Crizotinib (trade name Xalkori) is an anti-cancer medication acting as an anaplastic lymphoma kinase (ALK) and ROS1 (c-ros oncogene 1) inhibitor. It is approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and other countries.
Crizotinib has an aminopyridine structure1, 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, which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. The kinase activity of the fusion protein is inhibited by crizotinib.
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. The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.
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 children2.
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.
Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells. Other studies3 suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.
Crizotinib Lung Cancer Research
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 people treated4.
Most had adenocarcinoma, and had never smoked or were former smokers. 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.
They were given 250 mg crizotinib twice daily for a median duration of six months. Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea. Some responses to crizotinib have lasted up to 15 months.
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. These results were confirmed in a 2017 analysis.
Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP (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). J. Med. Chem. 54 (18): ↩︎
Janoueix-Lerosey I, Schleiermacher G, Delattre O (2010). Molecular pathogenesis of peripheral neuroblastic tumors. Oncogene. 29 (11): 1566–79. ↩︎
Zou HY, Li Q, Lee JH, Arango ME, McDonnell SR, Yamazaki S, Koudriakova TB, Alton G, Cui JJ, Kung PP, Nambu MD, Los G, Bender SL, Mroczkowski B, Christensen JG (2007). An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 67 (9): 4408–17 ↩︎
Bang Y, Kwak EL, Shaw AT, et al: Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-positive patients with non-small cell lung cancer. 2010 ASCO Annual Meeting. Abstract 3. Presented June 6, 2010. ↩︎