The protein anaplastic lymphoma kinase (ALK) helps control cell growth. It’s made by the ALK gene, which can be rearranged by some cancers, including non-small cell lung cancer (NSCLC), causing the cancer to grow and spread. One of the two main types of lung cancer – the other is small cell lung cancer – NSCLC accounts for around 80% to 85% of lung cancers, with ALK-positive tumors occurring in about 3% to 5% of those cases. ALK-positive NSCLC is typically more aggressive and seen in younger people with a light or non-smoking history.
Lorlatinib is a third-generation ALK inhibitor, the newest in a class of drugs that are the standard first-line treatment for patients with ALK-positive NSCLC. A recent international clinical trial led by the Peter MacCallum Cancer Center (Peter Mac) in Melbourne, Australia, assessed the drug’s effect on long-term disease progression in patients with advanced ALK-positive NSCLC. The results were remarkable.
“To our knowledge, these results are unprecedented,” said Peter Mac’s Professor Ben Solomon, the study’s lead and corresponding author, in an interview with The Guardian.
In the Phase III trial, 296 patients with previously untreated, advanced ALK-positive NSCLC were randomly assigned to receive either lorlatinib or crizotinib, a first-generation ALK inhibitor sold as Xalkori. Lorlatinib is given as a once-a-day tablet, while crizotinib is given twice daily. The study’s primary endpoint was progression-free survival; the key secondary endpoint was overall survival. Another secondary endpoint was whether the cancer had metastasized to the brain.
Five years after treatment, 60% of patients given lorlatinib were still alive without signs of disease progression, compared to 8% of patients on crizotinib. There was also an 81% reduction in the risk of cancer progression or death and a 94% reduction in the progression of brain metastasis compared to crizotinib.
The current trial was an update on follow-up at the three-year mark, which showed similar progression-free survival and brain progression rates.
“This updated analysis shows that lorlatinib helped patients live longer without disease progression, with the majority of patients experiencing sustained benefit for over five years, including nearly all patients having protection from progression of disease in the brain,” Solomon said
Consistent with the data from previous trials, Lorlatinib was associated with a higher incidence of adverse events than crizotinib, 77% versus 57%, mostly due to increased blood lipids (cholesterol and triglycerides). However, cardiovascular adverse events were similar between the treatment groups. Adverse events related to lorlatinib were manageable with a dose reduction without affecting the drug’s efficacy. The progression-free survival rates and time-to-brain progression were similar in patients whose dose was reduced within the first 16 weeks and those who didn’t take a reduced dose.
After five years of follow-up, the study’s findings represent the longest progression-free survival data ever reported with any single-agent targeted treatment in advanced NSCLC and across all metastatic solid cancer tumors.
“These improvements in outcomes for patients with ALK-positive NSCLC represent a remarkable advancement in lung cancer,” said Solomon.
The trial results were presented at the 2024 American Society of Clinical Oncology (ASCO) annual scientific meeting, currently being held in Chicago, and published simultaneously in the Journal of Clinical Oncology.
Source: Peter MacCallum Cancer Centre
