Real-world profile and clinical impact of central nervous system adverse events in patients with ALK-positive NSCLC treated with first-line lorlatinib in Japan: The first interim analysis from the ROYAL study

Background Lorlatinib is a selective, brain-penetrant anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with demonstrated efficacy against both systemic disease and intracranial metastases in patients with ALK -positive advanced or recurrent non–small cell lung cancer. While its clinical benefits are well established, central nervous system adverse events (CNS AEs) remain a distinctive and clinically relevant safety concern, particularly regarding their management in routine clinical practice in Japan. Methods ROYAL is an observational study at clinical centers throughout Japan (EUPAS1000000117). Using data collected retrospectively, this interim analysis evaluated real-world incidence and management of CNS AEs, including patients’ chief complaints and the clinical impact of CNS AEs, the most significant AEs associated with lorlatinib. Results Among 38 patients, 13 (34.2%) reported ≥1 CNS AE, totaling 25 events. Of the 25 CNS events observed, cognitive effects were the most common (n=11 [44.0%]) and median time from first dose to CNS AE onset was 65 days. Chief complaints included forgetfulness, impaired memory, confusion, depression, and anxiety. CNS AEs were managed with dose reductions (n=8), dose interruptions (n=4), and dose discontinuation (n=1). No treatment discontinuations due to disease progression were reported. Only one patient required medication for a CNS AE, which was acetaminophen for headache. Conclusion Most CNS AEs associated with lorlatinib were manageable with appropriate dose modification and rarely led to treatment discontinuation. These findings underscore the role of proactive monitoring and timely dose adjustment in the management of CNS AEs. Longer follow-up will further clarify the long-term clinical impact of lorlatinib-associated CNS AEs.