Adagrasib Receives Accelerated Approval for KRAS G12C Mutated NSCLC

Adagrasib has received accelerated approval for KRAS G12C mutated non–small cell lung cancer. The prescribing label comes with warnings for gastrointestinal toxicities, QTC interval prolongation, hepatotoxicity, and interstitial lung disease.

Adagrasib (Krazati) has received accelerated approval for the treatment of patients with locally advanced or metastatic KRAS G12C–mutant non–small cell lung cancer (NSCLC) who have already received at least 1 systemic therapy.The prescribing label comes with warnings for gastrointestinal toxicities, QTC interval prolongation, hepatotoxicity, and interstitial lung disease (ILD).1

The agent’s approval is backed by findings from the multicenter, single arm, open-label, KRYSTAL-1 trial (NCT03785249), which showed that the overall response rate among adagrasib recipients in this patient population was 43% (95% CI, 34%-53%) and the median duration of response was 8.5 months (95% CI, 6.2-13.8), as evaluated by blinded independent central review.1,2

The trial enrolled 112 patients who had progressive disease on or following platinum-based chemotherapy and an immune checkpoint inhibitor that was administered either concurrently or sequentially. These patients received adagrasib at a dose of 600 mg orally twice daily until disease progression or unacceptable toxicity.

The most common (≥ 20%) adverse events (AEs) in the trial included diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.2

The most common laboratory abnormalities (≥ 25%) included decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium, and decreased potassium.2

Providers should monitor patients for diarrhea, nausea and vomiting and provide supportive care as needed.

Patients should not be taking products known to prolong QTc intervals. If concomitant use cannot be avoided, or if patients have congestive heart failure, bradyarrhythmia, electrolyte abnormalities, patients will need their ECG and electrolytes to be monitored throughout treatments.

Hepatotoxicity was reported for 37% of patients and 12% of patients required dose interruption or reduction because of this toxicity. Liver laboratory tests (aspartate transaminase, alanine transaminase, alkaline phosphatase, and total bilirubin) should be collected prior to treatment initiation and every 3 months thereafter.2

For these toxicities, withholding, reducing, or discontinuing the agent may be necessary, depending on severity.

Patients will also require monitoring for new or worsening respiratory symptoms. In the trial, 41% of patients developed ILD/pneumonitis and 0.8% of patients discontinued treatment because of ILD or pneumonitis. The median time to symptom onset was 12 weeks (range, 5-31). The agent should be withheld if ILD/pneumonitis is suspected and should be permanently withheld if no other potential causes are identified.2

Adagrasib comes in 200 mg tablets. The recommended dose is 600 mg orally twice daily. It should be swallowed whole, with or without food.

The FDA also approved the QIAGEN therascreen KRAS RGQ PCR kit for tissue and the Agilent Resolution ctDx FIRST Assay for plasma. These companion diagnostics are intended to aide in patient treatment selection. According to the FDA, plasma should be assessed first. If no mutation is detected in the plasma, then the tumor tissue should be tested.

Continued approval for adagrasib will be contingent upon confirmatory trials.


  1. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed December 12, 2022.
  2. Krazati. Prescribing information. Mirati Therapeutics, Inc. 2022. Accessed December 12, 2022.
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