormick/), [Kevan M. Shokat](https://onco.cc/people/kevan-shokat/), [Tanios Bekaii-Saab](https://onco.cc/people/tanios-bekaii-saab/)
- key papers: [CodeBreaK 100: sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer](https://onco.cc/key-papers/paper-codebreak-100-sotorasib-kras-g12c-pancreatic-nejm-2023/), [CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug](https://onco.cc/key-papers/paper-codebreak-200-lancet-2023/), [KRYSTAL-1: adagrasib in advanced solid tumours harbouring a KRAS G12C mutation, including pancreatic cancer](https://onco.cc/key-papers/paper-krystal-1-adagrasib-kras-g12c-solid-tumours-jco-2023/), [Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable](https://onco.cc/key-papers/paper-ostrem-kras-g12c-nature-2013/)
- biomarkers: [KRAS G12C](https://onco.cc/biomarkers/kras-g12c/)

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