Muller Journal of Medical Sciences and Research

REVIEW ARTICLE
Year
: 2017  |  Volume : 8  |  Issue : 2  |  Page : 65--67

Crizotinib in treatment of lung cancer


Arpita Singh1, Anubhuti Singh2, Kislay Kishore3, Ajay K Verma2, Surya Kant2,  
1 Department of Pharmacology, Government Medical College, Kannauj, Uttar Pradesh, India
2 Department of Respiratory Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India
3 Department of Respiratory Medicine, Command Hospital (Central Command), Lucknow, Uttar Pradesh, India

Correspondence Address:
Surya Kant
Department of Respiratory Medicine, King George's Medical University, Chowk, Lucknow - 226 003, Uttar Pradesh
India

Abstract

Lung cancer is one of the most common malignancies and is the leading cause of cancer-related mortality throughout the world. Despite advances in surgery and chemotherapy, survival is still poor. Crizotinib is an oral inhibitor of multiple kinases, including anaplastic lymphoma kinase (ALK), and is indicated in the treatment of patients with locally advanced or metastatic? non small cell lung carcinoma (NSCLC) harboring ALK mutation as a targeted therapy. This is short drug review of crizotinib in the treatment of advanced lung cancer.



How to cite this article:
Singh A, Singh A, Kishore K, Verma AK, Kant S. Crizotinib in treatment of lung cancer.Muller J Med Sci Res 2017;8:65-67


How to cite this URL:
Singh A, Singh A, Kishore K, Verma AK, Kant S. Crizotinib in treatment of lung cancer. Muller J Med Sci Res [serial online] 2017 [cited 2018 Oct 20 ];8:65-67
Available from: http://www.mjmsr.net/text.asp?2017/8/2/65/212416


Full Text

 Introduction



Once thought to be among the rarest forms of cancer, lung cancer is now one of the most common cancers in the world and is also the leading cause of cancer-related deaths among both men and women. Worldwide, there are 1.8 million new cases of lung cancer per year and 1.6 million deaths from lung cancer.[1] In India, the age-adjusted incidence of lung cancer ranges from 7.4 to 13.1/100,000 among males and from 3.9 to 5.8/100,000 among females.[2]

Histologically, lung cancer is broadly classified into small cell lung carcinoma and nonsmall cell lung cancer (NSCLC) which is further classified into large cell carcinoma, adenocarcinoma, and squamous cell carcinoma. For NSCLC Stages I, II, and IIIA, combined modality treatment using surgical resection, radiotherapy and chemotherapy are preferred, while for advanced Stages (IIIB and IV), platinum-based doublet chemotherapy is the treatment of choice. By the time, patients report to a health-care facility; they already have advanced disease. More than 70% lung cancer patients present in the advanced stage when the tumor is usually unresectable.[3] Chemotherapy is, therefore, the main focus for newer research today.

Despite tremendous advances in the field of genetic mapping of the cancer cell and utilization of this knowledge for the development of targeted therapy, there has been a marginal improvement in the survival of these patients. The prognosis of lung cancer remains poor even today with an overall 5 years survival of approximately 15% in the developed and 5% in the developing countries.[4] There is a need for the development of newer drugs to prolong survival and improve the quality of life (QoL) in patients with this fatal disease.

 Genetic Mutations in Lung Cancer



Almost all chemotherapy agents have reached a plateau of effectiveness in the treatment of advanced lung cancer, with none of the drugs having any substantial benefit over each other in terms of response or survival. This has led to major advances in the understanding of oncogenesis in recent years. Most of the signaling pathways which have been discovered involve trans-membrane receptors, which once activated by an extracellular ligand, trigger a successive cascade of kinases resulting in transcriptional changes required for malignant transformation and metastasis. This has provided specific targets for which selective agents can be developed. The important mutations in lung cancer involve epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten Rous Sarcoma virus (K-RAS) oncogene.

 Echinoderm Microtubule-associated Protein-like 4 - Anaplastic Lymphoma Kinase Fusion Gene



ALK is a trans-membrane tyrosine kinase receptor of the insulin receptor superfamily. Mutation in ALK gene (inversion at 2p) leads to fusion between ALK and other proteins, most commonly echinoderm microtubule-associated protein like 4 (EML4).[5] This rearrangement causes dimerization of the fusion proteins, leading to an intracellular signaling cascade, ultimately resulting in oncogenic transformation of the cell and acquiring properties of inhibition of apoptosis, proliferation, invasion, and metastasis. Its tumorigenic potential was discovered in 2007. Around 3%–7% of patients with NSCLC have this genetic mutation.[6]

ALK is expressed more commonly in nonsmokers and females, with a median age of 50 years (younger than the average lung cancer patient) and patients with adenocarcinoma. It is a driver mutation, i.e., it induces and sustains tumor genesis. Furthermore, the presence of ALK mutation is mutually exclusive with other driver mutations such as EGFR and K-RAS.[7]

 Detection of Anaplastic Lymphoma Kinase in Clinical Samples



There is no standardized detection method for ALK fusion gene in clinical samples. The commonly used methods include fluorescent in situ hybridization, reverse transcription-polymerase chain reaction and immunohistochemistry.[8] A number of EML4-ALK variants have been identified (with the difference in truncation of EML4). Further research is underway for standardization of an optimum detection technique.

 About the Drug



Crizotinib is an oral, selective inhibitor of ALK and mesenchymal epidermal growth factor (c-met)/hepatocyte growth factor receptor kinases.[9] Binding of adenosine triphosphate (ATP) is essential for phosphorylation and activation of the ALK enzyme. Crizotinib attaches to the ATP binding site, preventing this step.[8] It was approved via accelerated drug approval by the United States Food and Drug Administration in 2011, based on the encouraging findings of early clinical trials in patients with ALK-positive NSCLC.[10]

 Efficacy



In a randomized, controlled, open-label, phase three trial comparing crizotinib with standard chemotherapy (pemetrexed or docetaxel) in patients with advanced, previously treated ALK-positive NSCLC, the median progression-free survival (PFS) was 7.7 months in crizotinib group and 3.0 months in chemotherapy group (P < 0.001); the response rate (RR) were 65% with crizotinib and 20% with chemotherapy (P < 0.001). The overall survival (OS) showed no significant difference.[11]

A meta-analysis of clinical trials was conducted to assess the efficacy and safety of crizotinib, on the basis of six clinical trials. In patients with locally advanced or metastatic ALK-positive NSCLC, crizotinib treatment showed improved 1 year OS, PFS as well as improved objective RR (ORR).[10]

The results of the first study to evaluate crizotinib as the first line therapy in chemo-naïve patients in comparison to conventional platinum-based chemotherapy doublet in ALK-positive NSCLC (PROFILE 1014 Phase III) have recently come out.[12] Crizotinib treatment was found to be superior to pemetrexed and cisplatin chemotherapy in the context of PFS, ORR, reduction in lung cancer symptoms and improvement in QoL.

 Adverse Effect Profile



The most common adverse effect of crizotinib is vision disorder, including visual impairment, blurring of vision and photopsia. These vision disorders are transient and reversible. Elevated liver enzymes, diarrhea, nausea, and vomiting are other adverse effects. A few cases (incidence: 1.6%) of severe, life-threatening treatment-related pneumonitis have been reported with crizotinib.[13]

 Indications



Crizotinib is indicated in a dosage of 250 mg twice a day in ALK-positive NSCLC patients with locally advanced or metastatic disease. It is given until disease progression or development of unacceptable toxicity.

 Resistance



Certain mutations have been recognized, which are conferring resistance to crizotinib. Gatekeeper mutations in the ALK gene (L1196) and other mutations in kinase domain have been identified.[14] Various studies are underway to develop second generation ALK inhibitor to overcome resistance to crizotinib, with phase one trials of ceritinib providing positive results.[15]

 Future Directions



A standard diagnostic technique for the detection of ALK mutations in clinical samples is required. Although crizotinib has shown significant improvements in RRs, QoL, and improvement in symptoms, there has not been any survival benefit. In addition, issues of resistance to crizotinib have emerged. Further studies are warranted for irreversible ALK inhibitors which have better survival advantage than the existing drugs. Efficacy of crizotinib as switch maintenance and third line chemotherapy also needs to be evaluated.

 Conclusion



Crizotinib is a targeted chemotherapeutic agent against ALK mutation in patients with advanced NSCLC. It has improved efficacy with good tolerability. Targeted therapy has thus opened the door to immense possibilities for drug therapy in lung cancer. Targeted therapy along with preventive measures like smoking cessation programs promise to serve as the most effective tools in the battle against lung cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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