Crizotinib

Crizotinib

Clinical data
Other names	PF-02341066 1066
Routes of administration	Oral
Identifiers
IUPAC name 3-[(1R)-1-(2, 6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
CAS Number	877399-52-5
PubChem CID	11626560
CompTox Dashboard (EPA)	DTXSID701009329
ECHA InfoCard	100.166.440
Chemical and physical data
Formula	C21H22Cl2FN5O0
Molar mass	450.337 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES C1(=C(C=CC(=C1[C@H](OC2=C(N=CC(=C2)C3=C[N](N=C3)C4CCNCC4)N)C)Cl)F)Cl

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).

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. Crizotinib competes with ATP for the ALK kinase domain of this fusion protein. The ELM4-ALK fusion transcript was first described in a 2007 study published in Nature. Patients with this gene inversion typically non-smokers who do not have mutations in the epidermal growth factor receptor gene (EGFR) or mutations in the KRAS gene. 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 annually.

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. Tumors shrank at least 30% in 57% of the patients treated. In the study, patients were given 250 mg twice daily. The median duration of treatment with crizotinib was 6 months. Side effects included nausea, vomiting, and diarrhea. Approximately 50% of the patients studied had at least one symptom. Most patients were never-smokers or former smokers and had adenocarcinoma. These patients had undergone treatment with an average of three other drugs prior to receiving crizotinib, and only 10% were expected to respond to this prior treatment. Those who responded to therapy have had responses that last up to 15 months thus far. This study did not have a control group, but a phase 3 trial, PROFILE 1007, will compare crizotinib with stanard of care chemotherapy in the treatment of ALK-positive NSCLC. Additionally, a phase 2 trial, PROFILE 1005, will study patients meeting similar criteria who have receive more than one line of prior chemotherapy.