Crizotinib – a newer drug for advanced lung cancer

With improved understanding of lung carcinogenesis, targeted therapy for specific mutations in lung cancer are being increasingly developed. In recent experience with targeted therapy, Erlotinib, a tyrosine kinase inhibitor used for epidermal growth factor receptor (EGFR) positive lung cancer has shown improvement in overall survival in patients with advanced lung cancer. This led to the search for other acquired genetic changes in lung cancers that could act as therapeutic targets for drugs.

Crizotinib, a dual inhibitor of ALK and C-MET was recently approved by the US FDA in August 2011. ALK stands for Anaplastic Lymphoma Kinase and is expressed in about 4% of non-small cell lung cancer as EML4-ALK oncogenic fusion kinase. This mutation is known to occur in younger population with minimal to no smoking history and exclusively in adenocarcinoma variant of lung cancer. Studies have suggested excellent responsiveness of ALK positive lung cancer to crizotinib therapy. In a retrospective study of ALK positive advanced lung cancer the 1 year overall survival was 74% and 2-year overall survival was 54%. The overall survival was improved compared to crizotinib naïve controls. In view of the encouraging results of the early studies crizotinib received accelerated approval by the US FDA for treatment of locally advanced or metastatic ALK positive non-small cell lung cancer.

All patients diagnosed to have advanced non-small cell lung cancer are tested for EGFR and KRAS mutations. EGFR mutated NSCLC accounts for nearly 10% of the cases. If EGFR is negative, then testing for ALK mutation can be done either by fluorescence in situ hybridization (FISH), Immunohistochemisty (IHC) or RT-PCR. Though RT-PCR is more sensitive, analysis by FISH is more clinically feasible. EGFR and ALK mutations are generally mutually exclusive. The presence of one mutation indicates the absence of the other, though rarely an individual can harbour both mutations.

Acquired resistance to crizotinib has been reported and is thought to be due to the natural resistance of the tumor sub populations to crizotinib and acquired mutations in the target ALK domain. In case of relapse, if resistance is suspected rebiopsy might help in elucidating the mutation status. Crizotinib is taken orally in a dosage of 250mg twice daily. It is usually well tolerated and side effects include nausea, diarrhoea, increased liver enzymes and visual disturbances.  

Reference

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2811%2970232-7/abstract