Indication
Crizotinib (Xalkori) is
an oral inhibitor of receptor tyrosine kinases including anaplastic
lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR,
c-Met), and recepteur d'origine nantais (RON). In August 2011, the
FDA granted the drug accelerated approval for the treatment of
patients with locally advanced or metastatic non-small cell lung
cancer (NSCLC) that is positive for rearrangements of the
ALK gene as detected by an FDA-approved test. 
Concurrent with crizotinib approval, the FDA
approved the Vysis ALK Break-Apart FISH (fluorescence in situ
hybridization) Probe Kit, a companion diagnostic test designed to
detect these rearrangements.
This indication for
crizotinib is based on response rate observed in two single-arm
trials in patients with locally advanced or metastatic
ALK-positive NSCLC, most of whom had received prior
systemic therapy (Fig. 1). No available data show improvement of
survival. In one study in 136 patients, which used the Vysis kit to
identify ALK-positive NSCLC, there was 1 complete response
and 67 partial responses, for an overall response rate of 50%.
Median duration of treatment was 22 weeks, and median response
duration was 42 weeks. In another study in 119 patients, which used
several local clinical trial assays to identifyALK-positive NSCLC,
there were 2 complete responses and 69 partial responses, for an
overall response rate of 61%. Median duration of treatment was 32
weeks and median response duration was 48 weeks. Responses were
observed within 8 weeks in 79% and 55% of responders in the two
trials.
How It
Works
Translocations in the
ALK gene can result in the expression of oncogenic fusion
proteins. The formation of ALK fusion proteins results in
activation and dysregulation of the expression and signaling of the
gene, which can contribute to increased cell proliferation and
survival in tumors expressing these proteins. Crizotinib inhibits
ALK and c-Met phosphorylation, blocking activity of the gene; it
has shown antitumor activity in xenografts expressing EML4- or
NPM-ALK fusion proteins or c-MET. Approximately 5% of NSCLC
patients harbor ALK translocations.
How It Is
Given
Crizotinib is taken
orally twice daily at a dose of 250 mg for as long as the patient
is deriving clinical benefit. Capsules are swallowed whole and can
be taken with or without food. If required, dose reductions are
first to 200 mg twice daily and then to 250 mg once daily.
Safety
Profile
The most common adverse reactions
(≥ 25%) observed in both studies supporting crizotinib approval
were vision disorder, nausea, diarrhea, vomiting, edema, and
constipation. Vision disorders included visual impairment,
photopsia, blurred vision, vitreous floaters, photophobia, and
diplopia. Grade 3 or 4 adverse reactions in at least 4% of patients
included increased ALT and neutropenia. Severe, life-threatening,
or fatal treatment-related pneumonitis occurred in 1.6% of
crizotinib patients in clinical trials. All cases occurred within 2
months after treatment initiation.
Cost-The
cost of crizotinib therapy is estimated at $9,600 per month, or
$115,000 per year. ■
Suggested
Readings
Cui JJ, Tran-Dube M,
Shen H, et al: Structure based drug design of crizotinib
(PF-02341066), a potent and selective dual inhibitor of
mesenchymal-epithelial transition factor (c-MET) kinase and
anaplastic lymphoma kinase (ALK). J Med Chem
54:6342-6363, 2011.
Hallberg B, Palmer RH:
Crizotinib-latest champion in the cancer wars? N Engl J
Med 363:1760-1762, 2010.
Kwak EL, Bang Y-J,
Camidge DR, et al: Anaplastic lymphoma kinase inhibition in
non-small-cell lung cancer. N Engl J
Med 363:1693-1703, 2010.
U.S. Food and Drug
Administration: Crizotinib. Available at
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm270058.htm.
Accessed October 13, 2011.
XALKORI® (crizotinib) capsules, oral. Prescribing
information. Pfizer Labs, August 2011. Available at http://labeling.pfizer.com/showlabeling.aspx?id=676.
Accessed October 13, 2011.
