Crizotinib

Human anaplastic lymphoma kinase in complex with crizotinib. PDB 2xp2[6]

Crizotinib has an aminopyridine structure, and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases. About 4% of patients with non-small cell lung carcinoma have a chromosomal rearrangement that generates a fusion gene between EML4 ('echinoderm microtubule-associated protein-like 4') and ALK ('anaplastic lymphoma kinase'), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype.[7] The kinase activity of the fusion protein is inhibited by crizotinib.[7] Patients with this gene fusion are typically younger non-smokers who do not have mutations in either the epidermal growth factor receptor gene (EGFR) or in the K-Ras gene.[7][8] The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.[9][10]

ALK mutations are thought to be important in driving the malignant phenotype in about 15% of cases of neuroblastoma, a rare form of peripheral nervous system cancer that occurs almost exclusively in very young children.[11]

Crizotinib inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms.[12]

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.[12][13] Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.[14]

On August 26, 2011, the U.S. Food and Drug Administration approved crizotinib (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene.[1] Approval required a companion molecular test for the EML4-ALK fusion. In March 2016, the U.S. Food and Drug Administration approved crizotinib in ROS1-positive non-small cell lung cancer.[15]

On October 2012, the European Medicines Agency approved the use of crizotinib (Xalkori) to treat non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene[16]

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene.[8][9] Tumors shrank at least 30% in 57% of people treated.[9] [17] Most had adenocarcinoma, and had never smoked or were former smokers.[8] They had undergone treatment with an average of three other drugs prior to receiving crizotinib, and only 10% were expected to respond to standard therapy.[8][18] They were given 250 mg crizotinib twice daily for a median duration of six months.[8] Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea.[18] Some responses to crizotinib have lasted up to 15 months.[18]

A phase 3 trial, PROFILE 1007,[19] compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC.[5][10][20] Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.[10]

Crizotinib is also being tested in clinical trials of advanced disseminated anaplastic large-cell lymphoma,[12] and neuroblastoma.[21]

In February 2016 the J-ALEX phase III study comparing alectinib with crizotinib ALK-positive metastatic NSCLC was terminated early because an interim analysis showed that progression-free survival was longer with alectinib.[22] These results were confirmed in a 2017 analysis.[23]

In Bangladesh it is under the trade name Crizonix.

• ALK inhibitor
• Targeted molecular therapy for neuroblastoma
• Entrectinib - ALK/ROS1/NTRK inhibitor in phase II clinical testing