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Targeted Therapy Drugs: Crizotinib

Targeted Therapy Drugs: Crizotinib-Introduction

Crizotinib, developed by Pfizer, Inc., a targted therapy drug for both ALK and ROS1. It is approved to treat patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive in 2016. And in 2013 it is also indicated for patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Targeted Therapy Drugs: Crizotinib-Target

The target of this drug is ROS1 and ALK. ROS1 is a receptor tyrosine kinase (RTK) of the insulin receptor family. ROS1 fusions contain an intact tyrosine kinase domain. To date, those tested biologically possess oncogenic activity. Signaling downstream of ROS1 fusions results in activation of cellular pathways known to be involved in cell growth and cell proliferation. ROS1 fusions are associated with sensitivity in vitro to tyrosine kinase inhibitors that inhibit ROS1. The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is aberrant in a variety of malignancies. The various N-terminal fusion partners promote dimerization and therefore constitutive kinase activity. Signaling downstream of ALK fusions results in activation of cellular pathways known to be involved in cell growth and cell proliferation.

Targeted Therapy Drugs: Crizotinib-Efficacy

An open-label, active-controlled, multinational, randomized trial enrolled 347 patients with ALK-positive, metastatic NSCLC. Patients were required to have progressed following platinum-based chemotherapy and to have ALK expression in tumor specimens detected by fluorescence in situ hybridization on central laboratory testing. Patients were randomized to receive either crizotinib 250 mg orally twice daily (n=173) or chemotherapy (n=174). Patients randomized to chemotherapy received pemetrexed (58%) or docetaxel (42%) if they had received prior pemetrexed. Approximately 64% of patients on the chemotherapy arm subsequently received crizotinib.
The trial demonstrated significantly prolonged progression-free survival (PFS) for crizotinib treatment compared to chemotherapy [HR=0.49, (95% CI: 0.37, 0.64), p<0.0001]. Median PFS was 7.7 and 3.0 months on the crizotinib and chemotherapy arms, respectively. The ORR was significantly higher for the crizotinib arm (65% vs. 20%) with median response durations of 7.4 and 5.6 months in the crizotinib and chemotherapy arms, respectively. No difference in overall survival was noted between the two arms [HR= 1.02 (95% CI: 0.68, 1.54)] in a planned interim analysis.

Targeted Therapy Drugs: Crizotinib-Side Effect

Common adverse reactions in clinical trials with crizotinib, occurring at an incidence of 25% or higher, included visual disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.
Safety data from this trial was evaluated in 172 crizotinib-treated patients. Serious adverse events were reported in 37% of crizotinib-treated patients. The most common serious adverse reactions of crizotinib were pneumonia, pulmonary embolism, dyspnea, and interstitial lung disease. Fatal adverse reactions occurred in 9 crizotinib-treated patients and included acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, interstitial lung disease, respiratory failure, and sepsis.