KRAS G12C-mutant non-small-cell lung cancer
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.
Overview
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.
State of the art
- 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.
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- 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.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowFainting or palpitations
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowBowel perforation
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
- Emergency services nowHypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
- Check before combiningDocetaxel with Adagrasib: major interaction
CYP3A4: Adagrasib (strong inhibitor) raises Docetaxel exposure (sensitive substrate).. Avoid strong inhibitors; if unavoidable, reduce the dose by 50% (ketoconazole raised exposure 2.2-fold).
- Check before combiningPaclitaxel / nab-paclitaxel with Adagrasib: major interaction
CYP2C8: Adagrasib (strong inhibitor) raises Paclitaxel exposure.. Avoid strong CYP2C8 inhibitors or reduce the dose per label.
See all on the product pages:AdagrasibCarboplatinDaraxonrasibDivarasibDocetaxelOlomorasibPaclitaxel / nab-paclitaxelPembrolizumabPemetrexedRamucirumabSotorasib·Printable cards in the navigator
Anatomy and lymph node drainage
- Central airways (squamous, small-cell)
- Periphery (adenocarcinoma)
- Apex (Pancoast)
- Pleura (mesothelioma)
- Thymus (anterior mediastinum)
- Nodes: hilar (N1)
- Nodes: mediastinal (N2)
- Nodes: supraclavicular (N3)
Central tumours arise in the large airways, peripheral ones in the alveoli; both drain to hilar then mediastinal nodes, and the pleural lining is a separate cancer site.
- Central airways (squamous, small-cell)
- Periphery (adenocarcinoma)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)
- Apex (Pancoast)
- Pleura (mesothelioma)
- Thymus (anterior mediastinum)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)
- hilar (N1)
- mediastinal (N2)
- supraclavicular (N3)
Same organ: Non-small-cell lung cancer, Lung cancer (all types), Small-cell lung cancer, Mesothelioma, Pleural mesothelioma, Thymoma and thymic carcinoma, Childhood lung and airway tumours (pleuropulmonary blastoma, tracheobronchial tumours), Inflammatory myofibroblastic tumour (IMT), EGFR-mutated non-small-cell lung cancer, ALK-positive non-small-cell lung cancer, ROS1-positive non-small-cell lung cancer, MET exon 14 and MET-amplified non-small-cell lung cancer, RET fusion-positive non-small-cell lung cancer, BRAF V600E-mutant non-small-cell lung cancer, HER2-mutant non-small-cell lung cancer, NTRK fusion-positive non-small-cell lung cancer, PD-L1-high non-small-cell lung cancer without a driver mutation, Resectable stage I to III non-small-cell lung cancer, Unresectable stage III non-small-cell lung cancer, Limited-stage small-cell lung cancer, Extensive-stage small-cell lung cancer, Lung neuroendocrine tumours (typical and atypical carcinoid)
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.
- Liquid biopsy (ctDNA)Standard of care
Nothing recorded yet.
Nothing recorded yet.
Also on OnCo: Symptoms and red flags · Early detection roadmap.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
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.
Sotorasib (CodeBreaK 200) or adagrasib (KRYSTAL-12), preferred to docetaxel; adagrasib for active brain metastases; docetaxel with or without ramucirumab afterwards.
Divarasib versus sotorasib or adagrasib (Krascendo 1); olomorasib or adagrasib with pembrolizumab first line (SUNRAY-01, KRYSTAL-7); pan-RAS inhibitors.
Subtypes & biomarkers
top- 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)
- 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
How often this target appears
- 1982KRAS identified as a human oncogene in lung cancer cell lines
- 2013Ostrem and Shokat trap mutant G12C cysteine in the switch-II pocket
- 2021Sotorasib approved after CodeBreaK 100: the first KRAS inhibitor
- 2022Adagrasib approved after KRYSTAL-1, with brain activity
- 2023CodeBreaK 200: sotorasib beats docetaxel on progression-free but not overall survival
- 2024KRYSTAL-12: adagrasib beats docetaxel; divarasib enters phase 3 (Krascendo 1)
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 16 changes by month →- 2026-09-17This recordKRAS G12C-mutant non-small-cell lung cancerFacts on this page last checked
When this page itself was last checked or edited.
- 2026Trial resultKrascendo 1Krascendo 1 reported
Superior PFS and OS vs approved G12C inhibitors (topline, July 2026).
- 2024ApprovalAdagrasibAdagrasib approved in EU
KRAS G12C NSCLC after ≥1 line; 5 Jan 2024 (conditional)
- 2024Trial resultKRYSTAL-12KRYSTAL-12 reported
PFS HR 0.
- 2024MilestoneKRYSTAL-12KRYSTAL-12: adagrasib beats docetaxel; divarasib enters phase 3 (Krascendo 1)
A milestone in how this cancer is treated.
- 2023MilestoneCodeBreaK 200CodeBreaK 200: sotorasib beats docetaxel on progression-free but not overall survival
A milestone in how this cancer is treated.
What is in development for KRAS G12C-mutant non-small-cell lung cancer, drawn from the whole corpus: 11 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Drugs in phase 3 · 3
Trials under way · 3
- 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 · phase 3 · Eli Lilly and Company
- 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 · phase 2/3 · Mirati Therapeutics Inc.
- A Clinical Study of Calderasib (MK-1084) and Other Treatments for Participants With Non-Small Cell Lung Cancer (MK-1084-007/KANDLELIT-007) · phase 3 · Merck Sharp & Dohme
Trials reported · 3
- Krascendo 1 · phase 3 · 2026 · positive
- CodeBreaK 200 · phase 3 · 2022 · positive
- KRYSTAL-12 · phase 3 · 2024 · positive
Ideas not yet in a trial · 2
Open problems and what is being done
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.
and how the field plans to fix it →What is being done about thisSide effects and quality of lifeAvailable now- Immune checkpoint inhibitorsStandard of care
In trialsNothing recorded yet.
Ideas and roadmapsNothing recorded yet.
Also on OnCo: Side effects by symptom · Immune-related side effects · Toxicity compare · Survivorship planner.
STK11 and KEAP1 co-mutations predict poor outcome with every treatment and have no targeted therapy.
and how the field plans to fix it →What is being done about thisCancers without a drug targetAvailable now- AdagrasibApproved
- DaraxonrasibApproved
- KRAS & RAS inhibitorsApproved
- SotorasibApproved
In trials- CodeBreaK 200Positive
- KRYSTAL-12Positive
Background: RAS / RAF / MEK / ERK (MAPK). Also on OnCo: Targets · KRAS roadmap.
Resistance is polyclonal and mechanistically diverse, arguing for combinations from the start.
and how the field plans to fix it →What is being done about thisResistance to treatmentAvailable now- Comprehensive genomic profilingStandard of care
- Liquid biopsy (ctDNA)Standard of care
- Small-molecule kinase inhibitorsStandard of care
In trialsNothing recorded yet.
Ideas and roadmapsNothing recorded yet.
Background: Drug resistance (primary and acquired). Also on OnCo: Resistance atlas · Lines of therapy.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Houston · cancer center | United States | 0 | 6,724 | 95,007 | #2 | ||
Baltimore · cancer center | United States | 0 | 2,955 | 41,449 | #10 | ||
| United States | 0 | 4,335 | 73,845 | none recorded | #15 | ||
San Francisco · cancer center | United States | 0 | 2,800 | 46,704 | #33 | ||
Amsterdam · cancer center | Netherlands | none recorded | 0 | 1,451 | 25,873 | #45 | |
Lausanne · hospital | Switzerland | none recorded | 0 | 509 | 9,176 | - | |
Brussels · cancer center | Belgium | none recorded | 0 | 489 | 8,689 | - | |
Candiolo · cancer center | Italy | none recorded | 0 | 324 | 4,466 | - | |
Frederick, MD · government | United States | none recorded | 0 | 318 | 4,032 | - | |
Glasgow · cancer center | United Kingdom | none recorded | 0 | 258 | 2,699 | - | |
Madrid · research institute | Spain | none recorded | 0 | 203 | 3,502 | - | |
Ljubljana · cancer center | Slovenia | none recorded | 0 | 187 | 2,566 | - | |
Philadelphia, PA · consortium | United States | none recorded | 0 | 165 | 1,237 | - | |
Washington, DC · cancer center | United States | 0 | 100 | 2,434 | - | ||
Neu-Isenburg · consortium | Germany | none recorded | 0 | 94 | 1,947 | none recorded | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with KRAS G12C-mutant non-small-cell lung cancer but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about KRAS G12C-mutant non-small-cell lung cancer
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example KRAS G12C by tissue or plasma sequencing, PD-L1 tumour proportion score, STK11 and KEAP1 co-mutations, TP53 co-mutation, Acquired KRAS mutations, MET amplification or bypass alterations at progression), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include KRAS G12C adenocarcinoma with high PD-L1, KRAS G12C adenocarcinoma with STK11 or KEAP1 co-mutation, KRAS G12C with brain metastases.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Advanced, first line
- For my situation (advanced, first line), which of the standard options do you recommend and why?Why: Guideline options include: 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.
- Am I a candidate for Pembrolizumab, Carboplatin, Pemetrexed or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of KEYNOTE-024 & KEYNOTE-189 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Advanced, after chemoimmunotherapy
- For my situation (advanced, after chemoimmunotherapy), which of the standard options do you recommend and why?Why: Guideline options include: Sotorasib (CodeBreaK 200) or adagrasib (KRYSTAL-12), preferred to docetaxel; adagrasib for active brain metastases; docetaxel with or without ramucirumab afterwards.
- Am I a candidate for Sotorasib, Adagrasib, Docetaxel or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of CodeBreaK 200 and KRYSTAL-12 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Advanced, clinical trials
- For my situation (advanced, clinical trials), which of the standard options do you recommend and why?Why: Guideline options include: Divarasib versus sotorasib or adagrasib (Krascendo 1); olomorasib or adagrasib with pembrolizumab first line (SUNRAY-01, KRYSTAL-7); pan-RAS inhibitors.
- Am I a candidate for Divarasib, Olomorasib, Daraxonrasib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of Krascendo 1 and 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 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Any stage
- Are there clinical trials I could join, for example of Divarasib, Krascendo 1, 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?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “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”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Liver toxicity when a G12C inhibitor follows or accompanies a checkpoint inhibitor limits first-line combinations”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with KRAS G12C-mutant non-small-cell lung cancer, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
9targets
4drugs
14companies
9pathways
3terms
7trials
7ideas
2people
5key papers
2Patients with KRAS G12C lung cancer that has progressed after chemo-immunotherapy can take an oral KRAS inhibitor instead of docetaxel and gain a somewhat longer time to progression with fewer severe side effects, but should understand that most tumours become resistant within a year and that survival is not improved. KRAS G12C testing is worthwhile, but first-generation inhibitors are a step rather than a cure; combinations and next-generation inhibitors are the active research fronts.
The most frequently mutated oncogene in cancer stopped being undruggable, and patients with KRAS G12C lung and bowel cancers now have targeted pills. The approach, exploiting a mutation-created chemical handle and an inactive-state pocket, has become a template for other hard targets.
Latest papers
topQuery for this cancer: (TITLE:"KRAS G12C-mutant non-small-cell lung cancer" OR ABSTRACT:"KRAS G12C-mutant non-small-cell lung cancer" OR TITLE:"KRAS G12C lung cancer" OR ABSTRACT:"KRAS G12C lung cancer" OR TITLE:"KRAS-mutant NSCLC" OR ABSTRACT:"KRAS-mutant NSCLC" OR TITLE:"KRAS p.G12C non-small-cell lung cancer" OR ABSTRACT:"KRAS p.G12C non-small-cell lung cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about KRAS G12C-mutant non-small-cell lung cancer, not a curated reading list.
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