For decades, the KRAS gene was considered undruggable. A single mutation in it drives roughly one in seven non-small cell lung cancers. On December 15, 2022, that wall cracked. Mirati Therapeutics won approval for Adagrasib, an oral pill sold as Krazati, that directly targets the G12C mutation in the KRAS GTPase. It is the second drug of its kind to reach the market. The first arrived only months earlier.
The mutation is specific. It changes a single amino acid in a protein that normally switches cell growth on and off. When broken, the switch sticks to “on.” Cells divide without restraint. Adagrasib binds to that broken switch and locks it in the off position. It is taken by mouth. For patients who have watched their cancer progress through chemotherapy and immunotherapy, that matters. No infusion chair. No hospital trip for treatment.
Mirati Therapeutics, based in San Diego, built the drug. The company has no other approved product. Adagrasib was its first. The approval covers patients with advanced non-small cell lung cancer whose tumors carry the KRAS G12C mutation and who have already received at least one prior systemic therapy. That group is not small. Lung cancer kills more people annually than any other cancer. Non-small cell lung cancer accounts for about 85 percent of all lung cancer cases. Of those, roughly 13 percent carry the G12C mutation.
Approval did not come without conditions. The drug carries a long list of adverse reactions. Diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation are all documented. Laboratory abnormalities show up too: decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium. These are not rare outliers. They are the most common side effects reported during trials.
Hepatotoxicity and renal impairment are the ones that demand attention. The liver and kidneys process the drug. When they struggle, the dose gets adjusted or treatment stops. QTc prolongation affects the heart’s electrical cycle and can lead to dangerous arrhythmias. Patients on Adagrasib need regular blood draws and electrocardiograms. The convenience of an oral pill comes with the burden of constant monitoring.
The drug works by fitting into a pocket on the mutant KRAS protein that only appears when the protein is in its inactive, GDP-bound state. It traps the protein there. That mechanism is what made the KRAS target seem impossible for so long. The pocket is shallow. The protein is round. For years, chemists could not find a molecule that would stick. Adagrasib was designed with a specific shape and a slow off-rate. It stays bound longer than similar compounds. That sustained inhibition is what the company bet on.
What the approval means in practice is still being worked out. Doctors now have a second targeted option for patients with this mutation. The first, sotorasib, was approved in 2021. Having two drugs gives oncologists a backup if one fails. It also creates the possibility of sequencing them, though no data yet supports that approach. Resistance will emerge. It always does. The cancer will find a way around the blockade. That is what makes this a step forward, not a finish line.
Mirati has trials running to test Adagrasib in earlier stages of the disease and in combination with other drugs. The goal is to hit the cancer before it spreads and before it learns to resist. For now, the drug is approved for patients who have already run through other options. That is where the need is sharpest. That is where the data was strongest. And that is where treatment begins.
, the second oral drug targeting the KRAS G12C mutation in advanced non-small cell lung cancer.){kind=link}