Adagrasib Receives Accelerated Approval for KRAS G12C Mutated NSCLC

Adagrasib (Krazati) has been granted accelerated approval for the treatment of patients with locally advanced or metastatic KRAS G12C–mutant non–small cell lung cancer (NSCLC) who have 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 approval is backed by findings from the multicenter, single-arm, open-label KRYSTAL-1 trial (NCT03785249), which showed overall response rate to be 43% (95% CI, 34%-53%) and the median duration of response to be 8.5 months (95% CI, 6.2-13.8), as evaluated by blinded independent central review.^1,2

The trial enrolled 112 patients whose disease had progressed on or after platinum-based chemotherapy with concurrent or sequential immune checkpoint inhibitor. These patients received a 600-mg oral dose of adagrasib twice daily until disease progression or unacceptable toxicity.

The most common (≥20%) adverse events (AEs) 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 offer supportive care as needed.²

Patients should not be taking products known to prolong QTc intervals.² If concomitant use cannot be avoided or if patients have congestive heart failure, bradyarrhythmia, or electrolyte abnormalities, their cardiac electrical activity and electrolytes must be monitored throughout treatment.

In a pooled safety analysis of 366 patients, hepatotoxicity was reported in 37% of patients. Of those, 12% required dose interruption or reduction. 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 Depending on the severity of these toxicities, it may be necessary to withhold, reduce, or discontinue the agent.

Patients will also require monitoring for new or worsening respiratory symptoms. During the trial, 41% of patients developed ILD/pneumonitis and 0.8% 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 permanently withheld if no other potential causes are identified.²

Adagrasib comes in 200-mg tablets. The recommended dose is 600 mg swallowed whole, with or without food, twice daily.²

The FDA also approved 2 companion diagnostics—the therascreen KRAS RGQ PCR Kit for tissue biopsy (QIAGEN) and the Resolution ctDx FIRST assay for liquid biopsy (Agilent)—to aid in patient treatment selection. According to the agency, plasma should be assessed first and if no mutation is detected, tumor tissue should then be tested.¹

Continued approval for adagrasib will be contingent upon confirmatory trials.¹

References

1. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed April 12, 2023. https://bit.ly/3WdCKPs
2. Krazati. Prescribing information. Mirati Therapeutics; 2022. Accessed April 12, 2023. https://bit.ly/3PlROsc