# 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

## 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

- 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 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/), [CodeBreaK 200](https://onco.cc/trials/codebreak-200/), [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/), [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/)
- people: [Ferdinandos Skoulidis](https://onco.cc/people/ferdinandos-skoulidis/), [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/), [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/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)

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