Xalkori (crizotinib), by Pfizer, is an approved medication that interferes with the growth and spread of cancer cells. It is used to treat people with advanced, metastatic non-small cell lung cancer (NSCLC) whose disease is caused by a defect in the ALK (anaplastic lymphoma kinase) or ROS1 genes. The ALK gene defect can be determined by a test that is also approved by the U.S. Food and Drug Administration (FDA).
How Xalkori works
Xalkori is an inhibitor of multiple receptor tyrosine kinases, including ALK and ROS1. It only works in cancer cells that have an overactive version of ALK or ROS1.
In the case of NSCLC with genetic defects (rearrangements) in the ALK gene, a formation of ALK fusion proteins results in abnormal activation and signaling. This, in turn, supports the proliferation and survival of tumors that express these fusion proteins.
Xalkori is a potent inhibitor of ALK phosphorylation and signal transduction. This inhibition was observed in preclinical and clincial studies to be associated with cell cycle arrest and the induction of programmed cell death in ALK-positive cancer cells.
Xalkori in clinical trials
The FDA gave full approval to Xalkori for ALK-positive NSCLC in 2013, following a Phase 3 clinical trial (NCT00932893) in 347 patients with confirmed ALK-positive metastatic NSCLC whose cancer had progressed despite platinum-based chemotherapy. Patients were randomized to receive either oral crizotinib, 250 mg twice daily, or chemotherapy. Results demonstrated significantly longer progression-free survival (PFS) in the treated group, with these patients recording a median PFS of 7.7 months compared to 3.0 months in those given chemotherapy. The objective response rate (ORR) — defined as the percentage of patients who showed a reduction in tumor size — was also significantly higher in those given crizotinib, with median response durations of 7.4 months versus 5.6 months. Xalkori was previously awarded conditional, or accelerated, FDA approval based on two two randomized, multicenter, single-arm safety and efficacy studies in patients with late-stage ALK-positive NSCLC. Prior to patient randomization, ALK gene defects were determined by an assay called Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) probe kit. Most patients enrolled had received prior chemotherapy. In the first study, ORR was 50 percent with a median response duration of 42 weeks. In the second, ORR was 61 percent with a median response duration of 48 weeks.
The FDA expanded the use of Xalkori to treat ROS1-positive metastatic NSCLC in 2016 based on a multicenter, single-arm study that evaluated its safety and efficacy in this group of patients. The patients were given the drug twice daily to study its effect on their tumors. Results showed that 66 percent of patients showed complete or partial tumor shrinkage (ORR), an effect that lasted about 18 months. Safety results of this study were consistent with the safety profile of Xalkori evaluated in patients with ALK-positive metastatic NSCLC.
Dosage and administration
Xalkori is available in two dosage strengths – 200 mg and 250 mg capsules. The recommended dose of Xalkori is 250 mg orally, twice daily, until disease progression or the drug no longer tolerated by the patient. The recommended dose of Xalkori in patients with severe kidney problems not requiring dialysis is 250 mg orally, once daily.
It may be taken with or without food. The capsules should be swallowed whole with a glass of water. If a dose is missed, that dose can be skipped if the next dose is due within six hours.
Warnings and precautions
Xalkori may be toxic to the liver, and may cause severe vision loss, interstitial lung disease (ILD) or pneumonitis, and an abnormally slow heart beat. A physician should be advised immediately of such problems, and may recommend that the dose be reduced or suspended.
Grapefruit and its products may interact with Xalkori and must be avoided. The concurrent use with certain medications should also be avoided. It is advised not to breastfeed while taking Xalkori. It is not known if it is safe and effective in children.
The most common side effects caused by Xalkori are vision disorders, nausea, diarrhea, vomiting, edema, constipation, fatigue, decreased appetite, upper respiratory infection, dizziness, and nerve damage (neuropathy, or numbness in the hands and feet).
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