KRAS G12C Mutation in Lung & Colorectal Cancer

KRAS is a gene. It makes a switch protein that controls cell growth. A mutation at position 12 swaps one building block, glycine, for another, cysteine. That leaves the switch stuck in the on position. This specific change is called G12C.

For decades, KRAS was considered undruggable. The protein's surface offered nothing for a drug to grab. G12C broke that. The cysteine it introduces gives inhibitors a place to bind tightly. The first KRAS-blocking drug, sotorasib, received accelerated approval on May 28, 2021.

NCI says about 13% of people with non-small cell lung cancer have a KRAS G12C mutation. In colorectal cancer it is less common, about 3%.

The mutation is found by molecular testing of tumor tissue, or in some cases of blood. In lung cancer it is usually part of the broad panel done when advanced disease is diagnosed. In colorectal cancer, KRAS testing has been standard for years. But it was done only to work out whether EGFR antibodies could be used at all. Older reports may say "KRAS mutant" without naming which codon. If yours does, it is worth asking whether the specific variant is recorded.

Sotorasib and adagrasib are both pills, taken once or twice a day. They lock the G12C protein in its off state. Both have accelerated approval for KRAS G12C-mutated advanced non-small cell lung cancer after at least one earlier treatment. That approval rests on tumor shrinkage and how long it lasted, and confirmatory trials are required. In the trial behind sotorasib's lung approval, tumors shrank in 36% of participants. Responses lasted a median of about 10 months.

Here is the part that is genuinely surprising, and easy to miss. The same drugs, given the same way, work poorly against colorectal cancer on their own.

The reason is biology, not dosing. Colorectal tumors lean heavily on signals from the EGFR receptor. When a KRAS G12C inhibitor shuts KRAS off, EGFR signaling switches the pathway back on around the block. The tumor routes around the roadblock. Lung tumors depend far less on that particular feedback loop. That is why single-agent inhibitors do more there.

Blocking EGFR at the same time closes that route. So both colorectal approvals are combinations, not single drugs.

• June 21, 2024: FDA granted accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated locally advanced or metastatic colorectal cancer after earlier chemotherapy. In KRYSTAL-1, the overall response rate was 34%, with a median duration of response of 5.8 months.
• January 16, 2025: FDA approved sotorasib with panitumumab for KRAS G12C-mutated metastatic colorectal cancer after earlier chemotherapy. In CodeBreaK 300, the overall response rate was 26% and median progression-free survival was 5.6 months, against 2 months with standard treatment. The final overall survival analysis was not statistically significant.

Suppose you have colorectal cancer with this mutation, and someone offers you a KRAS G12C drug. The partner antibody is not an optional extra. It is what makes the approach work.

They are pills. That is a real quality-of-life difference from infusion chemotherapy. But they are not free of side effects. Diarrhea, nausea, tiredness, and muscle aches are common. Both drugs can raise liver enzymes, so you will have blood tests regularly.

Adagrasib can lengthen the QT interval on an ECG, a heart tracing. It also interacts with a long list of other medicines. Sotorasib's label says to avoid proton pump inhibitors and H2 blockers, two kinds of acid-reducing drugs, and gives timing rules if an antacid is needed. So bring a complete list of everything you take, including supplements.

Adding cetuximab or panitumumab brings an acne-like rash on the face and chest, which can be marked. Ask your team what skin care they suggest before the first dose, not after the rash appears.

Ask whether your report names the exact KRAS variant. Ask where a G12C inhibitor sits in your sequence, relative to chemotherapy and immunotherapy. Ask about clinical trials, because newer KRAS inhibitors and first-line combinations are being studied right now. And in colorectal cancer, ask specifically which antibody would be paired with it.

• Call 911 or go to an emergency department if you black out, or your heart pounds and will not settle, while taking adagrasib. That drug can lengthen the QT interval. Do not drive yourself.
• Call 911 or go to an emergency department if you become suddenly breathless or struggle for air at rest. Both drugs can inflame the lungs. Do not drive yourself.
• Reach your cancer team without waiting, at any hour, if you run a fever of 100.4°F (38°C) or higher, or have shaking chills and feel very unwell. Infection while on cancer treatment is handled as an emergency. If they cannot be reached quickly, go to an emergency department and tell them you are on cancer treatment.
• Call your care team right away if a new cough starts, or you are more short of breath than usual, or your temperature is up. MedlinePlus lists new or worse breathlessness, cough or fever on both drugs as reasons to call at once. The label says the drug is held while lung inflammation is checked.
• Call your care team right away if the whites of your eyes or your skin look yellow, your urine turns dark, or you have pain on the right side of your belly. MedlinePlus lists these liver signs as reasons to call at once.
• Call your care team right away if you see blood in your stool or vomit, or you feel dizzy or faint. On adagrasib, MedlinePlus lists these as reasons to call at once.
• Call your care team if loose stools keep coming despite anti-diarrhea medicine, or the EGFR-antibody rash starts to weep or crust, and ask how soon they want to see you.

• DailyMed: LUMAKRAS (sotorasib) prescribing information
• FDA: Accelerated approval of adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer
• NCI: Sotorasib approved for KRAS G12C lung cancer
• NCI: Drugs approved for colon and rectal cancer
• NCI: Targeted therapy to treat cancer
• FDA: Sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer
• DailyMed: KRAZATI (adagrasib) prescribing information
• NCI: KRAS-targeted drugs and immunotherapy (KRAS G12C frequency)
• MedlinePlus: Sotorasib
• MedlinePlus: Adagrasib
• CDC: Fever during chemotherapy