1365P Neurocognitive adverse events related to lorlatinib in non-small cell lung cancer: A systematic review and meta-analysis

Lorlatinib (LOR), a 3rd generation tyrosine kinase inhibitor (TKI), has shown promising activity in NSCLC. However, the treatment has been associated with an increasing number of neurocognitive adverse events (NAEs). This systematic review and meta-analysis evaluated the NAEs associated with LOR therapy in NSCLC patients. PubMed, Scopus, and the Cochrane Library were searched for clinical trials and observational cohort studies investigating LOR for NSCLC patients. NAEs were defined as the cluster terms of cognitive effects, mood effects, speech effects, and psychotic effects. Heterogeneity was examined with the I2 statistics and random-effect model was used to pool studies. Sixteen studies were included with 1,147 patients, of whom 56% were female, 8% were Asians, 8% had a history of smoking, 62% had brain metastasis, and 1% ECOG 2 or higher. Most patients had previously received an early-generation TKI before the LOR. A pooled analysis of NAEs showed a prevalence of cognitive effects in 15.57% of overall population (95% CI 8.40 – 22.73, I2 90%), mood effects in 11.93% (95% CI 5.80 – 18.06, I2 89%), speech effects in 6.56% (95% CI 1.79 – 11.34, I2 91%), and psychotic effects in 4.15% (95% CI 1.46 – 6.83, I2 74%). In a subgroup analysis, we found higher rates of cognitive effects in clinical trials than in real-world data (23.57% vs. 9.36%, p = 0.05), and a significant difference was also seen in mood effects (18.64% vs. 3.70%, p < 0.01). NAEs were manageable with dose modification, temporary interruption, and/or concomitant medication. Our study revealed that LOR is associated with cognitive, mood, speech and psychotic effects in approximately 16%, 12%, 7%, and 4% of patients, respectively. We found significant differences in the prevalence of cognitive and mood effects between clinical trials and real-world data. Additionally, all analyses had a high heterogeneity among studies. Collectively, these findings underscore the importance of educating patients and healthcare professionals regarding LOR-associated NAEs to facilitate early detection and management of NAEs, aiming to improve NSCLC patients' quality of life.