KRAS G12C-Mutant Non-Small Cell Lung Cancer

MONDO:0005061 Pathograph 4 non-small cell lung carcinoma

KRAS G12C-mutant non-small cell lung cancer (NSCLC) is a molecularly-defined lung cancer subtype driven by the KRAS G12C point mutation. This mutation accounts for approximately 13% of NSCLC and was historically considered undruggable until the development of covalent KRAS G12C inhibitors. The G12C mutation substitutes cysteine for glycine at codon 12, creating a unique druggable pocket in the GDP-bound inactive state. Sotorasib and adagrasib represent the first approved targeted therapies for KRAS-mutant cancers, a breakthrough after decades of failed attempts to target RAS.

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Mappings

Definitions

Inheritance

Differentials

Datasets

Trials

Models

References

Deep Research

🏷

Classifications

Harrison's Chapter

ICD-O Morphology

◆

Subtypes

KRAS G12C Adenocarcinoma

The majority of KRAS G12C NSCLC presents as adenocarcinoma histology. Associated with smoking history in most cases.

KRAS G12C with STK11/LKB1 Co-mutation

Co-occurring STK11/LKB1 inactivation is common (~20-30%) and associated with worse prognosis and reduced immunotherapy response. May still respond to KRAS G12C inhibitors.

KRAS G12C with KEAP1 Co-mutation

Co-occurring KEAP1 mutations (~15-20%) are associated with worse outcomes and may confer resistance to KRAS G12C inhibitors.

⚙

Pathophysiology

KRAS G12C Oncogenic Mutation

The KRAS G12C mutation substitutes cysteine for glycine at codon 12, impairing GTPase activity and trapping KRAS in the active GTP-bound state. However, unlike other KRAS mutations, G12C retains some GTPase activity, cycling between active (GTP-bound) and inactive (GDP-bound) states. This cycling creates a therapeutic window for covalent inhibitors that bind the mutant cysteine in the GDP-bound state.

type II pneumocyte link

small GTPase mediated signal transduction link ↑ INCREASED

Downstream

Constitutive RAS Signaling Impaired GTPase activity leads to prolonged active state

Show evidence (1 reference)

PMID:33618059 PARTIAL

"The KRAS glycine-to-cysteine mutation (G12C) composes approximately 44% of KRAS mutations in non-small cell lung cancer, with mutant KRasG12C present in approximately 13% of all patients with lung adenocarcinoma."

This abstract explicitly describes the KRAS G12C substitution and its frequency in NSCLC, supporting the oncogenic mutation context.

Constitutive RAS Signaling

Mutant KRAS drives constitutive activation of downstream effector pathways including RAF-MEK-ERK (proliferation) and PI3K-AKT-mTOR (survival). The MAPK pathway is the predominant driver of oncogenic phenotypes in KRAS-mutant NSCLC.

MAPK cascade link ↑ INCREASED phosphatidylinositol 3-kinase signaling link ↑ INCREASED

Downstream

Cell Proliferation and Survival Sustained mitogenic and survival signaling

Show evidence (1 reference)

PMID:33618059 PARTIAL Human Clinical

"Mutation in the gene that encodes Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic driver in advanced non-small cell lung cancer, occurring in approximately 30% of lung adenocarcinomas."

Supports KRAS as a major oncogenic driver in NSCLC; downstream RAF/MEK/ERK and PI3K/AKT activation are mechanistic interpretation beyond this abstract snippet.

Cell Proliferation and Survival

Constitutive KRAS signaling promotes uncontrolled cell proliferation through ERK-mediated transcription of cell cycle genes and survival through AKT-mediated inhibition of apoptosis.

cell population proliferation link ↑ INCREASED

Downstream

KRAS G12C Inhibitor Resistance Selective pressure from KRAS G12C inhibitors drives secondary mutations and bypass pathway activation

KRAS G12C Inhibitor Resistance

Resistance to KRAS G12C inhibitors develops through multiple mechanisms: secondary KRAS mutations (Y96C, R68S, H95D/Q/R), KRAS amplification, bypass pathway activation (MET, EGFR, FGFR, PI3K), and histologic transformation. Adaptive feedback through RTK reactivation (EGFR, FGFR, SHP2) is common.

response to drug link ⚠ ABNORMAL

✶

Histopathology

Adenocarcinoma Predominance VERY_FREQUENT

Adenocarcinoma is the most common histologic subtype in NSCLC.

Show evidence (1 reference)

PMID:32657049 PARTIAL

"Of 256 patients with NSCLC, 219 were adenocarcinoma"

Abstract reports a NSCLC cohort dominated by adenocarcinoma.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Lung Adenocarcinoma VERY_FREQUENT Neoplastic HP:0030078

Show evidence (1 reference)

PMID:33618059 SUPPORT Human Clinical

Directly supports lung adenocarcinoma as the predominant histologic context in which KRAS G12C mutations are found.

Smoking Association VERY_FREQUENT Clinical HP:0100526

Show evidence (1 reference)

PMID:23014527 SUPPORT Human Clinical

"KRAS G12C, the most common G > T transversion mutation in smokers, was more frequent in women (P = 0.007) and these women were younger than men with the same mutation (median 65 vs. 69, P = 0.0008) and had smoked less."

Directly links KRAS G12C to the G>T transversion pattern observed in smokers with lung adenocarcinoma.

Brain Metastases FREQUENT Clinical HP:0004375

🧬

Genetic Associations

KRAS (Somatic Activating Mutation)

Somatic

Show evidence (1 reference)

PMID:33618059 SUPPORT Human Clinical

"Over 80% of oncogenic KRAS mutations occur at codon 12, where the glycine residue is substituted by different amino acids, leading to genomic heterogeneity of KRas-mutant tumors."

Directly supports somatic activating KRAS codon-12 mutations (including G12C) as the canonical molecular driver in this NSCLC subtype.

STK11 (Co-occurring Inactivation)

Somatic

Show evidence (1 reference)

PMID:32312757 SUPPORT Human Clinical

"Somatic mutations in STK11 and KEAP1, frequently comutated in non-squamous non-small cell lung cancer (NSQ NSCLC), have been associated with poor response to immune checkpoint blockade (ICB)."

Directly supports somatic STK11 co-mutation as a frequent event in NSCLC with implications for immunotherapy outcomes.

KEAP1 (Co-occurring Inactivation)

Somatic

Show evidence (1 reference)

PMID:32312757 SUPPORT Human Clinical

"Mutations in STK11 or KEAP1 were associated with poor outcomes across multiple therapeutic classes and were not specifically associated with poor outcomes in ICB cohorts."

Directly supports somatic KEAP1 mutation as a prognostically adverse alteration in lung adenocarcinoma, independent of treatment class.

💊

Treatments

Sotorasib

Action: pharmacotherapy MAXO:0000058

Agent: sotorasib ↗

First-in-class KRAS G12C inhibitor. Covalently binds mutant cysteine in the GDP-bound inactive state, locking KRAS in the off position. FDA approved for previously treated KRAS G12C NSCLC based on CodeBreaK 100 trial.

🔬 3D Structures:

6OIM X-ray 1.65 Å ⚗️ sotorasib

KRAS G12C in complex with sotorasib (AMG 510) covalently bound to Cys12, trapping the switch II pocket in the GDP-bound inactive state

Show evidence (1 reference)

PMID:34096690 SUPPORT

"An objective response was observed in 46 patients (37.1%"

Phase 2 trial reports objective responses to sotorasib in KRAS G12C NSCLC.

Adagrasib

Action: pharmacotherapy MAXO:0000058

Agent: adagrasib ↗

Second KRAS G12C inhibitor to gain FDA approval. Has longer half-life than sotorasib and demonstrated intracranial activity. Approved based on KRYSTAL-1 trial.

Show evidence (1 reference)

PMID:35658005 SUPPORT

"Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response."

KRYSTAL-1 abstract reports objective responses to adagrasib in KRAS G12C NSCLC.

KRAS G12C Inhibitor Combinations

Action: pharmacotherapy MAXO:0000058

Combinations with SHP2 inhibitors, SOS1 inhibitors, or EGFR inhibitors are being explored to prevent adaptive resistance and improve response durability. Rational combinations target feedback reactivation of RTK-RAS signaling.

Show evidence (1 reference)

PMID:39103541 SUPPORT Model Organism

"Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib."

Directly supports SOS1 plus KRAS G12C inhibitor combination treatment as a strategy evaluated in KRAS G12C mutant lung cancer models.

Immunotherapy

Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262

Checkpoint inhibitors (pembrolizumab, nivolumab) are used for KRAS-mutant NSCLC, particularly those without STK11 co-mutation. KRAS-mutant tumors often have high TMB from smoking. Combination with KRAS G12C inhibitors is under investigation.

Chemotherapy

Action: chemotherapy MAXO:0000647

Platinum-based chemotherapy remains standard for patients who progress on targeted therapy or as first-line with immunotherapy.

🔬

Biochemical Markers

KRAS Mutation Testing

Show evidence (1 reference)

PMID:33618059 SUPPORT Human Clinical

"pathologists, medical oncologists, and community practitioners will need to incorporate routine testing for emerging biomarkers such as MET amplification, ERBB2 (alias HER2), and KRAS mutations, particularly KRAS G12C, considering the promising development of direct inhibitors of KRasG12C protein."

Directly supports routine KRAS (especially G12C) mutation testing as part of molecular profiling to guide targeted therapy selection.

{ }

Source YAML

click to show

name: KRAS G12C-Mutant Non-Small Cell Lung Cancer
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-09T17:39:56Z'
description: >-
  KRAS G12C-mutant non-small cell lung cancer (NSCLC) is a molecularly-defined lung
  cancer subtype driven by the KRAS G12C point mutation. This mutation accounts for
  approximately 13% of NSCLC and was historically considered undruggable until the
  development of covalent KRAS G12C inhibitors. The G12C mutation substitutes cysteine
  for glycine at codon 12, creating a unique druggable pocket in the GDP-bound inactive
  state. Sotorasib and adagrasib represent the first approved targeted therapies for
  KRAS-mutant cancers, a breakthrough after decades of failed attempts to target RAS.
categories:
- Molecularly-Defined Cancer
- Lung Cancer Subtype
- Solid Tumor
parents:
- non-small cell lung carcinoma
has_subtypes:
- name: KRAS G12C Adenocarcinoma
  description: >-
    The majority of KRAS G12C NSCLC presents as adenocarcinoma histology.
    Associated with smoking history in most cases.
- name: KRAS G12C with STK11/LKB1 Co-mutation
  description: >-
    Co-occurring STK11/LKB1 inactivation is common (~20-30%) and associated with
    worse prognosis and reduced immunotherapy response. May still respond to
    KRAS G12C inhibitors.
- name: KRAS G12C with KEAP1 Co-mutation
  description: >-
    Co-occurring KEAP1 mutations (~15-20%) are associated with worse outcomes
    and may confer resistance to KRAS G12C inhibitors.
pathophysiology:
- name: KRAS G12C Oncogenic Mutation
  description: >-
    The KRAS G12C mutation substitutes cysteine for glycine at codon 12, impairing
    GTPase activity and trapping KRAS in the active GTP-bound state. However, unlike
    other KRAS mutations, G12C retains some GTPase activity, cycling between active
    (GTP-bound) and inactive (GDP-bound) states. This cycling creates a therapeutic
    window for covalent inhibitors that bind the mutant cysteine in the GDP-bound
    state.
  evidence:
  - reference: PMID:33618059
    reference_title: "KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing."
    supports: PARTIAL
    snippet: The KRAS glycine-to-cysteine mutation (G12C) composes approximately 44% of KRAS mutations in non-small cell lung cancer, with mutant KRasG12C present in approximately 13% of all patients with lung adenocarcinoma.
    explanation: This abstract explicitly describes the KRAS G12C substitution and its frequency in NSCLC, supporting the oncogenic mutation context.
  cell_types:
  - preferred_term: type II pneumocyte
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  biological_processes:
  - preferred_term: small GTPase mediated signal transduction
    modifier: INCREASED
    term:
      id: GO:0007264
      label: small GTPase mediated signal transduction
  downstream:
  - target: Constitutive RAS Signaling
    description: Impaired GTPase activity leads to prolonged active state
- name: Constitutive RAS Signaling
  description: >-
    Mutant KRAS drives constitutive activation of downstream effector pathways
    including RAF-MEK-ERK (proliferation) and PI3K-AKT-mTOR (survival). The MAPK
    pathway is the predominant driver of oncogenic phenotypes in KRAS-mutant NSCLC.
  evidence:
  - reference: PMID:33618059
    reference_title: "KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation in the gene that encodes Kirsten rat sarcoma viral oncogene
      homolog (KRAS) is the most common oncogenic driver in advanced
      non-small cell lung cancer, occurring in approximately 30% of lung
      adenocarcinomas.
    explanation: >-
      Supports KRAS as a major oncogenic driver in NSCLC; downstream
      RAF/MEK/ERK and PI3K/AKT activation are mechanistic interpretation
      beyond this abstract snippet.
  biological_processes:
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  - preferred_term: phosphatidylinositol 3-kinase signaling
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  downstream:
  - target: Cell Proliferation and Survival
    description: Sustained mitogenic and survival signaling
- name: Cell Proliferation and Survival
  description: >-
    Constitutive KRAS signaling promotes uncontrolled cell proliferation through
    ERK-mediated transcription of cell cycle genes and survival through AKT-mediated
    inhibition of apoptosis.
  downstream:
  - target: KRAS G12C Inhibitor Resistance
    description: Selective pressure from KRAS G12C inhibitors drives secondary mutations and bypass pathway activation
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
- name: KRAS G12C Inhibitor Resistance
  description: >-
    Resistance to KRAS G12C inhibitors develops through multiple mechanisms:
    secondary KRAS mutations (Y96C, R68S, H95D/Q/R), KRAS amplification, bypass
    pathway activation (MET, EGFR, FGFR, PI3K), and histologic transformation.
    Adaptive feedback through RTK reactivation (EGFR, FGFR, SHP2) is common.
  pdb_structures:
  - pdb_id: 6OIM
    description: Sotorasib/KRAS-G12C co-crystal — Y96C resistance mutation disrupts the switch II pocket where sotorasib's covalent warhead engages Cys12, blocking drug binding
    method: X-ray
    resolution_angstrom: 1.65
    ligand: sotorasib
    target_protein: KRAS G12C (reference for mapping resistance mutations)
  biological_processes:
  - preferred_term: response to drug
    modifier: ABNORMAL
    term:
      id: GO:0009410
      label: response to xenobiotic stimulus
histopathology:
- name: Adenocarcinoma Predominance
  finding_term:
    preferred_term: Lung Adenocarcinoma
    term:
      id: NCIT:C3512
      label: Lung Adenocarcinoma
  frequency: VERY_FREQUENT
  description: Adenocarcinoma is the most common histologic subtype in NSCLC.
  evidence:
  - reference: PMID:32657049
    reference_title: "Genetic profile of non-small cell lung cancer (NSCLC): A hospital-based survey in Jinhua."
    supports: PARTIAL
    snippet: "Of 256 patients with NSCLC, 219 were adenocarcinoma"
    explanation: Abstract reports a NSCLC cohort dominated by adenocarcinoma.

phenotypes:
- category: Neoplastic
  name: Lung Adenocarcinoma
  frequency: VERY_FREQUENT
  description: >-
    KRAS G12C NSCLC is predominantly adenocarcinoma histology, though can occur
    in squamous cell carcinoma. Often presents as peripheral lung mass.
  phenotype_term:
    preferred_term: Lung adenocarcinoma
    term:
      id: HP:0030078
      label: Lung adenocarcinoma
  evidence:
  - reference: PMID:33618059
    reference_title: "KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The KRAS glycine-to-cysteine mutation (G12C) composes approximately
      44% of KRAS mutations in non-small cell lung cancer, with mutant
      KRasG12C present in approximately 13% of all patients with lung
      adenocarcinoma.
    explanation: >-
      Directly supports lung adenocarcinoma as the predominant histologic
      context in which KRAS G12C mutations are found.
- category: Clinical
  name: Smoking Association
  frequency: VERY_FREQUENT
  description: >-
    Unlike EGFR/ALK/ROS1 alterations, KRAS G12C mutations are strongly associated
    with smoking history. The G>T transversion pattern is characteristic of
    tobacco-induced mutagenesis.
  phenotype_term:
    preferred_term: Neoplasm of the lung
    term:
      id: HP:0100526
      label: Neoplasm of the lung
  evidence:
  - reference: PMID:23014527
    reference_title: >-
      Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung
      adenocarcinomas: higher susceptibility of women to smoking-related
      KRAS-mutant cancers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KRAS G12C, the most common G > T transversion mutation in smokers, was
      more frequent in women (P = 0.007) and these women were younger than
      men with the same mutation (median 65 vs. 69, P = 0.0008) and had
      smoked less.
    explanation: >-
      Directly links KRAS G12C to the G>T transversion pattern observed in
      smokers with lung adenocarcinoma.
- category: Clinical
  name: Brain Metastases
  frequency: FREQUENT
  description: >-
    Brain metastases occur in KRAS G12C NSCLC, though CNS penetration of current
    KRAS inhibitors (sotorasib, adagrasib) varies. Adagrasib has demonstrated
    intracranial activity.
  phenotype_term:
    preferred_term: Neoplasm of the nervous system
    term:
      id: HP:0004375
      label: Neoplasm of the nervous system
biochemical:
- name: KRAS Mutation Testing
  notes: >-
    KRAS mutation testing is part of standard molecular profiling for advanced
    NSCLC. Methods include PCR-based assays and next-generation sequencing.
    G12C is the most common KRAS mutation in NSCLC (~40% of KRAS mutations).
    Testing should distinguish G12C from other KRAS mutations (G12D, G12V)
    which are not targetable with current approved agents.
  evidence:
  - reference: PMID:33618059
    reference_title: "KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pathologists, medical oncologists, and community practitioners will
      need to incorporate routine testing for emerging biomarkers such as
      MET amplification, ERBB2 (alias HER2), and KRAS mutations,
      particularly KRAS G12C, considering the promising development of
      direct inhibitors of KRasG12C protein.
    explanation: >-
      Directly supports routine KRAS (especially G12C) mutation testing
      as part of molecular profiling to guide targeted therapy selection.
genetic:
- name: KRAS
  association: Somatic Activating Mutation
  inheritance:
  - name: Somatic
  notes: >-
    KRAS (12p12.1) encodes a small GTPase in the RAS family. G12C is the most
    common KRAS mutation in NSCLC, resulting from a G>T transversion associated
    with smoking. Other common KRAS mutations include G12D and G12V. KRAS mutations
    are generally mutually exclusive with EGFR, ALK, and ROS1 alterations.
  evidence:
  - reference: PMID:33618059
    reference_title: "KRAS G12C-Mutant Non-Small Cell Lung Cancer: Biology, Developmental Therapeutics, and Molecular Testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over 80% of oncogenic KRAS mutations occur at codon 12, where the
      glycine residue is substituted by different amino acids, leading to
      genomic heterogeneity of KRas-mutant tumors.
    explanation: >-
      Directly supports somatic activating KRAS codon-12 mutations
      (including G12C) as the canonical molecular driver in this NSCLC
      subtype.
- name: STK11
  association: Co-occurring Inactivation
  inheritance:
  - name: Somatic
  notes: >-
    STK11/LKB1 (19p13.3) encodes a serine/threonine kinase tumor suppressor.
    Co-mutation with KRAS G12C occurs in ~20-30% of cases and is associated with
    reduced immunotherapy benefit. May still respond to KRAS G12C inhibitors.
  evidence:
  - reference: PMID:32312757
    reference_title: STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Somatic mutations in STK11 and KEAP1, frequently comutated in
      non-squamous non-small cell lung cancer (NSQ NSCLC), have been
      associated with poor response to immune checkpoint blockade (ICB).
    explanation: >-
      Directly supports somatic STK11 co-mutation as a frequent event in
      NSCLC with implications for immunotherapy outcomes.
- name: KEAP1
  association: Co-occurring Inactivation
  inheritance:
  - name: Somatic
  notes: >-
    KEAP1 (19p13.2) encodes a negative regulator of NRF2 antioxidant response.
    Co-mutation with KRAS G12C (~15-20%) associated with worse outcomes and
    potential resistance to targeted therapy.
  evidence:
  - reference: PMID:32312757
    reference_title: STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in STK11 or KEAP1 were associated with poor outcomes across
      multiple therapeutic classes and were not specifically associated
      with poor outcomes in ICB cohorts.
    explanation: >-
      Directly supports somatic KEAP1 mutation as a prognostically adverse
      alteration in lung adenocarcinoma, independent of treatment class.
treatments:
- name: Sotorasib
  description: >-
    First-in-class KRAS G12C inhibitor. Covalently binds mutant cysteine in the
    GDP-bound inactive state, locking KRAS in the off position. FDA approved for
    previously treated KRAS G12C NSCLC based on CodeBreaK 100 trial.
  pdb_structures:
  - pdb_id: 6OIM
    description: KRAS G12C in complex with sotorasib (AMG 510) covalently bound to Cys12, trapping the switch II pocket in the GDP-bound inactive state
    resolution_angstrom: 1.65
    method: X-ray
    ligand: sotorasib
    target_protein: KRAS G12C
    publication: PMID:31666701
  evidence:
  - reference: PMID:34096690
    reference_title: "Sotorasib for Lung Cancers with KRAS p.G12C Mutation."
    supports: SUPPORT
    snippet: "An objective response was observed in 46 patients (37.1%"
    explanation: "Phase 2 trial reports objective responses to sotorasib in KRAS G12C NSCLC."
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: sotorasib
      term:
        id: CHEBI:178199
        label: sotorasib
- name: Adagrasib
  description: >-
    Second KRAS G12C inhibitor to gain FDA approval. Has longer half-life than
    sotorasib and demonstrated intracranial activity. Approved based on KRYSTAL-1
    trial.
  evidence:
  - reference: PMID:35658005
    reference_title: "Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation."
    supports: SUPPORT
    snippet: "Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response."
    explanation: "KRYSTAL-1 abstract reports objective responses to adagrasib in KRAS G12C NSCLC."
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: adagrasib
      term:
        id: NCIT:C157493
        label: Adagrasib
- name: KRAS G12C Inhibitor Combinations
  description: >-
    Combinations with SHP2 inhibitors, SOS1 inhibitors, or EGFR inhibitors are
    being explored to prevent adaptive resistance and improve response durability.
    Rational combinations target feedback reactivation of RTK-RAS signaling.
  evidence:
  - reference: PMID:39103541
    reference_title: >-
      Co-targeting SOS1 enhances the antitumor effects of KRAS(G12C)
      inhibitors by addressing intrinsic and acquired resistance.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we assessed the antitumor responses of KRASG12C mutant lung and
      colorectal cancer models to combination treatment with a SOS1 inhibitor
      (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib.
    explanation: >-
      Directly supports SOS1 plus KRAS G12C inhibitor combination treatment
      as a strategy evaluated in KRAS G12C mutant lung cancer models.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
- name: Immunotherapy
  description: >-
    Checkpoint inhibitors (pembrolizumab, nivolumab) are used for KRAS-mutant NSCLC,
    particularly those without STK11 co-mutation. KRAS-mutant tumors often have
    high TMB from smoking. Combination with KRAS G12C inhibitors is under investigation.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
- name: Chemotherapy
  description: >-
    Platinum-based chemotherapy remains standard for patients who progress on
    targeted therapy or as first-line with immunotherapy.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
disease_term:
  preferred_term: lung adenocarcinoma
  term:
    id: MONDO:0005061
    label: lung adenocarcinoma

classifications:
  icdo_morphology:
    classification_value: Carcinoma
  harrisons_chapter:
  - classification_value: cancer
  - classification_value: solid tumor
references:
- reference: DOI:10.1002/cncr.35783
  title: Advances in the treatment of <i>KRAS</i><sup><i>G12C</i></sup> mutant non–small cell lung cancer
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenic drivers in metastatic non–small cell lung cancer (NSCLC).
    supporting_text: Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenic drivers in metastatic non–small cell lung cancer (NSCLC).
    evidence:
    - reference: DOI:10.1002/cncr.35783
      reference_title: Advances in the treatment of <i>KRAS</i><sup><i>G12C</i></sup> mutant non–small cell lung cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenic drivers in metastatic non–small cell lung cancer (NSCLC).
      explanation: Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.
- reference: DOI:10.1007/s12325-024-03020-7
  title: Real-World Evaluation of Treatment Patterns, Healthcare Costs, and Healthcare Resource Utilization Among Patients with Non-small Cell Lung Cancer in the US Receiving Sotorasib
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: Real-World Evaluation of Treatment Patterns, Healthcare Costs, and Healthcare Resource Utilization Among Patients with Non-small Cell Lung Cancer in the US Receiving Sotorasib
    supporting_text: Real-World Evaluation of Treatment Patterns, Healthcare Costs, and Healthcare Resource Utilization Among Patients with Non-small Cell Lung Cancer in the US Receiving Sotorasib
- reference: DOI:10.1080/14796694.2024.2407280
  title: An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer
    supporting_text: An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer
- reference: DOI:10.1080/14796694.2024.2430172
  title: Sotorasib for the treatment of locally advanced/metastatic non-small cell lung cancer
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: Sotorasib for the treatment of locally advanced/metastatic non-small cell lung cancer
    supporting_text: Sotorasib for the treatment of locally advanced/metastatic non-small cell lung cancer
- reference: DOI:10.1158/1078-0432.ccr-24-2310
  title: Impact of Co-mutations and Transcriptional Signatures in Non–Small Cell Lung Cancer Patients Treated with Adagrasib in the KRYSTAL-1 Trial
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: KRAS inhibitors are revolutionizing the treatment of non–small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.
    supporting_text: KRAS inhibitors are revolutionizing the treatment of non–small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.
    evidence:
    - reference: DOI:10.1158/1078-0432.ccr-24-2310
      reference_title: Impact of Co-mutations and Transcriptional Signatures in Non–Small Cell Lung Cancer Patients Treated with Adagrasib in the KRYSTAL-1 Trial
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: KRAS inhibitors are revolutionizing the treatment of non–small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.
      explanation: Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.
- reference: DOI:10.1200/jco.22.02524
  title: 'Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated <i>KRAS</i> G12C-Mutated Non–Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100'
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: Clinical trials frequently include multiple end points that mature at different times.
    supporting_text: Clinical trials frequently include multiple end points that mature at different times.
    evidence:
    - reference: DOI:10.1200/jco.22.02524
      reference_title: 'Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated <i>KRAS</i> G12C-Mutated Non–Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Clinical trials frequently include multiple end points that mature at different times.
      explanation: Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.
- reference: DOI:10.21037/tcr-23-1477
  title: 'CodeBreak 200: study limitations, and future directions'
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: 'CodeBreak 200: study limitations, and future directions'
    supporting_text: 'CodeBreak 200: study limitations, and future directions'
- reference: DOI:10.3389/fonc.2024.1357898
  title: Resistance to KRAS inhibition in advanced non-small cell lung cancer
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: Lung cancer remains the leading cause of cancer death globally.
    supporting_text: Lung cancer remains the leading cause of cancer death globally.
    evidence:
    - reference: DOI:10.3389/fonc.2024.1357898
      reference_title: Resistance to KRAS inhibition in advanced non-small cell lung cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Lung cancer remains the leading cause of cancer death globally.
      explanation: Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.
- reference: DOI:10.3390/cancers15235582
  title: Targeted Therapies for Kirsten Rat Sarcoma (KRAS) G12C Mutant Metastatic Non-Small-Cell Lung Cancers
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy.
    supporting_text: Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy.
    evidence:
    - reference: DOI:10.3390/cancers15235582
      reference_title: Targeted Therapies for Kirsten Rat Sarcoma (KRAS) G12C Mutant Metastatic Non-Small-Cell Lung Cancers
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy.
      explanation: Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.
- reference: DOI:10.3390/cancers17030353
  title: Emerging Targeted Therapies in Non-Small-Cell Lung Cancer (NSCLC)
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer.
    supporting_text: Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer.
    evidence:
    - reference: DOI:10.3390/cancers17030353
      reference_title: Emerging Targeted Therapies in Non-Small-Cell Lung Cancer (NSCLC)
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer.
      explanation: Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.
- reference: DOI:10.3390/jcm14196826
  title: 'KRAS G12C Mutation Predicts Improved Survival in NSCLC Patients Receiving Immunotherapy: Insights from a Real-World Cohort'
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC), with KRAS G12C emerging as a therapeutically targetable subtype.
    supporting_text: KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC), with KRAS G12C emerging as a therapeutically targetable subtype.
    evidence:
    - reference: DOI:10.3390/jcm14196826
      reference_title: 'KRAS G12C Mutation Predicts Improved Survival in NSCLC Patients Receiving Immunotherapy: Insights from a Real-World Cohort'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC), with KRAS G12C emerging as a therapeutically targetable subtype.
      explanation: Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.
- reference: DOI:10.3390/ph18101574
  title: 'Sex-Related Safety Signals of Sotorasib in Non-Small Cell Lung Cancer: A Real-World, Pharmacovigilance Study from the EudraVigilance Database'
  found_in:
  - KRAS_G12C_Mutant_NSCLC-deep-research-falcon.md
  findings:
  - statement: Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs).
    supporting_text: Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs).
    evidence:
    - reference: DOI:10.3390/ph18101574
      reference_title: 'Sex-Related Safety Signals of Sotorasib in Non-Small Cell Lung Cancer: A Real-World, Pharmacovigilance Study from the EudraVigilance Database'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs).
      explanation: Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.

📚

References & Deep Research

References

DOI:10.1002/cncr.35783

Advances in the treatment of KRASG12C mutant non–small cell lung cancer

1 finding

Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenic drivers in metastatic non–small cell lung cancer (NSCLC).

"Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenic drivers in metastatic non–small cell lung cancer (NSCLC)."

Show evidence (1 reference)

DOI:10.1002/cncr.35783 SUPPORT Human Clinical

"Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenic drivers in metastatic non–small cell lung cancer (NSCLC)."

Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.

DOI:10.1007/s12325-024-03020-7

Real-World Evaluation of Treatment Patterns, Healthcare Costs, and Healthcare Resource Utilization Among Patients with Non-small Cell Lung Cancer in the US Receiving Sotorasib

1 finding

Real-World Evaluation of Treatment Patterns, Healthcare Costs, and Healthcare Resource Utilization Among Patients with Non-small Cell Lung Cancer in the US Receiving Sotorasib

"Real-World Evaluation of Treatment Patterns, Healthcare Costs, and Healthcare Resource Utilization Among Patients with Non-small Cell Lung Cancer in the US Receiving Sotorasib"

DOI:10.1080/14796694.2024.2407280

An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer

1 finding

An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer

"An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer"

DOI:10.1080/14796694.2024.2430172

Sotorasib for the treatment of locally advanced/metastatic non-small cell lung cancer

1 finding

Sotorasib for the treatment of locally advanced/metastatic non-small cell lung cancer

"Sotorasib for the treatment of locally advanced/metastatic non-small cell lung cancer"

DOI:10.1158/1078-0432.ccr-24-2310

Impact of Co-mutations and Transcriptional Signatures in Non–Small Cell Lung Cancer Patients Treated with Adagrasib in the KRYSTAL-1 Trial

1 finding

KRAS inhibitors are revolutionizing the treatment of non–small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.

"KRAS inhibitors are revolutionizing the treatment of non–small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration."

Show evidence (1 reference)

DOI:10.1158/1078-0432.ccr-24-2310 SUPPORT Human Clinical

"KRAS inhibitors are revolutionizing the treatment of non–small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration."

Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.

DOI:10.1200/jco.22.02524

Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients With Pretreated KRAS G12C-Mutated Non–Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100

1 finding

Clinical trials frequently include multiple end points that mature at different times.

"Clinical trials frequently include multiple end points that mature at different times."

Show evidence (1 reference)

DOI:10.1200/jco.22.02524 SUPPORT Human Clinical

"Clinical trials frequently include multiple end points that mature at different times."

Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.

DOI:10.21037/tcr-23-1477

CodeBreak 200: study limitations, and future directions

1 finding

CodeBreak 200: study limitations, and future directions

"CodeBreak 200: study limitations, and future directions"

DOI:10.3389/fonc.2024.1357898

Resistance to KRAS inhibition in advanced non-small cell lung cancer

1 finding

Lung cancer remains the leading cause of cancer death globally.

"Lung cancer remains the leading cause of cancer death globally."

Show evidence (1 reference)

DOI:10.3389/fonc.2024.1357898 SUPPORT Human Clinical

"Lung cancer remains the leading cause of cancer death globally."

Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.

DOI:10.3390/cancers15235582

Targeted Therapies for Kirsten Rat Sarcoma (KRAS) G12C Mutant Metastatic Non-Small-Cell Lung Cancers

1 finding

Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy.

"Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy."

Show evidence (1 reference)

DOI:10.3390/cancers15235582 SUPPORT Human Clinical

"Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy."

Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.

DOI:10.3390/cancers17030353

Emerging Targeted Therapies in Non-Small-Cell Lung Cancer (NSCLC)

1 finding

Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer.

"Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer."

Show evidence (1 reference)

DOI:10.3390/cancers17030353 SUPPORT Human Clinical

"Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer."

Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.

DOI:10.3390/jcm14196826

KRAS G12C Mutation Predicts Improved Survival in NSCLC Patients Receiving Immunotherapy: Insights from a Real-World Cohort

1 finding

KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC), with KRAS G12C emerging as a therapeutically targetable subtype.

"KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC), with KRAS G12C emerging as a therapeutically targetable subtype."

Show evidence (1 reference)

DOI:10.3390/jcm14196826 SUPPORT Human Clinical

"KRAS mutations are among the most common oncogenic drivers in non-small cell lung cancer (NSCLC), with KRAS G12C emerging as a therapeutically targetable subtype."

Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.

DOI:10.3390/ph18101574

Sex-Related Safety Signals of Sotorasib in Non-Small Cell Lung Cancer: A Real-World, Pharmacovigilance Study from the EudraVigilance Database

1 finding

Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs).

"Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs)."

Show evidence (1 reference)

DOI:10.3390/ph18101574 SUPPORT Human Clinical

"Sotorasib, a KRAS G12C inhibitor, is approved for treating non-small cell lung cancer (NSCLC) and has shown a distinct safety profile in randomized clinical trials (RCTs)."

Deep research cited this publication as relevant literature for KRAS G12C Mutant NSCLC.

Deep Research

Falcon ▸

1. Disease Information

Edison Scientific Literature 29 citations 2026-05-09T09:54:04.123162

1. Disease Information

Concise overview

KRAS G12C‑mutant NSCLC refers to NSCLC (most commonly lung adenocarcinoma) in which tumor cells harbor a somatic KRAS p.G12C substitution (glycine→cysteine at codon 12). This is a driver oncogene alteration that has become clinically actionable through covalent “OFF‑state” KRAS G12C inhibitors such as sotorasib and adagrasib. (mina2025emergingtargetedtherapies pages 2-4, sreter2024resistancetokras pages 1-2)

Key identifiers and terminologies

Disease ontology identifiers available from retrieved evidence:
NSCLC: EFO_0003060 (Open Targets evidence) (OpenTargets Search: non-small cell lung carcinoma-KRAS)
Lung adenocarcinoma: EFO_0000571 (Open Targets evidence) (OpenTargets Search: non-small cell lung carcinoma-KRAS)
MeSH / ICD‑10 / ICD‑11 / Orphanet / OMIM: Not explicitly provided in the retrieved sources for this molecular subtype; therefore not asserted here.

Common synonyms / alternative names

“KRASG12C‑mutant NSCLC”
“KRAS p.G12C‑positive NSCLC”
“KRAS G12C‑mutated advanced/metastatic NSCLC” (Usage and wording in clinical trial reporting and reviews.) (dy2023longtermoutcomesand pages 2-3, langen2023sotorasibversusdocetaxel pages 8-10)

Evidence provenance (individual vs aggregated)

Most information below is derived from: - Aggregated clinical-trial evidence (CodeBreaK 100/200; KRYSTAL‑1 and later analyses) (dy2023longtermoutcomesand pages 2-3, langen2023sotorasibversusdocetaxel pages 8-10) - Real‑world observational datasets (claims/registry cohorts) (sultan2024realworldevaluationof pages 1-2, gecgel2025krasg12cmutation pages 9-11) - Preclinical model studies and mechanistic reviews (resistance/combination rationale) (sreter2024resistancetokras pages 1-2, shaverdashvili2025advancesinthe pages 2-3)

2. Etiology

Disease causal factors

Primary causal factor (mechanistic): An activating, oncogenic KRAS p.G12C mutation that dysregulates downstream signaling—classically MAPK/ERK and PI3K/AKT/mTOR—supporting malignant proliferation and survival. (mina2025emergingtargetedtherapies pages 2-4, sreter2024resistancetokras pages 1-2)

Risk factors

Smoking association: KRAS mutations are reported as more frequent in smokers than nonsmokers (example values: 30% vs 11%) and more common in Western vs Asian populations (26% vs 11%) in a 2024 overview review. (tenekeci2024anupdatedoverview pages 2-3)

Protective factors

No protective genetic or environmental factors specific to developing KRAS G12C‑mutant NSCLC were identified in the retrieved evidence.

Gene–environment interactions

The retrieved evidence supports a correlation between smoking exposure and KRAS mutation frequency, consistent with a gene–environment relationship; however, specific quantitative interaction models were not captured in the retrieved sources. (tenekeci2024anupdatedoverview pages 2-3)

3. Phenotypes

Clinical phenotype (NSCLC context)

The retrieved evidence is focused on molecular stratification and treatment outcomes rather than detailed symptom frequencies. As a molecular subtype of NSCLC, phenotypes are generally those of advanced NSCLC; however, phenotype frequencies and HPO mappings were not reported in the retrieved clinical-trial excerpts.

Suggested HPO terms (knowledge-base suggestions; not extracted from the above trials)

Because the phenotype spectrum is not explicitly described in the retrieved sources, the following are standard NSCLC‑relevant HPO suggestions for a knowledge base entry (flagged as suggestions rather than evidence‑extracted): - Cough (HP:0012735) - Dyspnea (HP:0002094) - Chest pain (HP:0100749) - Hemoptysis (HP:0002105) - Weight loss (HP:0001824) - Fatigue (HP:0012378) - Metastatic lesions (HP:0033006; broad)

4. Genetic / Molecular Information

Causal gene

KRAS (KRAS proto‑oncogene, GTPase) is strongly associated with NSCLC and lung adenocarcinoma in Open Targets evidence. (OpenTargets Search: non-small cell lung carcinoma-KRAS)

Pathogenic variant

KRAS p.G12C (somatic missense) is a canonical oncogenic driver in lung adenocarcinoma and the key actionable allele for currently approved direct KRAS inhibitors in NSCLC. (sreter2024resistancetokras pages 1-2, mina2025emergingtargetedtherapies pages 2-4)

Co-mutations / molecular modifiers (prognostic and predictive)

Co‑alterations shape prognosis and response to KRAS G12C inhibitors. - In a clinico‑genomic analysis of adagrasib‑treated KRAS G12C NSCLC (KRYSTAL‑1), KEAP1 and STK11 co‑mutations were associated with markedly worse outcomes: - KEAP1: PFS 4.1 vs 9.9 months; OS 5.4 vs 19.0 months (HRs ~2.7–3.6; P<0.01) (negrao2025impactofcomutations pages 1-2) - STK11: PFS 4.2 vs 11.0 months; OS 9.8 months vs not reached (HRs ~2.2–2.6; P<0.01) (negrao2025impactofcomutations pages 1-2) - High NRF2 signaling (including KEAP1/NRF2 axis activation) correlated with shorter survival on adagrasib even in KEAP1WT tumors. (negrao2025impactofcomutations pages 1-2) - A favorable molecular group (KEAP1WT/STK11WT/NRF2LOW) represented ~32% of adagrasib‑treated patients and showed longer PFS and OS than comparison groups in that analysis. (negrao2025impactofcomutations pages 1-2)

Functional consequence (high-level)

The KRAS G12C mutation yields a KRAS protein state exploitable by covalent inhibitors that bind the cysteine at position 12 and stabilize the GDP‑bound (inactive) form. (mina2025emergingtargetedtherapies pages 2-4, tenekeci2024anupdatedoverview pages 2-3)

Suggested GO terms (mechanism-oriented; consistent with retrieved pathway statements)

MAPK cascade (GO:0000165) (sreter2024resistancetokras pages 1-2)
PI3K/AKT signaling (GO:0014065; broad) (sreter2024resistancetokras pages 1-2)
Regulation of cell proliferation (GO:0042127; broad)

5. Environmental Information

Key environmental/lifestyle factors

Tobacco smoke exposure is the most clearly supported lifestyle association in the retrieved evidence through its association with higher KRAS mutation frequency. (tenekeci2024anupdatedoverview pages 2-3)

No infectious agents specific to this molecular subtype were identified in the retrieved evidence.

6. Mechanism / Pathophysiology

Core signaling pathways

KRAS activation drives downstream oncogenic signaling including: - MAPK pathway (RAF–MEK–ERK axis) and - PI3K–AKT–mTOR axis as summarized in recent reviews of KRAS‑mutant NSCLC and KRAS inhibition resistance. (sreter2024resistancetokras pages 1-2, mina2025emergingtargetedtherapies pages 2-4)

Therapeutic mechanism of KRAS G12C inhibitors

Covalent KRAS G12C inhibitors exploit the mutant cysteine to bind KRAS in a state that reduces signaling output; nonetheless, clinical activity is often limited by adaptive and acquired resistance. (mina2025emergingtargetedtherapies pages 2-4, shaverdashvili2025advancesinthe pages 2-3)

Resistance mechanisms (current understanding)

The retrieved evidence emphasizes that resistance to KRAS G12C inhibition is frequent and can be: - On‑target (secondary KRAS alterations preventing drug binding) and - Off‑target / bypass (reactivation via alternative oncogenic nodes or pathways), including RTK‑driven upstream reactivation and downstream pathway rewiring. (shaverdashvili2025advancesinthe pages 2-3)

A high‑impact 2024 preclinical study supports a concrete combination rationale: - Co‑targeting SOS1 (using BI‑3406) plus the KRAS G12C inhibitor adagrasib produced stronger suppression of RAS–MAPK signaling, delayed acquired resistance, and restored responses in adagrasib‑resistant models; resistance was associated with MRAS activity, which SOS1 and SHP2 inhibition can suppress. (sreter2024resistancetokras pages 1-2)

Cell types (CL) and tissues (UBERON)

The evidence is primarily genotype/therapy focused; histology indicates most cases are lung adenocarcinoma (UBERON:0002048 lung; tissue subtype not explicitly curated in retrieved excerpts). (OpenTargets Search: non-small cell lung carcinoma-KRAS)

7. Anatomical Structures Affected

Primary organ: Lung (NSCLC; often lung adenocarcinoma). (OpenTargets Search: non-small cell lung carcinoma-KRAS)
Central nervous system involvement: CodeBreaK 100 included an intracranial efficacy subset (16 evaluable) with intracranial complete responses and high intracranial disease control on sotorasib, supporting clinically relevant CNS metastatic disease considerations in this population. (dy2023longtermoutcomesand pages 2-3)

Suggested ontology terms: - UBERON:0002048 (lung) - UBERON:0000955 (brain) for CNS metastasis context

8. Temporal Development

KRAS G12C‑mutant NSCLC is typically an adult-onset malignancy and frequently diagnosed in advanced stage, but stage-at-diagnosis distributions specific to this genotype were not extracted in the retrieved evidence.

In the therapeutic setting, acquired resistance typically emerges within months on KRAS G12C inhibitors, motivating combination strategies; the retrieved evidence emphasizes transience of response and rapid resistance emergence. (shaverdashvili2025advancesinthe pages 2-3)

9. Inheritance and Population

Inheritance pattern

This is overwhelmingly a somatic (tumor-acquired) driver alteration in NSCLC; no germline inheritance pattern is implied by the retrieved evidence.

Epidemiology: frequency of KRAS and KRAS G12C in NSCLC

KRAS mutations occur in roughly ~29–32% of lung adenocarcinomas in a 2024 resistance review. (sreter2024resistancetokras pages 1-2)
Across KRAS point mutations in lung adenocarcinoma, G12C is the most common (~39%) in that review. (sreter2024resistancetokras pages 1-2)
Another 2024 overview reports KRAS mutations in ~20–40% of lung adenocarcinomas and that G12C comprises ~39–42% of KRAS variants in lung adenocarcinoma; it also reports higher KRAS mutation frequency in smokers and in Western populations. (tenekeci2024anupdatedoverview pages 2-3)

Real‑world demographic notes (example cohort)

In a Finnish real‑world registry cohort of advanced/unresectable or metastatic NSCLC undergoing NGS testing, all KRAS‑mutant patients were previous/current smokers; KRAS G12C was identified in n=35 (within KRAS‑mutant subgroup) and KRAS G12C was associated with poorer survival in that cohort (pre‑KRAS‑G12C inhibitor era context and access limitations may apply). (sultan2024realworldevaluationof pages 1-2)

10. Diagnostics

Molecular testing approaches and implementation

The evidence supports the clinical need for timely identification of KRAS G12C and co‑alterations.

Broad NGS testing and reflex workflows: A real‑world study of squamous NSCLC showed that broad DNA/RNA NGS can identify actionable alterations including KRAS G12C and argues for reflex testing across NSCLC histologies rather than restricting by smoking status/age. (mina2025emergingtargetedtherapies pages 2-4)
Turnaround time and rapid assays: A 2023 review notes NGS turnaround can be 12–15 days and describes the Idylla rapid oncology assay (<3 hours) to detect KRAS hotspot mutations from FFPE without DNA extraction, citing high concordance with NGS in studies it summarizes. (o’leary2023targetedtherapiesfor pages 4-5)
Tissue and plasma use in trials: CodeBreaK 200 exploratory analyses used tissue and/or plasma targeted NGS for genomic alteration analyses. (alharbi2024codebreak200study pages 2-4)

Biomarkers beyond KRAS G12C

Co‑mutation profiling (e.g., STK11, KEAP1, NRF2 pathway readouts) can stratify expected outcomes to KRAS G12C inhibitors, particularly for adagrasib in KRYSTAL‑1 analyses. (negrao2025impactofcomutations pages 1-2)

Liquid biopsy for resistance monitoring (expert interpretation supported by retrieved review statement)

A recent review explicitly highlights that “Tissue and liquid biopsies and genotyping of resistant clinical samples can elucidate resistance mechanisms and guide therapeutic decisions.” (shaverdashvili2025advancesinthe pages 2-3)

11. Outcome / Prognosis

Outcomes under KRAS G12C targeted therapy (key statistics)

Pivotal and long‑term trial outcomes for sotorasib in previously treated advanced KRAS G12C NSCLC: - CodeBreaK 200 (phase 3): sotorasib improved PFS vs docetaxel (median 5.6 vs 4.5 months, HR 0.66, p=0.0017), improved ORR (28.1% vs 13.2%), but did not improve OS (median 10.6 vs 11.3 months, HR 1.01). (langen2023sotorasibversusdocetaxel pages 8-10) - CodeBreaK 100 (2‑year update): ORR 41%, median DOR 12.3 months, median PFS 6.3 months, median OS 12.5 months, and 2‑year OS rate 33%; long‑term clinical benefit (PFS ≥12 months) in 23%. (dy2023longtermoutcomesand pages 2-3)

Prognostic modifiers

Co‑mutations (e.g., KEAP1, STK11, NRF2 signaling state) define distinct outcome strata under KRAS G12C inhibitor therapy in adagrasib‑treated patients. (negrao2025impactofcomutations pages 1-2)

Real‑world outcomes / utilization proxies

In a US claims‑based cohort receiving sotorasib (2L+), adherence was high (PDC 94.9%) and median treatment duration 4.3 months; median time to next treatment among those with subsequent therapy was 6.8 months, comparable in magnitude to PFS observed in trials (acknowledging TTNT is not a direct PFS measure). (sultan2024realworldevaluationof pages 1-2)

12. Treatment

12.1 Approved targeted therapies (current standard in previously treated setting)

Sotorasib (KRAS G12C inhibitor)
CodeBreaK 200 (Lancet 2023): improved PFS and ORR vs docetaxel, no OS difference. (langen2023sotorasibversusdocetaxel pages 8-10)
Key safety signal: diarrhea and transaminase elevations are characteristic; grade ≥3 TRAEs 33% with sotorasib vs 40% with docetaxel. (langen2023sotorasibversusdocetaxel pages 8-10)
Adagrasib (KRAS G12C inhibitor)
A 2025 NSCLC targeted-therapy review summarizes KRYSTAL‑1 phase II outcomes: ORR 43% (48/112), median PFS 6.5 months, median OS 12.6 months, intracranial ORR 42% in a CNS subset. (mina2025emergingtargetedtherapies pages 2-4)

Key practical safety consideration: hepatotoxicity risk can be higher when sotorasib is started soon after prior immunotherapy; pooled and comparative summaries highlight this clinically relevant sequencing issue. (higgins2025sotorasibforthe pages 3-4, speranza2025sexrelatedsafetysignals pages 9-11)

12.2 Treatment sequencing and guideline‑adjacent expert framing

The retrieved evidence emphasizes that KRAS G12C inhibitors are widely positioned after progression on standard first‑line regimens (often immunotherapy‑based), with ongoing trials moving them into earlier lines and combinations. (tenekeci2024anupdatedoverview pages 2-3, o’leary2023targetedtherapiesfor pages 10-11)

12.3 Combination strategies (research frontier; mechanistic rationale)

KRAS G12C inhibitor + SOS1 inhibitor: stronger RAS–MAPK suppression and delayed resistance in preclinical KRAS G12C lung cancer models. (sreter2024resistancetokras pages 1-2)
Co‑mutation–informed combinations: adagrasib plus mTOR inhibition showed enhanced efficacy in STK11/KEAP1 co‑mutant preclinical models and is proposed as a rational approach for poor‑prognosis genomics. (negrao2025impactofcomutations pages 1-2)

12.4 Selected ongoing clinical trials (real‑world implementation pipeline)

From retrieved ClinicalTrials.gov records: - NCT06497556 (Phase 3): divarasib vs sotorasib or adagrasib in previously treated KRAS G12C‑positive advanced/metastatic NSCLC. (NCT06936644 chunk 1) - NCT05074810 (Phase 1/2): avutometinib (VS‑6766) + sotorasib with/without defactinib; includes KRAS G12C inhibitor‑naïve and previously exposed cohorts. (NCT05074810 chunk 1) - NCT06936644 (Phase 2, 1L): fulzerasib (IBI351) + ivonescimab (AK‑112) for first‑line advanced/metastatic KRAS G12C NSCLC. (NCT06936644 chunk 1) - NCT07198841 (Phase 2, 1L): IBI351 + cetuximab β in untreated advanced/metastatic KRAS G12C NSCLC. (NCT07198841 chunk 1) - NCT05504278 (Phase Ib/III, 1L): IBI351 monotherapy and combinations (with sintilimab; with pemetrexed/platinum; with cetuximab) in advanced/metastatic KRAS G12C nonsquamous NSCLC. (NCT05504278 chunk 1) - NCT05840510 (KRYSTAL‑19, Phase 1/2): adagrasib + nab‑sirolimus (terminated; enrolled 6). (NCT05840510 chunk 1)

Suggested MAXO terms (treatment actions; suggestions)

Targeted molecular therapy (MAXO:0000058; broad suggestion)
Antineoplastic agent therapy (MAXO:0000011)
Drug combination therapy (MAXO:0000747)

13. Prevention

No KRAS G12C‑specific primary prevention interventions were identified in the retrieved evidence. Prevention aligns with lung cancer prevention more generally (e.g., smoking reduction) and with secondary prevention via screening in eligible high‑risk populations, but guideline details were not retrieved here.

14. Other Species / Natural Disease

Not addressed in the retrieved evidence.

15. Model Organisms / Model Systems

The retrieved evidence base in this run contains limited KRAS G12C‑specific model system detail (beyond resistance/combination preclinical studies). However: - A high‑impact preclinical study used KRAS G12C mutant lung cancer models to demonstrate benefit of SOS1 inhibitor + adagrasib and implicated MRAS/SHOC2 biology in resistance and combination response. (sreter2024resistancetokras pages 1-2)

General model types referenced across evidence include cell lines and xenograft models used in clinico‑genomic correlates and resistance studies. (negrao2025impactofcomutations pages 1-2, sreter2024resistancetokras pages 1-2)

Key statistics (2023–2024 anchored) and evidence table

The following table compiles the major quantitative benchmarks used in contemporary practice and research:

Study (year, journal)	Population/line	Treatment	Key efficacy	Key safety notes	URL / PMID if mentioned
CodeBreaK 200 (2023, The Lancet)	Previously treated KRAS G12C-mutant advanced NSCLC; randomized phase 3; n=171 sotorasib, n=174 docetaxel	Sotorasib 960 mg daily vs docetaxel 75 mg/m²	ORR 28.1% vs 13.2%; median PFS 5.6 vs 4.5 mo; PFS HR 0.66 (95% CI 0.51–0.86; p=0.0017); 12-mo PFS 24.8% vs 10.1%; median OS 10.6 vs 11.3 mo; OS HR 1.01 (95% CI 0.77–1.33); DOR 8.6 vs 6.8 mo; time to response 1.4 vs 2.8 mo (langen2023sotorasibversusdocetaxel pages 8-10, higgins2025sotorasibforthe pages 3-4, langen2023sotorasibversusdocetaxel media 446eaaec)	Grade ≥3 TRAEs 33% vs 40%; serious TRAEs 11% vs 23%; common grade ≥3 with sotorasib: diarrhea 12%, ALT increase 8%, AST increase 5%; fatal TRAEs: 1 (<1%) vs 2 (1%); hepatotoxicity risk higher when started soon after prior immunotherapy (langen2023sotorasibversusdocetaxel pages 8-10, higgins2025sotorasibforthe pages 3-4, speranza2025sexrelatedsafetysignals pages 9-11)	https://doi.org/10.1016/S0140-6736(23)00221-0
CodeBreaK 100 long-term update (2023, Journal of Clinical Oncology)	Pretreated KRAS G12C-mutant advanced NSCLC; phase I/II; n=174	Sotorasib 960 mg daily	ORR 41% (95% CI 33.3–48.4); DCR 84%; median DOR 12.3 mo; median PFS 6.3 mo; median OS 12.5 mo; 2-year OS 33%; long-term clinical benefit (PFS ≥12 mo) in 23% (dy2023longtermoutcomesand pages 1-2, dy2023longtermoutcomesand pages 2-3)	Any-grade TRAEs 70%; grade 3 20%, grade 4 1%, no grade 5 new-onset TRAEs in long-term follow-up; common AEs: diarrhea 30%, ALT increase 18%, AST increase 18%; among >1-year treated patients, few late-onset toxicities (dy2023longtermoutcomesand pages 1-2, dy2023longtermoutcomesand pages 2-3)	https://doi.org/10.1200/JCO.22.02524
KRYSTAL-1 phase II (2025 review summarizing trial data)	Advanced KRAS G12C-mutant NSCLC; previously treated	Adagrasib	ORR 43% (48/112); median DOR 8.5 mo (95% CI 6.2–13.8); median PFS 6.5 mo; median OS 12.6 mo; intracranial ORR 42% (95% CI 20.3–66.5) (mina2025emergingtargetedtherapies pages 2-4)	Signature AEs included nausea, diarrhea, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment; separate review notes high-grade toxicity burden but exact phase II grade ≥3 rate not provided in the evidence snippet used here (mina2025emergingtargetedtherapies pages 2-4)	https://doi.org/10.3390/cancers17030353
Real-world sotorasib claims study (2024, Advances in Therapy)	US claims-based cohort; KRAS G12C-mutant NSCLC receiving sotorasib; 2L+ subset n=140	Sotorasib in routine practice	Mean adherence (PDC) 94.9%; median treatment duration 4.3 mo; among those with subsequent treatment (n=31), median time to next treatment 6.8 mo; mean monthly costs US$23,063 during treatment vs US$25,541 pre-index (sultan2024realworldevaluationof pages 1-2)	Resource utilization during treatment: mean 3.87 outpatient, 0.09 inpatient, 0.11 emergency visits/month; this study did not report trial-style grade ≥3 TRAEs (sultan2024realworldevaluationof pages 1-2)	https://doi.org/10.1007/s12325-024-03020-7

Table: This table compacts the main quantitative clinical evidence for KRAS G12C-mutant NSCLC across pivotal sotorasib and adagrasib studies plus an early real-world sotorasib analysis. It highlights efficacy benchmarks, comparative outcomes, and the most clinically relevant safety signals for rapid reference.

Expert analysis (synthesis grounded in retrieved authoritative sources)

Clinical benefit is real but modest in randomized evidence: CodeBreaK 200 demonstrates statistically significant PFS and ORR improvements versus docetaxel but no OS benefit, likely influenced by subsequent KRAS G12C inhibitor exposure and crossover. (langen2023sotorasibversusdocetaxel pages 8-10, langen2023sotorasibversusdocetaxel pages 37-39)
Durable benefit occurs in a subset: Long‑term CodeBreaK 100 follow‑up shows a clinically meaningful tail with a 2‑year OS rate of 33% and 23% achieving PFS ≥12 months, supporting continued use while optimizing patient selection. (dy2023longtermoutcomesand pages 2-3)
Co‑mutations are central to precision medicine for this subtype: KEAP1/STK11/NRF2 status stratifies outcomes with adagrasib and provides a rational basis for intensified or alternative strategies. (negrao2025impactofcomutations pages 1-2)
Implementation requires robust molecular testing infrastructure: Real‑world testing gaps (e.g., community NGS rates and regional reimbursement variability) and the potential role of rapid assays highlight that access to genotyping is a rate‑limiting step for equitable delivery of KRAS G12C targeted therapy. (alharbi2024codebreak200study pages 2-4, o’leary2023targetedtherapiesfor pages 4-5)

Visual evidence from pivotal trial publication

Cropped figures/tables from the CodeBreaK 200 Lancet trial show the key efficacy summaries (PFS HR/medians; OS; ORR) and are consistent with the numeric endpoints cited above. (langen2023sotorasibversusdocetaxel media 446eaaec, langen2023sotorasibversusdocetaxel media 3169850c, langen2023sotorasibversusdocetaxel media 9b269017, langen2023sotorasibversusdocetaxel media f94b5c79)

References

(OpenTargets Search: non-small cell lung carcinoma-KRAS): Open Targets Query (non-small cell lung carcinoma-KRAS, 7 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(mina2025emergingtargetedtherapies pages 2-4): Syeda A. Mina, Mohamed Shanshal, Konstantinos Leventakos, and Kaushal Parikh. Emerging targeted therapies in non-small-cell lung cancer (nsclc). Cancers, 17:353, Jan 2025. URL: https://doi.org/10.3390/cancers17030353, doi:10.3390/cancers17030353. This article has 28 citations.
(sreter2024resistancetokras pages 1-2): Katherina Bernadette Sreter, Maria Joana Catarata, Maximilian von Laffert, and Armin Frille. Resistance to kras inhibition in advanced non-small cell lung cancer. Frontiers in Oncology, May 2024. URL: https://doi.org/10.3389/fonc.2024.1357898, doi:10.3389/fonc.2024.1357898. This article has 8 citations.
(dy2023longtermoutcomesand pages 2-3): Grace K. Dy, Ramaswamy Govindan, Vamsidhar Velcheti, Gerald S. Falchook, Antoine Italiano, Jürgen Wolf, Adrian G. Sacher, Toshiaki Takahashi, Suresh S. Ramalingam, Christophe Dooms, Dong-Wan Kim, Alfredo Addeo, Jayesh Desai, Martin Schuler, Pascale Tomasini, David S. Hong, Piro Lito, Qui Tran, Simon Jones, Abraham Anderson, Antreas Hindoyan, Wendy Snyder, Ferdinandos Skoulidis, and Bob T. Li. Long-term outcomes and molecular correlates of sotorasib efficacy in patients with pretreated kras g12c-mutated non–small-cell lung cancer: 2-year analysis of codebreak 100. Journal of Clinical Oncology, 41:3311-3317, Jun 2023. URL: https://doi.org/10.1200/jco.22.02524, doi:10.1200/jco.22.02524. This article has 175 citations and is from a highest quality peer-reviewed journal.
(langen2023sotorasibversusdocetaxel pages 8-10): Adrianus Johannes de Langen, Melissa L Johnson, Julien Mazieres, Anne-Marie C Dingemans, Giannis Mountzios, Miklos Pless, Jürgen Wolf, Martin Schuler, Hervé Lena, Ferdinandos Skoulidis, Yasuto Yoneshima, Sang-We Kim, Helena Linardou, Silvia Novello, Anthonie J van der Wekken, Yuanbin Chen, Solange Peters, Enriqueta Felip, Benjamin J Solomon, Suresh S. Ramalingam, Christophe Dooms, Colin R Lindsay, Carlos Gil Ferreira, Normand Blais, Cynthia C Obiozor, Yang Wang, Bhakti Mehta, Tracy Varrieur, Gataree Ngarmchamnanrith, Björn Stollenwerk, David Waterhouse, and Luis Paz-Ares. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with krasg12c mutation: a randomised, open-label, phase 3 trial. The Lancet, 401:733-746, Mar 2023. URL: https://doi.org/10.1016/s0140-6736(23)00221-0, doi:10.1016/s0140-6736(23)00221-0. This article has 650 citations and is from a highest quality peer-reviewed journal.
(sultan2024realworldevaluationof pages 1-2): Ihtisham Sultan, David M. Waterhouse, Divyan Chopra, Alexander Lonshteyn, Derek Weycker, Thomas E. Delea, and Björn Stollenwerk. Real-world evaluation of treatment patterns, healthcare costs, and healthcare resource utilization among patients with non-small cell lung cancer in the us receiving sotorasib. Advances in Therapy, 41:4648-4659, Oct 2024. URL: https://doi.org/10.1007/s12325-024-03020-7, doi:10.1007/s12325-024-03020-7. This article has 4 citations and is from a peer-reviewed journal.
(gecgel2025krasg12cmutation pages 9-11): Aslı Geçgel, Buket Şahin Çelik, Pınar Peker, Zeynep Sıla Gökdere, Didem Koca, Burçak Karaca, Deniz Nart, and Erdem Göker. Kras g12c mutation predicts improved survival in nsclc patients receiving immunotherapy: insights from a real-world cohort. Journal of Clinical Medicine, 14:6826, Sep 2025. URL: https://doi.org/10.3390/jcm14196826, doi:10.3390/jcm14196826. This article has 2 citations.
(shaverdashvili2025advancesinthe pages 2-3): Khvaramze Shaverdashvili and Timothy F. Burns. Advances in the treatment of kras g12c mutant non–small cell lung cancer. Cancer, Mar 2025. URL: https://doi.org/10.1002/cncr.35783, doi:10.1002/cncr.35783. This article has 21 citations and is from a domain leading peer-reviewed journal.
(tenekeci2024anupdatedoverview pages 2-3): Ates Kutay Tenekeci, Ahmet Arda Unal, Furkan Ceylan, and Mehmet Ali Nahit Sendur. An updated overview of k-ras g12c inhibitors in advanced stage non-small cell lung cancer. Future oncology, 20:1-20, Oct 2024. URL: https://doi.org/10.1080/14796694.2024.2407280, doi:10.1080/14796694.2024.2407280. This article has 13 citations and is from a peer-reviewed journal.
(negrao2025impactofcomutations pages 1-2): Marcelo V. Negrao, Alvaro G. Paula, David Molkentine, Laura Hover, Monique Nilsson, Natalie Vokes, Lars Engstrom, Andrew Calinisan, David M. Briere, Laura Waters, Jill Hallin, Lixia Diao, Mehmet Altan, George R. Blumenschein, Ferdinandos Skoulidis, Jing Wang, Scott E. Kopetz, David S. Hong, Don L. Gibbons, Peter Olson, James G. Christensen, and John V. Heymach. Impact of co-mutations and transcriptional signatures in non–small cell lung cancer patients treated with adagrasib in the krystal-1 trial. Clinical Cancer Research, pages OF1-OF13, Feb 2025. URL: https://doi.org/10.1158/1078-0432.ccr-24-2310, doi:10.1158/1078-0432.ccr-24-2310. This article has 28 citations and is from a highest quality peer-reviewed journal.
(o’leary2023targetedtherapiesfor pages 4-5): Cian O’Leary, Grace Murphy, Yong Yeung, Ming Tang, Vikram Jain, and Connor G O’Leary. Targeted therapies for kirsten rat sarcoma (kras) g12c mutant metastatic non-small-cell lung cancers. Cancers, 15:5582, Nov 2023. URL: https://doi.org/10.3390/cancers15235582, doi:10.3390/cancers15235582. This article has 3 citations.
(alharbi2024codebreak200study pages 2-4): Malak Alharbi, Muhammad Awidi, and Grace K. Dy. Codebreak 200: study limitations, and future directions. Translational Cancer Research, 13:15-21, Jan 2024. URL: https://doi.org/10.21037/tcr-23-1477, doi:10.21037/tcr-23-1477. This article has 8 citations.
(higgins2025sotorasibforthe pages 3-4): Jordyn P. Higgins, Jennifer W. Carlisle, Nader H. Moniri, Shruti Gupta, Eziafa I. Oduah, and Ticiana Leal. Sotorasib for the treatment of locally advanced/metastatic non-small cell lung cancer. Future oncology, 21:1-9, Nov 2025. URL: https://doi.org/10.1080/14796694.2024.2430172, doi:10.1080/14796694.2024.2430172. This article has 1 citations and is from a peer-reviewed journal.
(speranza2025sexrelatedsafetysignals pages 9-11): Desirèe Speranza, Mariapia Marafioti, Martina Musarra, Vincenzo Cianci, Fausto Omero, Calogera Claudia Spagnolo, Marco Calabrò, Nicola Silvestris, Natasha Irrera, and Mariacarmela Santarpia. Sex-related safety signals of sotorasib in non-small cell lung cancer: a real-world, pharmacovigilance study from the eudravigilance database. Pharmaceuticals, 18:1574, Oct 2025. URL: https://doi.org/10.3390/ph18101574, doi:10.3390/ph18101574. This article has 0 citations.
(o’leary2023targetedtherapiesfor pages 10-11): Cian O’Leary, Grace Murphy, Yong Yeung, Ming Tang, Vikram Jain, and Connor G O’Leary. Targeted therapies for kirsten rat sarcoma (kras) g12c mutant metastatic non-small-cell lung cancers. Cancers, 15:5582, Nov 2023. URL: https://doi.org/10.3390/cancers15235582, doi:10.3390/cancers15235582. This article has 3 citations.
(NCT06936644 chunk 1): Zhong Runbo. 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. Shanghai Chest Hospital. 2025. ClinicalTrials.gov Identifier: NCT06936644
(NCT05074810 chunk 1): Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients. Verastem, Inc.. 2022. ClinicalTrials.gov Identifier: NCT05074810
(NCT07198841 chunk 1): IBI351 Plus Cetuximab β in Untreated Advanced Non-small Cell Lung Cancer With KRAS G12C Mutation. Guangdong Association of Clinical Trials. 2025. ClinicalTrials.gov Identifier: NCT07198841
(NCT05504278 chunk 1): Efficacy and Safety of IBI351 in Combination With Chemotherapy in Advanced Non-squamous Non-small Cell Lung Cancer Subjects With KRAS G12C Mutation. Innovent Biologics (Suzhou) Co. Ltd.. 2022. ClinicalTrials.gov Identifier: NCT05504278
(NCT05840510 chunk 1): Adagrasib in Combination With Nab-Sirolimus in Patients With Advanced Solid Tumors and Non-Small Cell Lung Cancer With a KRAS G12C Mutation (KRYSTAL -19). Mirati Therapeutics Inc.. 2023. ClinicalTrials.gov Identifier: NCT05840510
(langen2023sotorasibversusdocetaxel media 446eaaec): Adrianus Johannes de Langen, Melissa L Johnson, Julien Mazieres, Anne-Marie C Dingemans, Giannis Mountzios, Miklos Pless, Jürgen Wolf, Martin Schuler, Hervé Lena, Ferdinandos Skoulidis, Yasuto Yoneshima, Sang-We Kim, Helena Linardou, Silvia Novello, Anthonie J van der Wekken, Yuanbin Chen, Solange Peters, Enriqueta Felip, Benjamin J Solomon, Suresh S. Ramalingam, Christophe Dooms, Colin R Lindsay, Carlos Gil Ferreira, Normand Blais, Cynthia C Obiozor, Yang Wang, Bhakti Mehta, Tracy Varrieur, Gataree Ngarmchamnanrith, Björn Stollenwerk, David Waterhouse, and Luis Paz-Ares. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with krasg12c mutation: a randomised, open-label, phase 3 trial. The Lancet, 401:733-746, Mar 2023. URL: https://doi.org/10.1016/s0140-6736(23)00221-0, doi:10.1016/s0140-6736(23)00221-0. This article has 650 citations and is from a highest quality peer-reviewed journal.
(dy2023longtermoutcomesand pages 1-2): Grace K. Dy, Ramaswamy Govindan, Vamsidhar Velcheti, Gerald S. Falchook, Antoine Italiano, Jürgen Wolf, Adrian G. Sacher, Toshiaki Takahashi, Suresh S. Ramalingam, Christophe Dooms, Dong-Wan Kim, Alfredo Addeo, Jayesh Desai, Martin Schuler, Pascale Tomasini, David S. Hong, Piro Lito, Qui Tran, Simon Jones, Abraham Anderson, Antreas Hindoyan, Wendy Snyder, Ferdinandos Skoulidis, and Bob T. Li. Long-term outcomes and molecular correlates of sotorasib efficacy in patients with pretreated kras g12c-mutated non–small-cell lung cancer: 2-year analysis of codebreak 100. Journal of Clinical Oncology, 41:3311-3317, Jun 2023. URL: https://doi.org/10.1200/jco.22.02524, doi:10.1200/jco.22.02524. This article has 175 citations and is from a highest quality peer-reviewed journal.
(langen2023sotorasibversusdocetaxel pages 37-39): Adrianus Johannes de Langen, Melissa L Johnson, Julien Mazieres, Anne-Marie C Dingemans, Giannis Mountzios, Miklos Pless, Jürgen Wolf, Martin Schuler, Hervé Lena, Ferdinandos Skoulidis, Yasuto Yoneshima, Sang-We Kim, Helena Linardou, Silvia Novello, Anthonie J van der Wekken, Yuanbin Chen, Solange Peters, Enriqueta Felip, Benjamin J Solomon, Suresh S. Ramalingam, Christophe Dooms, Colin R Lindsay, Carlos Gil Ferreira, Normand Blais, Cynthia C Obiozor, Yang Wang, Bhakti Mehta, Tracy Varrieur, Gataree Ngarmchamnanrith, Björn Stollenwerk, David Waterhouse, and Luis Paz-Ares. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with krasg12c mutation: a randomised, open-label, phase 3 trial. The Lancet, 401:733-746, Mar 2023. URL: https://doi.org/10.1016/s0140-6736(23)00221-0, doi:10.1016/s0140-6736(23)00221-0. This article has 650 citations and is from a highest quality peer-reviewed journal.
(langen2023sotorasibversusdocetaxel media 3169850c): Adrianus Johannes de Langen, Melissa L Johnson, Julien Mazieres, Anne-Marie C Dingemans, Giannis Mountzios, Miklos Pless, Jürgen Wolf, Martin Schuler, Hervé Lena, Ferdinandos Skoulidis, Yasuto Yoneshima, Sang-We Kim, Helena Linardou, Silvia Novello, Anthonie J van der Wekken, Yuanbin Chen, Solange Peters, Enriqueta Felip, Benjamin J Solomon, Suresh S. Ramalingam, Christophe Dooms, Colin R Lindsay, Carlos Gil Ferreira, Normand Blais, Cynthia C Obiozor, Yang Wang, Bhakti Mehta, Tracy Varrieur, Gataree Ngarmchamnanrith, Björn Stollenwerk, David Waterhouse, and Luis Paz-Ares. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with krasg12c mutation: a randomised, open-label, phase 3 trial. The Lancet, 401:733-746, Mar 2023. URL: https://doi.org/10.1016/s0140-6736(23)00221-0, doi:10.1016/s0140-6736(23)00221-0. This article has 650 citations and is from a highest quality peer-reviewed journal.
(langen2023sotorasibversusdocetaxel media 9b269017): Adrianus Johannes de Langen, Melissa L Johnson, Julien Mazieres, Anne-Marie C Dingemans, Giannis Mountzios, Miklos Pless, Jürgen Wolf, Martin Schuler, Hervé Lena, Ferdinandos Skoulidis, Yasuto Yoneshima, Sang-We Kim, Helena Linardou, Silvia Novello, Anthonie J van der Wekken, Yuanbin Chen, Solange Peters, Enriqueta Felip, Benjamin J Solomon, Suresh S. Ramalingam, Christophe Dooms, Colin R Lindsay, Carlos Gil Ferreira, Normand Blais, Cynthia C Obiozor, Yang Wang, Bhakti Mehta, Tracy Varrieur, Gataree Ngarmchamnanrith, Björn Stollenwerk, David Waterhouse, and Luis Paz-Ares. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with krasg12c mutation: a randomised, open-label, phase 3 trial. The Lancet, 401:733-746, Mar 2023. URL: https://doi.org/10.1016/s0140-6736(23)00221-0, doi:10.1016/s0140-6736(23)00221-0. This article has 650 citations and is from a highest quality peer-reviewed journal.
(langen2023sotorasibversusdocetaxel media f94b5c79): Adrianus Johannes de Langen, Melissa L Johnson, Julien Mazieres, Anne-Marie C Dingemans, Giannis Mountzios, Miklos Pless, Jürgen Wolf, Martin Schuler, Hervé Lena, Ferdinandos Skoulidis, Yasuto Yoneshima, Sang-We Kim, Helena Linardou, Silvia Novello, Anthonie J van der Wekken, Yuanbin Chen, Solange Peters, Enriqueta Felip, Benjamin J Solomon, Suresh S. Ramalingam, Christophe Dooms, Colin R Lindsay, Carlos Gil Ferreira, Normand Blais, Cynthia C Obiozor, Yang Wang, Bhakti Mehta, Tracy Varrieur, Gataree Ngarmchamnanrith, Björn Stollenwerk, David Waterhouse, and Luis Paz-Ares. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with krasg12c mutation: a randomised, open-label, phase 3 trial. The Lancet, 401:733-746, Mar 2023. URL: https://doi.org/10.1016/s0140-6736(23)00221-0, doi:10.1016/s0140-6736(23)00221-0. This article has 650 citations and is from a highest quality peer-reviewed journal.

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Classifications

Subtypes

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

Concise overview

Key identifiers and terminologies

Common synonyms / alternative names

Evidence provenance (individual vs aggregated)

2. Etiology

Disease causal factors

Risk factors

Protective factors

Gene–environment interactions

3. Phenotypes

Clinical phenotype (NSCLC context)

Suggested HPO terms (knowledge-base suggestions; not extracted from the above trials)

4. Genetic / Molecular Information

Causal gene

Pathogenic variant

Co-mutations / molecular modifiers (prognostic and predictive)

Functional consequence (high-level)

Suggested GO terms (mechanism-oriented; consistent with retrieved pathway statements)

5. Environmental Information

Key environmental/lifestyle factors

6. Mechanism / Pathophysiology

Core signaling pathways

Therapeutic mechanism of KRAS G12C inhibitors

Resistance mechanisms (current understanding)

Cell types (CL) and tissues (UBERON)

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

Inheritance pattern

Epidemiology: frequency of KRAS and KRAS G12C in NSCLC

Real‑world demographic notes (example cohort)

10. Diagnostics

Molecular testing approaches and implementation

Biomarkers beyond KRAS G12C

Liquid biopsy for resistance monitoring (expert interpretation supported by retrieved review statement)

11. Outcome / Prognosis

Outcomes under KRAS G12C targeted therapy (key statistics)

Prognostic modifiers

Real‑world outcomes / utilization proxies

12. Treatment

12.1 Approved targeted therapies (current standard in previously treated setting)

12.2 Treatment sequencing and guideline‑adjacent expert framing

12.3 Combination strategies (research frontier; mechanistic rationale)

12.4 Selected ongoing clinical trials (real‑world implementation pipeline)

Suggested MAXO terms (treatment actions; suggestions)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms / Model Systems

Key statistics (2023–2024 anchored) and evidence table

Expert analysis (synthesis grounded in retrieved authoritative sources)

Visual evidence from pivotal trial publication