KRAS G12C in Lung Cancer: Meaning

KRAS is a gene. G12C is an address and a swap. The 12 is the twelfth building block of the protein. The G is glycine, the amino acid that belongs there. The C is cysteine, the one that took its place.

That precision matters more here than with most markers. The drugs built for this are called KRAS G12C inhibitors, and their approvals are written for G12C specifically. A report that says only "KRAS mutation detected" does not answer the question. You need the exact variant.

KRAS was described decades ago and spent most of that time labeled undruggable. Drugs need a pocket to grab. KRAS did not offer a good one.

The Food and Drug Administration (FDA) granted the first accelerated approval for a KRAS G12C inhibitor on May 28, 2021. That is very recent for a gene that has been on pathology reports since the 1980s. If a family member had lung cancer before then, none of this existed for them.

The National Cancer Institute (NCI) notes in its lung cancer summary that "KRAS and BRAF variants are more common in smokers or former smokers." That is close to the mirror image of EGFR and ALK, which cluster in people who never smoked or smoked little.

Practically, this means KRAS testing should not be skipped in a heavy smoker on the theory that targeted therapy is unlikely. That is the group where G12C shows up.

Sotorasib (Lumakras). FDA granted accelerated approval on May 28, 2021 for "adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC)" who have had prior systemic therapy. The evidence came from CodeBreaK 100, a single-arm open-label trial in 124 patients whose cancer had progressed. The objective response rate was 36%, with a 95% confidence interval of 28% to 45%. Median duration of response was 10 months. The dose is "960 mg orally once daily with or without food."

Sotorasib and adagrasib are tablets taken at home, and the amounts quoted here are the label's. Yours comes from your own lung cancer team, who lower it if liver tests or diarrhoea call for that.

Adagrasib (Krazati). NCI lists it for metastatic non-small cell lung cancer "in patients who have received at least one other systemic therapy." It is also approved with cetuximab for colorectal cancer after chemotherapy "that included a fluoropyrimidine, oxaliplatin, and irinotecan hydrochloride."

Both are pills. Both are second-line or later in lung cancer, meaning something else comes first.

The sotorasib lung approval was granted on response rate and duration of response, and FDA stated that "continued approval [is] contingent upon verification and description of clinical benefit."

Translate that honestly. A response rate of 36% means about a third of tumors shrank by a defined amount. It does not by itself prove people lived longer. The confirmatory trial is the part that answers that question, and until it does, the approval is conditional.

This is not a reason to refuse the drug. It is a reason to ask your oncologist directly what the current confirmatory data show for your situation, and what the alternative would be.

FDA named two specific companion diagnostics with the sotorasib approval, and the pairing is worth knowing.

For tissue, the QIAGEN therascreen KRAS RGQ PCR kit. For blood, the Guardant360 CDx. The important footnote is FDA's instruction on blood testing: if the plasma test is negative, confirm with tissue.

That rule exists because blood tests can miss what is really there. A negative liquid biopsy is not the same as an absent mutation. NCI describes a liquid biopsy simply as a blood draw rather than a tissue sample, and notes that some tests check one biomarker while "others check for many biomarkers at the same time and may be called multigene tests or panel tests."

If your only KRAS result came from blood and it was negative, ask whether tissue was tested too.

This is the most useful thing to understand about G12C, and it explains a lot of confusing news coverage.

In colorectal cancer, a G12C drug alone works poorly. FDA approvals there pair it with an antibody that blocks EGFR, a different growth signal.

FDA granted accelerated approval to adagrasib with cetuximab on June 21, 2024, for adults with KRAS G12C-mutated advanced colorectal cancer after fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. In the KRYSTAL-1 trial the objective response rate was 34%, all partial responses, with a median duration of response of 5.8 months. Adagrasib was dosed at "600 mg orally twice daily until disease progression or unacceptable toxicity."

FDA then approved sotorasib with panitumumab on January 15, 2025 for the same setting. In CodeBreaK 300, a randomized trial in 160 patients, median progression-free survival was 5.6 months with the combination versus 2 months with standard care, a hazard ratio of 0.48. The response rate was 26% versus 0%. Sotorasib was taken once daily by mouth, with panitumumab given by vein every 14 days at a weight-based amount.

Same mutation. Different organ. Different partner drug required. If someone tells you a KRAS G12C result means the same thing everywhere, they are wrong.

For sotorasib in lung cancer, FDA lists these in at least 20% of patients: diarrhea, musculoskeletal pain, nausea, fatigue, liver toxicity, and cough.

Two of those need active management rather than endurance. Diarrhea is common enough that you should have a plan and a phone number before day one. Liver toxicity is why blood tests get scheduled, and why you should not skip them when you feel fine.

Does my report name the exact variant, G12C, or only "KRAS mutation"? Was the test run on tissue, on blood, or both, and if blood was negative, was tissue checked? Which drug are you considering, and is it approved for my cancer type and line of treatment? Is this an accelerated approval, and what do the confirmatory data show now? What comes first, before a KRAS drug? What is my diarrhea plan, and how often will liver tests be drawn? Is there a KRAS G12C trial open to me, including first-line trials? Will you retest at progression? NCI notes that "the biomarkers in your cancer can change over time."

These apply once you are taking sotorasib or adagrasib.

• Call 911 or go to an emergency department if you are newly breathless, or your breathing gets worse. MedlinePlus says new or worsening shortness of breath, cough or fever on sotorasib needs a call to the doctor immediately or emergency treatment. Lung inflammation is the reason.
• Call your care team the same day if you have a new cough, or a temperature of 100.4°F (38°C) or higher.
• One exception on the temperature. If chemotherapy has been given in the past few weeks, 100.4°F (38°C) is a medical emergency rather than a same-day call (CDC). Phone your team immediately whatever the time, and go to an emergency department if you cannot reach them.
• Call your care team the same day if your eyes or skin turn yellow, your urine goes dark, your stools go pale, or you have pain on the right side of your stomach area. Those point at the liver, which is why the blood tests are scheduled.
• Call your care team the same day if you bruise or bleed without an obvious cause, or you are suddenly much more tired or weak than usual.
• Call your care team within a day or two if the diarrhea plan you agreed is not holding it, or you cannot keep fluids down.

Start with Biomarker Testing and Understanding Your Pathology Report.

• https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc
• 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.cancer.gov/about-cancer/treatment/drugs/sotorasib
• https://www.cancer.gov/about-cancer/treatment/drugs/adagrasib
• https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq
• https://www.cancer.gov/about-cancer/treatment/types/biomarker-testing-cancer-treatment
• https://medlineplus.gov/druginfo/meds/a621036.html