# KRAS G12C-mutant non-small-cell lung cancer

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

## TL;DR

KRAS G12C lung cancer carries a mutation that was thought impossible to drug for forty years. Sotorasib and adagrasib now shrink about four in ten tumours after chemotherapy and immunotherapy, though the benefit is measured in months, and newer inhibitors and first-line combinations with immunotherapy are in trials.

## Summary

KRAS was the first human oncogene identified in a solid tumour, but its smooth surface and picomolar affinity for GTP defeated every attempt at a drug until 2013, when Kevan Shokat's laboratory showed that the mutant cysteine of G12C could be trapped by a covalent inhibitor in a pocket that exists only in the inactive, GDP-bound state. Unlike EGFR or ALK disease, KRAS-mutant lung cancer occurs in smokers, carries a high mutation burden, often expresses PD-L1 and responds to checkpoint inhibitors, so first-line treatment is chemoimmunotherapy or pembrolizumab alone as for driver-negative disease; co-mutations in STK11 and KEAP1, present in a quarter to a third, blunt that response.

Sotorasib produced a 37 percent response rate in previously treated patients in CodeBreaK 100 and received accelerated approval in May 2021, the first KRAS inhibitor; CodeBreaK 200 (2023) then showed it beat docetaxel on progression-free survival (5.6 versus 4.5 months, hazard ratio 0.66) but not overall survival, and the FDA required a new dose-comparison study. Adagrasib produced a 43 percent response rate in KRYSTAL-1 with activity in brain metastases and was approved in December 2022; KRYSTAL-12 (2024) showed progression-free survival of 5.5 versus 3.8 months against docetaxel (hazard ratio 0.58). Resistance emerges within months through secondary KRAS mutations, amplification, bypass through receptor tyrosine kinases and histological transformation, and both drugs have liver toxicity that is worse soon after immunotherapy.

The field is moving in three directions: more potent or better tolerated G12C inhibitors (divarasib, with a 53 percent response rate in phase 1 and the Krascendo 1 phase 3; olomorasib; glecirasib and garsorasib approved in China), first-line combinations with pembrolizumab (KRYSTAL-7, SUNRAY-01), and pan-RAS inhibitors such as daraxonrasib that bind the active state. Open questions are why lung tumours respond better than colorectal tumours, how to overcome STK11 and KEAP1 co-mutations, and whether a KRAS inhibitor can be combined safely with a checkpoint inhibitor from the start.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: KRAS G12C lung cancer; KRAS-mutant NSCLC; KRAS p.G12C non-small-cell lung cancer
- Tags: subtype-page; lung
- Group: lung
- Burden: KRAS is mutated in about a quarter of lung adenocarcinomas in Europe and North America, and G12C, the smoking-associated variant, accounts for about 13 percent of adenocarcinomas, making it the single commonest targetable driver in Western patients. It is rarer in East Asia.
- Subtypes: KRAS G12C adenocarcinoma with high PD-L1 (chemoimmunotherapy or pembrolizumab first, inhibitor second); KRAS G12C adenocarcinoma with STK11 or KEAP1 co-mutation (poor immunotherapy response); KRAS G12C with brain metastases (adagrasib has intracranial activity); Non-G12C KRAS mutations (G12D, G12V; pan-RAS inhibitors in trials)
- Biomarkers: KRAS G12C by tissue or plasma sequencing; PD-L1 tumour proportion score (first-line choice); STK11 and KEAP1 co-mutations (prognostic, immunotherapy resistance); TP53 co-mutation; Acquired KRAS mutations, MET amplification or bypass alterations at progression; Liver enzymes on a G12C inhibitor, especially soon after immunotherapy

## 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-nsclc/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-nsclc/#overview [4 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-nsclc/#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-nsclc/#finding-it [6 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-nsclc/#treating-it [3 settings, 3 decisions with options]
- Trials and papers (own page): 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-nsclc/evidence/ [43 trials, 3 key papers, 6 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-nsclc/#science [4 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-nsclc/where-you-are/ [34 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-nsclc/#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-nsclc/coming/ [14 medicines, 42 trials, 2 ideas, 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-nsclc/data/ [101 connected records]

## Standard of care

- Advanced, first line: As for driver-negative disease: pembrolizumab plus platinum doublet, or pembrolizumab alone if PD-L1 is 50 percent or more; KRAS inhibitors are not yet approved first line. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [KEYNOTE-024 & KEYNOTE-189](https://onco.cc/trials/keynote-024-189/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Tumour proportion score (TPS)](https://onco.cc/terms/tps/))
- Advanced, after chemoimmunotherapy: Sotorasib (CodeBreaK 200) or adagrasib (KRYSTAL-12), preferred to docetaxel; adagrasib for active brain metastases; docetaxel with or without ramucirumab afterwards. ([Sotorasib](https://onco.cc/drugs/sotorasib/), [CodeBreaK 200](https://onco.cc/trials/codebreak-200/), [Adagrasib](https://onco.cc/drugs/adagrasib/), [KRYSTAL-12](https://onco.cc/trials/krystal-12/), [Docetaxel](https://onco.cc/drugs/docetaxel/), [Ramucirumab](https://onco.cc/drugs/ramucirumab/), [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/))
- Advanced, clinical trials: Divarasib versus sotorasib or adagrasib (Krascendo 1); olomorasib or adagrasib with pembrolizumab first line (SUNRAY-01, KRYSTAL-7); pan-RAS inhibitors. ([Divarasib](https://onco.cc/drugs/divarasib/), [Krascendo 1](https://onco.cc/trials/krascendo-1/), [Olomorasib](https://onco.cc/drugs/olomorasib/), [A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer](https://onco.cc/trials/nct06119581/), [Phase 2 Trial of Adagrasib Monotherapy and in Combination With Pembrolizumab and a Phase 3 Trial of Adagrasib in Combination in Patients With a KRAS G](https://onco.cc/trials/nct04613596/), [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/))

## State of the art

- Two approved covalent G12C inhibitors after chemoimmunotherapy, both with progression-free survival gains over docetaxel of one to two months and response rates around 40 percent.
- Divarasib, olomorasib and the Chinese inhibitors glecirasib and garsorasib aim at deeper and longer responses.
- First-line KRAS inhibitor plus pembrolizumab combinations in phase 3.
- Pan-RAS and RAS(ON) inhibitors extend the approach to G12D and G12V.

## Open problems

- Responses to G12C inhibitors are shallower and shorter in lung cancer than EGFR or ALK inhibitors achieve, and no overall survival benefit over docetaxel has been shown.
- Liver toxicity when a G12C inhibitor follows or accompanies a checkpoint inhibitor limits first-line combinations.
- STK11 and KEAP1 co-mutations predict poor outcome with every treatment and have no targeted therapy.
- Resistance is polyclonal and mechanistically diverse, arguing for combinations from the start.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/KRAS
- Wikipedia: https://en.wikipedia.org/wiki/KRAS
- NCCN Guidelines: Non-Small Cell Lung Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450

## Connected records

- cancers: [Adenocarcinoma of the lung](https://onco.cc/cancers/lung-adenocarcinoma/), [ALK-positive non-small-cell lung cancer](https://onco.cc/cancers/alk-positive-nsclc/), [BRAF V600E-mutant non-small-cell lung cancer](https://onco.cc/cancers/braf-v600e-nsclc/), [EGFR-mutated non-small-cell lung cancer](https://onco.cc/cancers/egfr-mutant-nsclc/), [HER2-mutant non-small-cell lung cancer](https://onco.cc/cancers/her2-mutant-nsclc/), [Invasive mucinous adenocarcinoma of the lung](https://onco.cc/cancers/invasive-mucinous-adenocarcinoma-lung/), [KRAS G12C-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-g12c-pdac/), [MET exon 14 and MET-amplified non-small-cell lung cancer](https://onco.cc/cancers/met-altered-nsclc/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [PD-L1-high non-small-cell lung cancer without a driver mutation](https://onco.cc/cancers/pdl1-high-nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [KRAS](https://onco.cc/targets/kras/), [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/)
- drugs: [Adagrasib](https://onco.cc/drugs/adagrasib/), [Calderasib](https://onco.cc/drugs/calderasib/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/), [Divarasib](https://onco.cc/drugs/divarasib/), [Docetaxel](https://onco.cc/drugs/docetaxel/), [Garsorasib](https://onco.cc/drugs/garsorasib/), [Glecirasib](https://onco.cc/drugs/glecirasib/), [Olomorasib](https://onco.cc/drugs/olomorasib/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Ramucirumab](https://onco.cc/drugs/ramucirumab/), [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/), [Merck & Co. (MSD)](https://onco.cc/companies/merck/), [Roche / Genentech](https://onco.cc/companies/roche-genentech/)
- pathways: [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Driver mutation](https://onco.cc/terms/driver-mutation/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Hepatotoxicity (liver enzyme elevation)](https://onco.cc/terms/hepatotoxicity/), [KRAS mutation subtypes (G12C, G12D, G12V)](https://onco.cc/terms/kras-mutation-subtypes/), [Oncogene](https://onco.cc/terms/oncogene/), [Tumour proportion score (TPS)](https://onco.cc/terms/tps/)
- trials: [A Clinical Study of Calderasib (MK-1084) and Other Treatments for Participants With Non-Small Cell Lung Cancer (MK-1084-007/KANDLELIT-007)](https://onco.cc/trials/nct07190248/), [A Clinical Trial of Calderasib (MK-1084) and Durvalumab in People With Non-Small Cell Lung Cancer (MK-1084-015/KANDLELIT-015)](https://onco.cc/trials/nct07554339/), [A Multicenter, Single-arm Phase II Study to Evaluate the Efficacy and Safety of Fulzerasib (IBI351) in Combination With Ivonescimab (AK-112) in First-line Treatment of Advanced or Metastatic Non-small Cell Lung Cancer Patients With KRAS G12C Mutation](https://onco.cc/trials/nct06936644/), [A Phase 2 Clinical Study of Combination Therapy With ABSK043 and Glecirasib](https://onco.cc/trials/nct07164170/), [A Phase 3 Study of IN10018 in Combination With D-1553 Versus Standard Therapy for First Line Non-squamous Non-small Cell Lung Cancer With KRAS G12C Mutation](https://onco.cc/trials/nct07174908/), [A Phase 3 Study of Sosimerasib in Combination With IN10018 Versus Standard Therapy for First Line Non-squamous Non-small Cell Lung Cancer With KRAS G12C Mutatio](https://onco.cc/trials/nct07833202/), [A Study Evaluating FMC-376 in Participants With KRAS G12C Mutated Solid Tumors](https://onco.cc/trials/nct06244771/), [A Study Evaluating HS-10370 Plus Platinum-based Doublet Chemotherapy With or Without Adebrelimab vs. Tislelizumab Plus Chemotherapy as First-Line Therapy in Pat](https://onco.cc/trials/nct07822542/), [A Study Evaluating Sotorasib Platinum Doublet Combination Versus Pembrolizumab Platinum Doublet Combination as a Front-Line Therapy in Participants Wi](https://onco.cc/trials/nct05920356/), [A Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Particip](https://onco.cc/trials/nct06793215/), [A Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib as a Single Agent or in Combination With Other Anti-Cancer Therapies in Par](https://onco.cc/trials/nct05789082/), [A Study of Adagrasib Plus Pembrolizumab Plus Chemotherapy vs. Placebo Plus Pembrolizumab Plus Chemotherapy in Participants With Previously Untreated Non-squamous Non-small Cell Lung Cancer With KRAS G12C Mutation (KRYSTAL-4)](https://onco.cc/trials/nct06875310/), [A Study of BL-B01D1 Combined With Glecirasib in Patients With KRAS G12C-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer](https://onco.cc/trials/nct07827261/), [A Study of Calderasib (MK-1084) Plus Pembrolizumab (MK-3475) in Participants With KRAS G12C Mutant Non-small Cell Lung Cancer (NSCLC) With Programmed Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥50% (MK-1084-004/KANDLELIT-004)](https://onco.cc/trials/nct06345729/), [A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer](https://onco.cc/trials/nct06119581/), [A Study of JAB-21822 in Adult Patients With Advanced Solid Tumors Harboring KRAS p.G12C Mutation in China](https://onco.cc/trials/nct05009329/), [A Study of JAB-21822 in Advanced or Metastatic NSCLC With KRAS p.G12C and STK11 Co-mutation and Wild-type KEAP1](https://onco.cc/trials/nct05276726/), [A Study to Evaluate the Efficacy and Safety of Divarasib Compared With Investigator's Choice of Immunotherapy or Observation in Participants With Rese](https://onco.cc/trials/nct07541170/), [A Trial of HRS-7058 in Advanced or Metastatic Non-Small Cell Lung Cancer Patients Who Have Failed Standard Treatment](https://onco.cc/trials/nct07601048/), [Adagrasib + SRS for Patients With Metastatic KRAS G12C-mutated NSCLC With Untreated Brain Metastases](https://onco.cc/trials/nct06248606/), [CodeBreaK 200](https://onco.cc/trials/codebreak-200/), [Combination Therapies With Adagrasib in Patients With Advanced NSCLC With KRAS G12C Mutation](https://onco.cc/trials/nct05609578/), [D-1553 Tablet Versus Docetaxel Injection for KRAS G12C Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer After Prior Standar](https://onco.cc/trials/nct06300177/), [Fulzerasib Sequential Sintilimab Plus Platinum-Doublet Neoadjuvant Therapy for Resectable KRAS G12C-Mutant NSCLC](https://onco.cc/trials/nct07492342/), [Garsorasib In KRAS G12C Mutant Locally Advanced and Metastatic NSCLC](https://onco.cc/trials/nct07294261/), [IBI351 Plus Cetuximab β in Untreated Advanced Non-small Cell Lung Cancer With KRAS G12C Mutation](https://onco.cc/trials/nct07198841/), [JAB-21822 Combined With JAB-3312 Compared SOC in the First Line for Treatment of Advanced Non-small Cell Lung Cancer With KRAS p.G12C Mutation](https://onco.cc/trials/nct06416410/), [KEYNOTE-024 & KEYNOTE-189](https://onco.cc/trials/keynote-024-189/), [Krascendo 1](https://onco.cc/trials/krascendo-1/), [KRYSTAL-12](https://onco.cc/trials/krystal-12/), [MK-3475A±Calderasib (MK-1084) in Completely Resected Stage IIA-IIIB (N2) KRAS G12Cm NSCLC (MK-1084-013)](https://onco.cc/trials/nct07431827/), [Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients](https://onco.cc/trials/nct05074810/), [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 2 Trial of Adagrasib Monotherapy and in Combination With Pembrolizumab and a Phase 3 Trial of Adagrasib in Combination in Patients With a KRAS G](https://onco.cc/trials/nct04613596/), [Phase 3 Trial of JMKX001899 Versus Docetaxel in Previously Treated Advanced or Metastatic KRAS G12C-Mutant NSCLC](https://onco.cc/trials/nct07242274/), [Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation](https://onco.cc/trials/nct05358249/), [Study of Efficacy and Safety of JDQ443 Single-agent as First-line Treatment for Patients With Locally Advanced or Metastatic KRAS G12C- Mutated Non-small Cell Lung Cancer With a PD-L1 Expression < 1% or a PD-L1 Expression ≥ 1% and an STK11 Co-mutation.](https://onco.cc/trials/nct05445843/), [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 Comparison With Docetaxel in Participants With Locally Advanced or Metastatic KRAS G12C Mutant Non-small Cell Lung Cancer](https://onco.cc/trials/nct05132075/), [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 Olomorasib (LY3537982) in Combination With Standard of Care in Participants With Resected or Unresectable KRAS G12C-mutant Non-Small Cell Lung Cancer](https://onco.cc/trials/nct06890598/), [Study to Evaluate D-1553 in Subjects With Solid Tumors](https://onco.cc/trials/nct04585035/)
- people: [Ferdinandos Skoulidis](https://onco.cc/people/ferdinandos-skoulidis/), [Gary Middleton](https://onco.cc/people/gary-middleton/), [Kevan M. Shokat](https://onco.cc/people/kevan-shokat/), [Pasi A. Jänne](https://onco.cc/people/pasi-janne/), [Ramaswamy Govindan](https://onco.cc/people/ramaswamy-govindan/), [Tony S. K. Mok](https://onco.cc/people/tony-mok/)
- key papers: [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-12 plain language summary: adagrasib for non-small-cell lung cancer with KRAS G12C mutations](https://onco.cc/key-papers/paper-krystal-12-plain-language-summary-future-oncol-2026/), [Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable](https://onco.cc/key-papers/paper-ostrem-kras-g12c-nature-2013/)
- ideas: [Antibodies that see mutant KRAS and p53 fragments displayed on the cell surface](https://onco.cc/ideas/idea-bio1-pmhc-bispecifics-public-drivers/), [Off-the-shelf KRAS vaccines after pancreatic cancer surgery](https://onco.cc/ideas/idea-shared-kras-vaccine-adjuvant/)

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