Lorlatinib/Lorlatinib Slows Growth of ALK-Positive Lung Cancer, May Prevent Brain Metastases

The drug lorlatinib is better than crizotinib as initial treatment for patients with advanced non-small cell lung cancer (NSCLC) who have changes in the ALK gene, according to new results from a global clinical trial. These findings are new in studies in which participants were randomly assigned to receive lorlatinib or crizotinib advanced lung cancer with mutations in the ALK gene, a disease known as ALK-positive lung cancer.

Study investigators reported that participants who received lorlatinib lived longer without their disease getting worse, known as progression-free survival, than those who received crizotinib. Based on these interim results, the U.S. Food and Drug Administration (FDA) approved lorlatinib for patients with metastaticALK-positive non-small cell lung cancer. Crizotinib has previously been approved to treat this type of lung cancer.

After 5 years of follow-up data, researchers found that 60% of participants in the lorlatinib group did not experience disease progression, while only 8% of participants in the crizotinib group did not experience disease progression. Additionally, for patients whose lung cancer had spread to the brain, lorlatinib reduced their risk of tumor progression and helped prevent new brain metastases better than crizotinib.

1. Testing third-generationALK inhibitors

AtALK, approximately 5% of patients with non-small cell lung cancer are genetically modified. These people are typically younger than people with other forms of lung cancer and tend to be light smokers or never smokers. Because crizotinib was the standard initial treatment for ALK-positive lung cancer when the CROWN trial began in 2017, researchers used that drug as a comparator to evaluate lorlatinib.

Since then, other drugs, such as crizotinib and lorlatinib, block the activity of the mutatedALK protein and have been approved for ALK-positive non-small cell lung cancer. These include the so-called second-generation ALK inhibitors ceritinib and alectinib. Researchers designed the third-generation ALK inhibitor lorlatinib to be effective against tumors that have stopped responding to first- and second-generation ALK inhibitors and cross the blood-brain barrier. The drug's ability to reach the brain is important because ALK-positive lung cancer often spreads to the brain. In fact, up to 40% of patients develop brain metastases within two years of diagnosis.

2. The longest progression-free survival period in history, preventing brain metastasis

For theCROWN study, researchers randomly assigned 296 participants from 23 countries to receive either lorlatinib or crizotinib. After five years of follow-up, the median progression-free survival in the lorlatinib group had not been reached, meaning more than half of the people who received lorlatinib had not had any disease progression or died during that time. The median progression-free survival in the crizotinib group was 9 months. According to the researchers, this finding is consistent with the longest progression-free survival ever reported for patients with advanced NSCLC.

About 25% of CROWN trial participants had brain metastases when the study began. During 5 years of follow-up, only 8% of patients with brain metastases treated with lorlatinib had disease progression, but 79% of patients treated with crizotinib had disease progression. Of the 114 participants in the lorlatinib group who had no brain metastases at the start of the study, only four developed brain metastases. The results suggest the drug not only controls but also helps prevent brain metastases, the researchers wrote.

3. Control the side effects of lotinib

Treatment-related side effects were more common in the lorlatinib group than in the crizotinib group (77% vs. 57%), with the most common side effects including swelling caused by the accumulation of fluid in the tissues (edema), high cholesterol, and increased blood fat levels (hyperlipidemia). However, only 5% of participants in the lorlatinib group and 6% of participants in the crizotinib group discontinued treatment due to side effects. Some participants in the lorlatinib group discontinued treatment because of side effects such as attention and thinking problems, hyperlipidemia, and heart problems.

Reducing the dose of lorlatinib during the first 16 weeks of treatment to control side effects did not reduce the drug's efficacy. However, the drug's chronic side effects, including cognitive and mood changes, can significantly affect some patients' quality of life. So appropriate counseling, monitoring and management [of these side effects] are essential.