Crizotinib

Crizotinib is an oral, small-molecule tyrosine kinase inhibitor developed by Pfizer and marketed as Xalkori. It inhibits several oncogenic kinases, most notably anaplastic lymphoma kinase (ALK) and ROS1, and shows activity against MET in preclinical studies. By blocking ALK and ROS1 signaling, crizotinib reduces tumor cell proliferation and can induce tumor responses in cancers driven by these rearrangements.

It is approved for adults with metastatic non-small cell lung cancer whose tumors harbor ALK rearrangements or ROS1 rearrangements, as detected by FDA-approved tests. It has also been studied in other ALK- or ROS1-driven cancers and in pediatric patients under clinical trials.

Crizotinib binds to the ATP-binding sites of ALK and ROS1, inhibiting phosphorylation and downstream signaling through pathways such as PI3K/AKT and MAPK.

The drug is taken orally, typically at a dose of 250 mg twice daily, with adjustments for hepatic impairment or adverse effects. It is metabolized primarily by CYP3A4 and is subject to drug interactions with strong CYP3A4 inhibitors or inducers.

Common adverse effects include nausea, diarrhea, vomiting, edema, constipation, fatigue, and visual disturbances. Elevations in liver enzymes and rare cases of hepatotoxicity can occur; liver function tests should be monitored. Rare but serious events include interstitial lung disease and QT prolongation.

Acquired resistance may arise via secondary mutations in ALK or activation of alternative pathways.

Crizotinib was the first approved ALK inhibitor and helped establish targeted therapy for ALK- and ROS1-rearranged NSCLC, preceding newer generation ALK inhibitors.