Lorlatinib (PF-06463922) is an investigational treatment being developed by Pfizer for treating anaplastic lymphoma kinase-positive (ALK+) metastatic (advanced) non-small cell lung cancer (NSCLC).
How Lorlatinib works
Some types of NSCLC have an abnormal rearrangement in the ALK gene that causes it to be active outside of the brain. These are called ALK-positive (ALK+) tumors. ALK is a “receptor tyrosine kinase” (RTK) that is involved in transmitting signals to control cell growth, division and maturation. The mutated ALK promotes the growth and spread of cancer cells. ALK+ NSCLC tumors frequently spread to the brain.
In NSCLC cells, another RTK called ROS1 also may have a mutation that causes it to be constantly active. This is believed to contribute to tumor cell proliferation and survival.
Lorlatinib is a small molecule that targets and inhibits the action of ALK and ROS1, preventing tumor growth and spread.
Lorlatinib in clinical trials
Lorlatinib is being assessed in a Phase 1/2 clinical trial (NCT01970865), which currently is recruiting participants in sites across North America, Australia, Europe and Asia.
The aim of the Phase 1 portion of the trial was to assess the safety, pharmacokinetics, pharmacodynamics, and dosage of Lorlatinib in patients with ALK+ or ROS1+ metastatic NSCLC. The results of this portion of the trial were published in the Journal of Clinical Oncology and showed that the treatment was well-tolerated and showed clinical activity in patients. Based on these results, the trial has progressed to the Phase 2 portion with a dosage of 100 mg once daily. The Phase 2 portion aims to assess the safety and the effectiveness of the treatment in reducing brain metastasis.
Based on the results of the ongoing clinical trials, on April 27, 2017 Pfizer announced that Lorlatinib had been granted breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of ALK+ metastatic NSCLC that has been previously treated with one or more ALK inhibitors.
The most common adverse effects seen in the clinical trials were hypercholesterolemia (high cholesterol levels in the blood) and peripheral edema (swelling of tissues due to water retention), particularly in the arms and legs.
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