KRAS G12C in Colorectal Cancer

KRAS is a gene. The protein it makes acts as a switch inside the cell, flipping between on and off to control growth and survival.

G12C names the exact defect. Position 12 in the protein chain normally holds the amino acid glycine, abbreviated G. In this mutation it holds cysteine, abbreviated C. The switch gets stuck in the on position, and the cell keeps receiving a grow signal that nobody sent.

Other KRAS mutations exist at the same position, such as G12D and G12V. They are not the same target, and the drugs described here do not treat them.

NCI states that about a third of all cancers are driven by harmful mutations in the RAS family of genes. KRAS is the most commonly mutated of that family.

G12C specifically appears in about 13% of lung cancers and about 3% of colorectal cancers, plus 1% to 3% of other solid tumors.

Three percent sounds small. Colorectal cancer is common enough that it still means thousands of people each year in the United States.

KRAS was called undruggable for good reason. NCI describes why earlier work failed. Standard enzyme-blocking methods did not work on this protein. Indirect strategies had limited success.

The breakthrough came from the mutation itself. Cysteine has a reactive chemical group that glycine does not. That gave chemists something to grab. Sotorasib was designed to bind that cysteine and permanently lock KRAS G12C in the off position.

Early results split by cancer type. In the first trial NCI covered, 7 of the 13 lung cancer patients given the dose researchers judged optimal had a partial response, and 6 had stable disease. Among 19 people with colorectal cancer, none of the tumors shrank: 14 had stable disease and in 5 the cancer progressed.

That gap shaped everything after. Both FDA approvals in colorectal cancer pair the KRAS drug with a second antibody. That antibody blocks EGFR, a receptor on the cell surface that feeds the same growth pathway. Neither KRAS drug is approved alone for this cancer.

FDA granted accelerated approval for adults with KRAS G12C-mutated colorectal cancer that is locally advanced or has spread. Patients must already have had chemotherapy based on a fluoropyrimidine, oxaliplatin, and irinotecan. In the trial behind the approval, people also had to have had a VEGF inhibitor if they were eligible for one.

The evidence came from KRYSTAL-1, a multicenter, single-arm expansion cohort. Single-arm means there was no comparison group.

Results in the 94 patients analyzed:

• Overall response rate 34%, with a 95% confidence interval of 25% to 45%.
• Every response was a partial response. None were complete.
• Median duration of response 5.8 months, confidence interval 4.2 to 7.6.
• 31% of responders kept responding for at least 6 months.

Dosing is adagrasib 600 mg by mouth twice daily — the label's figure, which your oncologist may reduce for you. Cetuximab is given by vein either every two weeks, or weekly after a larger first infusion, at amounts the pharmacy calculates.

Accelerated approval is conditional. It rests on response rate rather than on survival, and a confirmatory trial is required.

This approval rests on a randomized trial, which makes it a different kind of evidence.

CodeBreaK 300 randomized 160 patients 1 to 1 to 1 across three arms. All had received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

For sotorasib 960 mg with panitumumab, against standard care:

• Median progression-free survival 5.6 months versus 2 months, hazard ratio 0.48, p equals 0.005.
• Overall response rate 26% versus 0%.
• Median duration of response 4.4 months.
• The final overall survival analysis was not statistically significant.

That last line matters. The combination delayed growth of the cancer. It did not show a proven survival gain in this trial.

Dosing is sotorasib 960 mg by mouth once daily — again the label's figure, and reduced for some people — with panitumumab given by vein every 14 days at a weight-based amount.

At least 20% of patients on sotorasib with panitumumab had these side effects. They were rash, dry skin, diarrhea, mouth sores, fatigue, and muscle or joint pain.

The adagrasib list is longer. It includes rash, nausea, diarrhea, vomiting, fatigue, and muscle or joint pain. It also includes liver toxicity, headache, dry skin, and belly pain. Appetite loss, swelling, anemia, cough, and dizziness are on it. So are constipation and nerve pain or numbness.

Two label rules deserve attention before your first dose.

Liver monitoring. The sotorasib label sets a schedule for liver blood tests. Draw them every 3 weeks for the first 3 months, then monthly. The drug is withheld if AST or ALT rises above 3 times the upper limit of normal, up to 5 times, with symptoms. It is stopped for good if AST or ALT is above 3 times normal and total bilirubin is above 2 times normal.

Lung inflammation. If interstitial lung disease or pneumonitis is suspected, sotorasib is withheld immediately. If no other cause is found, it is stopped for good. Report new or worsening cough, shortness of breath, or fever the same day. Do not wait for the next visit.

Sotorasib needs stomach acid to be absorbed properly. The label says to avoid proton pump inhibitors and H2 blockers. If a local antacid is needed, take sotorasib 4 hours before it or 10 hours after it.

Strong CYP3A4 inducers lower sotorasib levels and should be avoided. Bring every prescription, store-bought product, and supplement to the visit before you start. Include heartburn medicines. Many people do not count those as drugs.

Three more label rules. Take the first sotorasib dose before the first panitumumab infusion. Take it at the same time each day, with or without food. Swallow the tablets whole.

Both approvals require an FDA-approved test to confirm the mutation. For sotorasib with panitumumab, FDA named the therascreen KRAS RGQ PCR Kit from QIAGEN, run in a central laboratory.

If KRAS was tested years ago, the report may say only "KRAS mutated" without the specific change. That is not enough. Ask for the exact codon and substitution.

Questions worth asking:

• Does my report name G12C specifically, or only a KRAS mutation?
• Was the test an FDA-approved companion diagnostic?
• Which prior chemotherapy drugs do I have on record, and do they meet the eligibility wording?
• Is the proposed combination the accelerated-approval one or the randomized-trial one?
• How often will my liver tests be drawn, and who calls me with results?
• Which of my current medicines interfere with absorption?

• https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer
• https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sotorasib-panitumumab-kras-g12c-mutated-colorectal-cancer
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/214665s009lbl.pdf
• https://www.cancer.gov/news-events/cancer-currents-blog/2019/kras-inhibitor-amg-510-clinical-trial
• https://www.cancer.gov/about-cancer/treatment/drugs/adagrasib