Crizotinib Capsules (Xalkori®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
A new orally effective targeted therapy for the treatment of non-small cell lung cancer (NSCLC) has been approved by the FDA. Crizotinib is a receptor tyrosine kinase inhibitor including anaplastic lymphoma kinase (ALK). A companion diagnostic test (Vysis ALK Break Apart FISH Probe kit) was also approved to identify the target population. Crizotinib was approved under the agency's accelerated approval program and is marketed by Pfizer as Xalkori.
Crizotinib is indicated for the treatment of patients with locally advanced or metastatic NSCLC who are ALK-positive.1
The recommended dose is 250 mg taken orally twice daily with or without food.1 The dose may be interrupted or reduced to 200 mg twice daily or to 250 mg once daily due to individual safety or tolerability.
Crizotinib is available as 250 mg and 200 mg capsules.
In patients with advanced ALK-positive NSCLC, the overall response rate ranged from 50-61%.1,2
Common adverse events include vision disorder (62-64%), gastrointestinal-related events (40-57%), edema (28-38%), and fatigue (20-31%).1 Severe adverse events, including fatal pneumonitis, have been reported with a frequency of 1.6%. Concomitant administration of crizotinib and strong CYP3A inhibitors or inducers should be avoided. Dose reduction may be needed for drugs that are substrates of CYP3A and plasma levels of substrates of p-glycoprotein may be increased. Crizotinib can increase ALT and may prolong QTc interval.
Crizotinib is a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor. It has been shown to be effective in ALK-translocation-positive patients with NSCLC.2 The approval of crizotinib was based on two multicenter, single-arm studies in patients with late stage ALK-positive NSCLC (n = 255).1 The primary endpoint was objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumor (RECIST). ORR was 50% in one study (95% confidence interval [CI], 42%, 59%) and 61% in the second study (95% CI, 52%, 70%). Fifty-five percent (55%) to 79% of responses were achieved within the first 8 weeks of treatment. Median response durations were 41.9 weeks in the first study and 48.1 weeks in the second study. Dose interruptions were required in 36-45% of patients and dose reduction was required in 29% to 44%. Improvement in survival has not been demonstrated.
Crizotinib provides effective therapy for a small subset of patients with NSCLC, however, improved survival has yet to be demonstrated. The prevalence of ALK-positive disease is estimated to be 1-7%.3 Those with ALK-rearrangement tend to be younger, with little or no tobacco exposure, and have adenocarcinoma.2
1. Xalkori Prescribing Information. New York, NY: Pfizer Labs; August 2011.
2. Kwak EL, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010; 363:1693-1703.
3. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm. Accessed Sept. 4, 2011.