The global clinical trial CROWN has demonstrated that lorlatinib (Lorbrena) is superior to crizotinib (Xalkori) as an initial treatment for advanced non-small cell lung cancer (NSCLC) with ALK gene mutations, known as ALK-positive lung cancer. In this study, participants were randomly assigned to receive either lorlatinib or crizotinib. Previous findings showed that lorlatinib improved progression-free survival compared to crizotinib, leading to its approval by the FDA for metastatic ALK-positive NSCLC. After five years, 60% of patients on lorlatinib remained progression-free, compared to only 8% on crizotinib. Lorlatinib also better prevented brain metastases.
Dr. Benjamin Solomon presented these findings at the American Society of Clinical Oncology (ASCO) annual meeting, emphasizing lorlatinib’s significant impact on patient outcomes. Dr. Chen Zhao, not involved in the study, noted the new results confirm lorlatinib’s effectiveness and safety without revealing new side effects.
ALK mutations occur in about 5% of NSCLC patients, typically younger, lighter smokers, or non-smokers. The CROWN trial used crizotinib as a comparison since it was the standard treatment at the time. Other ALK inhibitors like ceritinib and alectinib have since been approved.
Lorlatinib, a third-generation ALK inhibitor, was designed to overcome resistance to earlier ALK inhibitors and to penetrate the blood-brain barrier, crucial for ALK-positive lung cancers prone to brain metastases. In the CROWN study, involving 296 participants from 23 countries, lorlatinib achieved a median progression-free survival that was not reached after five years, compared to nine months for crizotinib. Among participants with brain metastases at the start, disease progression occurred in only 8% treated with lorlatinib versus 79% with crizotinib. This suggests lorlatinib can control and prevent brain metastases.
However, treatment-related side effects were more common with lorlatinib (77%) than crizotinib (57%), including edema, high cholesterol, and hyperlipidemia. Despite this, only 5% of lorlatinib patients discontinued treatment due to side effects, compared to 6% for crizotinib. Dr. Jessica Lin highlighted that most side effects could be managed with dose adjustments without reducing efficacy, though chronic side effects like cognitive and mood changes need careful management.
Dr. Zhao pointed out the need to decide between lorlatinib and other ALK inhibitors like alectinib for initial treatment, considering factors like physician experience, drug availability, and patient insurance. Future studies comparing these drugs could provide clearer guidance. Dr. Solomon reflected on the transformative impact of ALK inhibitors, noting that patients with metastatic lung cancer now live much longer than in the past, with some surviving over 10 years.