Crizotinib
| Clinical data | |
|---|---|
| Other names | PF-02341066 1066 |
| Routes of administration | Oral |
| ATC code |
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| Pharmacokinetic data | |
| Elimination half-life | 46 hours |
| Identifiers | |
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| CAS Number | |
| PubChem CID | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.166.440 |
| Chemical and physical data | |
| Formula | C21H22Cl2FN5O |
| Molar mass | 450.337 g/mol g·mol−1 |
| 3D model (JSmol) | |
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Crizotinib (also known as PF-02341066 or 1066), is an ALK (anaplastic lymphoma kinase) inhibitor being developed by Pfizer Incorporated. It is currently undergoing clinical trials for its potential to treat advanced non-small cell lung carcinoma (NSCLC).[1]
Mechanism of action
Crizotinib is an oral ALK (anaplastic lymphoma kinase) inhibitor under study in patients with advanced NSCLC carrying the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion gene. The protein product of this fusion has constitutive kinase activity that is carcinogenic.[2] Crizotinib competes with ATP for the ALK kinase domain of this fusion protein.[2] The ELM4-ALK fusion transcript was first described in a 2007 study published in Nature.[3] Patients with this gene inversion are typically non-smokers who do not have mutations in the epidermal growth factor receptor gene (EGFR) or mutations in the KRAS gene.[2][4] Approximately 4% of the 220,000 Americans diagnosed with lung cancer each year have the ALK fusion gene, and 45,000 newly diagnosed NSCLC patients are ALK positive worldwide.[5][6]
Clinical trials
Researchers at the American Society of Clinical Oncology 2010 Annual Meeting presented data from an ongoing phase 1/2 study that show crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene.[4][5] Tumors shrank at least 30% in 57% of the patients treated.[5]
In the study, patients were given 250 mg twice daily.[4] The median duration of treatment with crizotinib was 6 months.[4] Side effects included nausea, vomiting, and diarrhea.[7] Approximately 50% of the patients studied had at least one side effect.[7]
Most patients were never-smokers or former smokers and had adenocarcinoma.[4] These patients had undergone treatment with an average of three other drugs prior to receiving crizotinib, and only 10% were expected to respond to standard therapy.[4][7] Those who responded to treatment have had responses that last up to 15 months thus far.[7]
This study did not have a control group, but a phase 3 trial, PROFILE 1007, will compare crizotinib with standard of care chemotherapy in the treatment of ALK-positive NSCLC.[1][6][8] Additionally, a phase 2 trial, PROFILE 1005, will study patients meeting similar criteria who have received more than one line of prior chemotherapy.[6]
References
- ^ a b Clinical trial number NCT00932451 at ClinicalTrials.gov
- ^ a b c "Maintenance Therapy for Non-Small Cell Lung Cancer". MedscapeCME. 2010-05-12. Retrieved 2010-06-07.
- ^ "Anaplastic Lymphoma Kinase; ALK". Online Mendelian Inheritance in Man. 2009-09-21. Retrieved 2010-06-07.
- ^ a b c d e f "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday. 2010-06-05. Retrieved 2010-06-07.
- ^ a b c "Advances Come in War on Cancer". The Wall Street Journal. 2010-06-07. Retrieved 2010-06-07.
- ^ a b c "Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types" (PDF) (Press release). Pfizer Oncology. 2010-05-20. Retrieved 2010-06-07.
{{cite press release}}: line feed character in|title=at position 64 (help) - ^ a b c d "Gene-based lung cancer drug shows promise". MSNBC.com. 2010-05-07. Retrieved 2010-06-07.
- ^ Clinical trial number NCT00932893 at ClinicalTrials.gov