What Does a KRAS G12C Mutation Mean?

KRAS is a gene. It makes a small protein that acts as an on-off switch for cell growth. G12C names one exact change. At codon 12, the amino acid glycine has been swapped for cysteine. That new cysteine gives drug designers something to grab. KRAS was called undruggable for decades. G12C was the first version to break that rule.

The number changes a lot by cancer type, and it is worth knowing which one applies.

In lung cancer, NCI reports KRAS variants in 25% to 30% of nonsquamous non-small cell lung cancer. G12C is the most frequent single one. It makes up roughly 13% of lung adenocarcinomas.

In colorectal cancer, NCI reports KRAS G12C in about 4% of cases, and notes it carries a poor prognosis.

Other cancers can carry it, but far less often. For those, NCI's drug summaries list no approved matched therapy. Trials are the route there.

Both labels also say the variant must be confirmed by an FDA-approved test. That is worth checking on the report itself. It is reasonable to ask which specimen was tested, tumor tissue or blood, and which assay was used.

Two drugs block KRAS G12C directly. Both are tablets. Both require an FDA-approved test to confirm the variant.

Sotorasib, sold as Lumakras, is 960 mg by mouth once daily. Adagrasib, sold as Krazati, is 600 mg by mouth twice daily. Both can be swallowed with or without food. Those are the approved label amounts, given here once so the figure on your own prescription looks familiar. Your oncologist may write something different, or pause and restart at a lower amount if side effects call for it, and their instruction is the one to follow.

For lung cancer, each is approved on its own. The label wording is the same for both. It covers locally advanced or metastatic NSCLC with a KRAS G12C variant. It applies to adults who have had at least one prior systemic therapy. So this is a later-line option, not a first move.

The response figures come from single-arm trials. In CodeBreaK 100, sotorasib gave an overall response rate of 37.1% among 124 evaluable patients. The median duration of response was 11.1 months. In the KRYSTAL-1 lung cohort, adagrasib gave a confirmed response rate of 42.9% among 112 evaluable patients. The median duration of response was 8.5 months. Almost everyone in that cohort had already had chemotherapy and immunotherapy.

In the bowel, neither drug is used alone. Sotorasib is paired with panitumumab. Adagrasib is paired with cetuximab. Both partners are anti-EGFR antibodies.

NCI gives the reason plainly. EGFR reactivation is a known resistance route to KRAS G12C blockade. Shutting KRAS alone lets the cell go around the block. The antibody closes that path.

The evidence is stronger here than in lung, because it is randomized. CodeBreaK 300 split 160 people with treated metastatic colorectal cancer into three arms. Median progression-free survival was 5.6 months with the full daily amount of sotorasib plus panitumumab. It was 3.9 months with a reduced amount of sotorasib plus panitumumab. It was 2.2 months with standard care. Objective response was 26.4%, 5.7%, and 0%.

Both labels restrict this to people who have already had fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Both lung indications, and the adagrasib colorectal indication, came through the FDA's accelerated approval pathway. The labels say so directly.

That pathway lets a drug reach patients on response rate and duration alone. Survival data do not yet exist. Continued approval may depend on confirmatory trials showing real benefit. This is not a lesser drug. It is a lesser stage of evidence. The difference is worth naming out loud.

G12C is one KRAS change among many. G12D and G12V are also common. The approved drugs do not target those. So "KRAS mutation" and "KRAS G12C" are not interchangeable words on a report, and it is worth confirming which one is written.

It is also not an immunotherapy biomarker. Checkpoint drug choices rest on separate tests. Those are chiefly PD-L1 expression and mismatch repair or microsatellite status. NCI notes about 4% of stage IV colorectal tumors are mismatch repair deficient or MSI-high. That is a different 4% from the G12C figure, and a different path.

And it does not promise durability. Resistance develops. The median durations of response above are measured in months, not years.

More on how these results are generated is in biomarker testing and precision medicine and liquid biopsy versus tissue biopsy.

The two drugs are watched differently, and the labels are specific.

For sotorasib, liver tests are checked every 3 weeks for the first 3 months, then monthly. Interstitial lung disease and pneumonitis carry a labeled warning. New or worsening breathing symptoms mean the drug is held at once. Acid-reducing drugs matter too. Proton pump inhibitors and H2 blockers should be avoided. A local antacid should be given 4 hours before or 10 hours after the dose.

For adagrasib, liver tests are checked before starting and monthly for 3 months. It carries a QTc prolongation warning, so ECG and electrolytes, particularly potassium and magnesium, are monitored in people at risk.

Common side effects overlap. With sotorasib alone in lung cancer, reactions at 20% or more were diarrhea, musculoskeletal pain, nausea, fatigue, liver toxicity, and cough. With adagrasib alone, at 25% or more, they were nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, liver toxicity, kidney impairment, swelling, breathlessness, and low appetite. Adding an anti-EGFR antibody adds skin toxicity. Rash, dry skin, and mouth sores stand out in the combination data, along with low magnesium.

Both drugs interact with strong CYP3A4 inducers, which should be avoided. For a wider view of this drug class, see targeted therapy.

• DailyMed — LUMAKRAS (sotorasib) prescribing information
• DailyMed — KRAZATI (adagrasib) prescribing information
• NCI PDQ — Non-Small Cell Lung Cancer Treatment (Health Professional Version)
• NCI PDQ — Colon Cancer Treatment (Health Professional Version)
• NCI — Sotorasib
• NCI — Adagrasib