Crizotinib isindicated for the treatment of metastatic non-small cell lung cancer (NSCLC) or relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive.[2][3]
It is also indicated for the treatment of unresectable, recurrent, or refractory inflammatory anaplastic lymphoma kinase (ALK)-positive myofibroblastic tumors (IMT).[2][10]
Human anaplastic lymphoma kinase in complex with crizotinib. PDB2xp2[11]
Crizotinib has anaminopyridine structure, and functions as aprotein kinase inhibitor by competitive binding within theATP-binding pocket of target kinases. About 4% of patients withnon-small cell lung carcinoma have achromosomal rearrangement that generates afusion gene betweenEML4 ('echinoderm microtubule-associated protein-like 4') andALK ('anaplastic lymphoma kinase'), which results in constitutivekinase activity that contributes tocarcinogenesis and seems to drive themalignantphenotype.[12] The kinase activity of the fusion protein is inhibited by crizotinib.[12] Patients with this gene fusion are typically younger non-smokers who do not have mutations in either theepidermal growth factor receptor gene (EGFR) or in theK-Ras gene.[12][13] The number of new cases ofALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.[14][15]
ALK mutations are thought to be important in driving the malignant phenotype in about 15% of cases ofneuroblastoma, a rare form of peripheral nervous system cancer that occurs almost exclusively in very young children.[16]
Crizotinib is thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.[6][17] Other studies suggest that crizotinib might also act via inhibition ofangiogenesis in malignant tumors.[18]
Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying theALK fusion gene.[13][14] Tumors shrank at least 30% in 57% of people treated.[14][21]Most had adenocarcinoma, and had never smoked or were former smokers.[13] 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.[13][22] They were given 250 mg crizotinib twice daily for a median duration of six months.[13] Approximately 50% of these patients had at least one side effect, such as nausea, vomiting, or diarrhea.[22] Some responses to crizotinib have lasted up to 15 months.[22]
A Phase III trial, PROFILE 1007,[23] compares crizotinib to standard second line chemotherapy (pemetrexed ortaxotere) in the treatment ofALK-positive NSCLC.[24][15][25] Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.[15]
In February 2016, the J-ALEX phase III study comparingalectinib with crizotinib ALK-positive metastatic NSCLC was terminated early because an interim analysis showed thatprogression-free survival was longer with alectinib.[26] These results were confirmed in a 2017 analysis.[27]
In people affected by relapsed or refractory ALK+ anaplastic large cell lymphoma, crizotinib produced objective response rates ranging from 65% to 90% and 3 year progression free survival rates of 60–75%. No relapse of the lymphoma was ever observed after the initial 100 days of treatment. Treatment must be continued indefinitely at present.[28][29][30]
^abClinical trial numberNCT00585195 for "A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer" atClinicalTrials.gov
^Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, et al. (September 2011). "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)".Journal of Medicinal Chemistry.54 (18):6342–63.doi:10.1021/jm2007613.PMID21812414.
^Clinical trial numberNCT00932451 for "An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene" atClinicalTrials.gov
^Clinical trial numberNCT00932893 for "An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene" atClinicalTrials.gov
^Gambacorti-Passerini C, et al. (2010). "Clinical Activity of Crizotinib In Advanced, Chemoresistant ALK+ Lymphoma Patients".Annual Meeting of the American Society of Hematology. Orlando, Florida.
"Crizotinib".NCI Drug Dictionary. National Cancer Institute.
"Crizotinib".National Cancer Institute. 11 October 2011.
Clinical trial numberNCT00585195 for "A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer (PROFILE 1001)" atClinicalTrials.gov
Clinical trial numberNCT00932893 for "An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene" atClinicalTrials.gov
Clinical trial numberNCT00939770 for "Crizotinib in Treating Younger Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma" atClinicalTrials.gov
Clinical trial numberNCT01154140 for "A Clinical Trial Testing The Efficacy Of Crizotinib Versus Standard Chemotherapy Pemetrexed Plus Cisplatin Or Carboplatin In Patients With ALK Positive Non Squamous Cancer Of The Lung (PROFILE 1014)" atClinicalTrials.gov
Clinical trial numberNCT01979536 for "Brentuximab Vedotin or Crizotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II-IV Anaplastic Large Cell Lymphoma" atClinicalTrials.gov
N
Y (what is this?) (verify)
This article incorporates text from this source, which is in thepublic domain.