ALK-rearranged non-small cell lung cancers: how best to optimize the safety of crizotinib in clinical practice?

Abstract

Crizotinib (XALKORI™, Pfizer) is a tyrosine kinase inhibitor targeting ALK, MET and ROS1, currently approved for the treatment of adults with ALK-rearranged non-small-cell lung cancer. Optimizing the management of frequent crizotinib-related adverse events is crucial to ensure its continuous administration and reproduce the response and survival rates reported in clinical trials. Here, we propose some practical measures, which are mostly derived from the recommendations given to the investigators of the PROFILE 1001, 1005, 1007 and 1014 trials and are based on experience and scientific findings regarding the management of these disorders. While visual disturbances or bradycardia are frequent but benign, the severity of the cardiac and hepatic adverse events requires special attention potential to QT interval prolongations and to the monitoring of electrolyte levels and liver function, taking into account potential drug–drug interactions.

Keywords:

• ALK
• crizotinib
• drug safety
• heart
• liver
• lung cancer

Financial & competing interests disclosure

This document was drafted during an expert board meeting organized at the initiative of Pfizer. However, Pfizer played no role in the interpretation and discussion of the data, or in the preparation of this manuscript. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Crizotinib (XALKORI™, Pfizer) is a tyrosine kinase inhibitor targeting ALK, MET and ROS1, currently approved for the treatment of adults with ALK-rearranged non-small-cell lung cancer. Optimizing the management of frequent adverse events of crizotinib is crucial to ensure its continuous administration, and to reproduce response and survival rates that were reported in clinical trials.

• Patients must be informed about potential ocular disorders and the precautions to take when driving or using machines in low light (tunnels, night driving). An ophthalmological evaluation is not required before starting crizotinib treatment.

• Crizotinib-related gastrointestinal disorders tend to be rarely persistent or severe. These adverse events can be managed with dietary measures and symptomatic treatment. It is, therefore, not recommended to adjust the crizotinib dose for low-grade gastrointestinal toxicity.

• Electrocardiograms should be performed prior to introduction of crizotinib treatment. Torsades de pointes should be considered in patients presenting with malaise or fainting.

• Hypogonadism should be considered in cases of fatigue, decreased libido or even depression. Given that these symptoms may be related to cancer, an early morning testosterone assay should be performed to identify patients requiring supplementation.

• Liver function tests, including an assay of transaminase and bilirubin levels, should be performed at least every week during the first 2 months of treatment and then every month.

Notes