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Crizotinib: A novel tyrosine kinase inhibitor
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Crizotinib is a new tyrosine kinase inhibitor with action against anaplastic lymphoma kinase and c-Met tyrosine kinases, and it has been approved for the treatment of non–small cell lung cancer patients with anaplastic lymphoma kinase-positive mutations. As a tyrosine kinase inhibitor, crizotinib decreases angiogenesis and tumor cell proliferation and survival.
Oncogenic mutations in the anaplastic lymphoma kinase (ALK) gene have been noted in anaplastic large cell lymphoma; neuroblastoma (about 10%); inflammatory myofibroblastic tumor; and some NSCLC. The reported prevalence in NSCLC is about 5% (range, 2%-7%). Although this is a small percentage, with more than 221,000 new cases of lung cancer per year in this country, this represents about 10,000 potential ALK-positive NSCLC patients per year. ALK mutations are seen more frequently in light/never smokers, adenocarcinomas and in patients who are younger. Crizotinib (Xalkori, Pfizer) is a specific inhibitor of the ALK and c-Met tyrosine kinases. This inhibition leads to reduction of downstream signaling, resulting in decreased tumor cell proliferation and survival.
Clinical trials
Crizotinib has been studied in two phase 1/2 non-comparative trials that show very similar results. Both study groups enrolled patients with recurrent, advanced or metastatic NSCLC with ALK-positive mutations who had been previously treated with other agents. The groups of patients were more likely to be younger, light/never smokers and have adenocarcinomas compared with patients without the ALK rearrangement. Both studies showed an overall response rate of at least 50%, with a small rate of patients with a complete response. In these patients, the median duration of response was 42 to 48 weeks. Results from these two trials are shown in Table 1.
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In addition, a recent analysis (Shaw 2011 and Shaw 2011) of a previous phase 1/2 trial (Kwak 2010) demonstrated an improved OS in ALK-positive patients treated with crizotinib compared with crizotinib-naive historical controls. These data are shown in Table 2. The researchers concluded that crizotinib is associated with a higher rate of OS compared with historical controls not treated with crizotinib. Randomized controlled trials are being conducted to confirm this advantage.
Pharmacokinetics
Crizotinib has moderate oral absorption (43%) with a T-max of 4 to 6 hours. Administration with food only slightly decreases the area under the curve (AUC) and Cmax. It has a very large volume of distribution and high plasma protein binding. Crizotinib is extensively metabolized in the liver, via the CYP3A4/5 enzymes. The half-life is about 42 hours. It is usually given in a dose of 250 mg orally twice daily, and there are no noted dose modifications required for renal or hepatic impairment. It can be taken without regard to meals and should be kept in its original container.
Drug interactions
As with most TKIs, there are many potential drug interactions with crizotinib. It is both a substrate and a moderate inducer of CYP3A4/5. Crizotinib increases the AUC and toxicity of substrates of CYP3A4/5 with narrow therapeutic ranges. Unfortunately, this may include a large number of medications. In addition, strong CYP3A4/5 inhibitors (eg, ketoconazole, clarithromycin, some HIV medications) will dramatically increase the AUC of crizotinib, thereby increasing the toxicity. Strong CYP3A4/5 inducers (eg, rifampin, carbamazepine, phenytoin, some HIV medications) will substantially decrease the AUC of crizotinib and also decrease the efficacy of crizotinib. It is recommended that strong CYP3A4 inducers and inhibitors not be used concurrently with crizotinib. Another potential interaction is that antacids, proton pump inhibitors and H2 blockers will reduce the bioavailability of crizotinib and potentially reduce its efficacy.
Adverse effects
Crizotinib is generally well tolerated. The most common adverse effects were mild (grades 1 to 2). The most commonly reported adverse effects were changes in vision (floaters, blurred vision, etc), nausea, vomiting and diarrhea. Less common grade-3 to -4 toxicities reported include pneumonitis, increased liver function tests and QTc prolongation. It is recommended to monitor the electrocardiogram periodically in patients at high risk for QTc prolongation. These include people with congestive heart failure, bradyarrhythmias, hypokalemia, hypomagnesemia, atrial fibrillation and those taking concomitant medications that also can prolong the QTc interval.
Summary
Crizotinib is an orally available TKI that appears to have activity in the treatment of patients with ALK-positive NSCLC. It is generally well tolerated, though there are uncommon but serious effects. There are many potential drug interactions with this medication.
Ongoing research with crizotinib is comparing it with pemetrexed-based chemotherapy regimens, and combined with erlotinib, and in other ALK-positive cancers in adults and children.
Lisa K. Lohr, PharmD, BCPS, BCOP, is clinical pharmacy specialist and oncology medication therapy management provider, Masonic Cancer Center, University of Minnesota/Fairview, Minneapolis, MN. She also is a HemOnc Today Editorial Board member. Disclosure: Dr. Lohr reports no relevant financial disclosures.
For more information:
- Camidge DR. #2501. Presented at: 2011 ASCO Annual Meeting; June 3-7; Chicago.
- Crino L. #7514. Presented at: 2011 ASCO Annual Meeting; June 3-7; Chicago.
- Kwak EL. N Engl J Med. 2010;363:1693-1703.
- Rodig SJ. Curr Opin Investig Drugs. 2010;11:1477-1490.
- Shaw AT. #7507. Presented at: 2011 ASCO Annual Meeting; June 3-7; Chicago.
- Shaw AT. Lancet Oncol. 2011;12:1004-1012.