The short answer
KRAS G12C can now be targeted with sotorasib or adagrasib. In lung cancer they are used alone; in colorectal cancer they must be paired with an EGFR antibody to work.
KRAS G12C occurs in roughly 13% of non-small cell lung cancers and roughly 3% to 4% of colorectal cancers.
Sotorasib and adagrasib are oral drugs that lock the mutated KRAS protein in its off position; sotorasib was the first KRAS-targeting drug approved, in May 2021.
In colorectal cancer, EGFR signalling rapidly reactivates the pathway around the block, so single-agent KRAS G12C inhibitors work poorly there.
Both colorectal approvals are combinations: adagrasib with cetuximab (June 2024) and sotorasib with panitumumab (January 2025).
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The full explanation.
What KRAS G12C is
KRAS is a gene that makes a switch protein controlling cell growth. A mutation at position 12, swapping glycine for cysteine, leaves the switch stuck in the on position. That specific change is called G12C.
KRAS was considered undruggable for roughly forty years. The protein's surface offered nothing for a drug to grab. G12C broke that, because the cysteine it introduces gives inhibitors a place to bind covalently. The first KRAS-targeting drug, sotorasib, was approved on May 28, 2021.
Who has it
Around 13% of people with non-small cell lung cancer have a KRAS G12C mutation, most often in adenocarcinoma and usually in people with a smoking history. In colorectal cancer it is less common, roughly 3% to 4%.
The mutation is found on molecular testing of tumor tissue or, in some cases, blood. In lung cancer it is typically part of the broad panel done at diagnosis of advanced disease. In colorectal cancer, KRAS testing has been standard for years, but historically only to determine whether EGFR antibodies could be used at all. Older reports may say "KRAS mutant" without specifying which codon. If yours does, it is worth asking whether the specific variant is recorded.
The two drugs
Sotorasib and adagrasib are both oral, once- or twice-daily inhibitors that lock the G12C protein in its off state. Both are approved for previously treated KRAS G12C-mutated advanced non-small cell lung cancer. In the trial supporting sotorasib's lung approval, tumors shrank in 36% of participants, with responses lasting a median of about 10 months.
The difference that matters
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 depend heavily on signaling from the EGFR receptor. When a KRAS G12C inhibitor shuts KRAS off, EGFR signaling rapidly reactivates the pathway around the block. The tumor routes around the roadblock within days. Lung tumors are far less dependent on that particular feedback loop, which is why single-agent inhibitors do more there.
Blocking EGFR at the same time closes that route. That is why 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. 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 prior chemotherapy. In CodeBreaK 300, the overall response rate was 26% and median progression-free survival was 5.6 months.
If you have colorectal cancer with this mutation and are told about a KRAS G12C drug, the partner antibody is not optional extra treatment. It is what makes the approach work.
What to expect on these drugs
They are pills, which is a real quality-of-life difference from infusion chemotherapy, but they are not side-effect free. Diarrhea, nausea, fatigue, and muscle aches are common. Both drugs can raise liver enzymes, so blood tests are checked regularly. Adagrasib can prolong the QT interval on an ECG and interacts with a long list of other medications and with acid-reducing drugs, 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 that can be significant. It is usually manageable with preventive antibiotics and skin care started before it appears, so ask about that in advance rather than after.
What to ask
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, since newer KRAS inhibitors and first-line combinations are actively being studied. And in colorectal cancer, ask specifically which antibody would be paired with it.
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Common questions
Why do I need a second drug when my friend with lung cancer only takes one pill?
Colorectal tumors depend heavily on EGFR signalling. When a KRAS G12C inhibitor shuts KRAS off, EGFR reactivates the pathway around the block within days. Lung tumors are much less dependent on that feedback loop. Blocking EGFR at the same time closes the escape route, which is why both colorectal approvals are combinations.
My report says KRAS mutant. Does that mean G12C?
Not necessarily. KRAS can be mutated at several positions, and only G12C is targetable by these drugs. Historically colorectal KRAS testing was done only to determine whether EGFR antibodies could be used at all, so some older reports do not specify the codon. Ask whether your exact variant is recorded.
How well do these drugs work?
In the trial supporting sotorasib's lung approval, tumors shrank in 36% of participants with responses lasting a median of about 10 months. In colorectal cancer, adagrasib with cetuximab produced a 34% response rate with a median duration of 5.8 months, and sotorasib with panitumumab a 26% response rate with median progression-free survival of 5.6 months.
What side effects should I expect?
Diarrhea, nausea, fatigue, and muscle aches are common. Both drugs can raise liver enzymes, so blood tests are monitored. Adagrasib can prolong the QT interval and interacts with many medications and acid-reducing drugs. EGFR antibodies add a facial and chest rash that can be significant.
Are these given first or after other treatment?
Current approvals are for previously treated disease in both lung and colorectal cancer, so they generally follow chemotherapy or immunotherapy. Where they sit in your particular sequence is worth asking, and first-line combinations are being studied in trials.
Questions to ask your doctor
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Written by: Cancer Explained Editorial TeamSources last checked: 2026-07-30Last updated: 2026-07-30Next planned review: 2027-07-30
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How this page was created
Cancer Explained does not originate medical claims. Every page restates guidance already published by the National Cancer Institute, the CDC, the USPSTF and the FDA, in plain language, with the source cited so you can check the original yourself. AI does the translating and organizing; automated checks test claims, citations, clarity and safety before anything publishes. We do not employ clinicians and do not intend to — our work is translation and navigation, not clinical judgment. Nothing here is personal medical advice, and no page can account for your particular situation.
Editorial status: Source verified — This page was created with AI assistance and checked against the sources listed on it. Source checking is not a medical review.
Human medical review: not completed. Cancer Explained is not clinician-reviewed, and that is a deliberate design choice rather than a gap we are waiting to close. We restate published federal guidance and cite it; the authority belongs to the source, not to us. That is why every page names where its claims come from — so you can verify us instead of trusting us. Use it to understand your situation and to ask better questions of the people treating you.
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