Crizotinib: a new treatment option for ALK-positive non-small cell lung cancer.

Abstract

OBJECTIVE:

To review the characteristics and clinical trial data of crizotinib in ALK-positive non-small cell lung cancer (NSCLC).

DATA SOURCE:

A literature search using PubMed/MEDLINE (up to December 2012) was performed using the terms crizotinib, ALK-positive, non-small cell lung cancer, and PF-02341066.

STUDY SELECTION/DATA EXTRACTION:

Phase 1, 2, and 3 trials evaluating the safety and efficacy of crizotinib in a cohort of patients with ALK rearrangements and advanced NSCLC were evaluated. All peer-reviewed articles with clinically relevant information were reviewed.

DATA SYNTHESIS:

ALK rearrangement results in an aberrant EML4-ALK fusion oncogene that constitutively activates ALK tyrosine kinase, resulting in inhibition of apoptosis and promotion of tumor cell proliferation. Approximately 3-5% of NSCLC exhibit this rearrangement. Crizotinib is an oral selective inhibitor of ALK and mesenchymal epithelial growth factor tyrosine kinases. Early phase trials with crizotinib showed improved response rates of 50-57% and extended duration of response of 6-10 months. Results of these studies led to accelerated Food and Drug Administration (FDA) approval of crizotinib. Further clinical trial results confirmed improvement in response rates, duration of response, as well as progression-free survival in ALK-positive patients with NSCLC receiving crizotinib. The drug undergoes hepatic metabolism by CYP3A4 and demonstrates autoinhibition of CY3A4, thus predisposing it to drug interactions. The most frequent toxicities with crizotinib include mild visual disturbances, nausea, vomiting, diarrhea, constipation, edema, and generally reversible, sometimes severe, elevations in aspartate aminotransferase and alanine aminotransferase.

CONCLUSIONS:

Crizotinib is a novel targeted anticancer agent that appears to be a favorable treatment option for patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test.

• Authors: Cindy L O'Bryant, Sarah D Wenger, Miryoung Kim, Lisa A Thompson
• Journal: The Annals of pharmacotherapy (Ann Pharmacother) Vol. 47 Issue 2 Pg. 189-97 (Feb 2013) ISSN: 1542-6270 [Electronic] United States
• PMID: 23386065 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Neoplasm Proteins
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridines
• Crizotinib
• ALK protein, human
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases

Topics

• Anaplastic Lymphoma Kinase
• Animals
• Antineoplastic Agents (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, metabolism)
• Clinical Trials as Topic
• Crizotinib
• Drug Interactions
• Drug Monitoring
• Humans
• Lung Neoplasms (drug therapy, enzymology, metabolism)
• Neoplasm Proteins (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Pyrazoles (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Pyridines (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)