Factors Associated With Developing Neurocognitive Adverse Events in Patients Receiving Lorlatinib After Progression on Other Targeted Therapies

The safety profile of lorlatinib includes neurocognitive adverse events (NAEs). Baseline factors associated with developing NAEs remain poorly characterized. Records from patients who received lorlatinib through prospective studies at Massachusetts General Hospital (MGH, n = 124) or the phase 1/2 B7461001 (NCT01970865; n = 248) study were reviewed to identify potential associations between comorbidities, baseline medications, and NAEs. Most patients experienced a NAE (MGH: 60%, B7461001: 49%). Cognitive effects occurred in 40% and 29% of patients in the MGH and B7461001 cohorts, respectively. Brain metastases (p = 0.008), brain radiation (p = 0.033), psychiatric illness (p = 0.008), psychiatric medications (p < 0.001), antiepileptics (p < 0.001), and stimulants (p = 0.026) were associated with developing cognitive effects in B7461001. Mood effects occurred in 36% and 23% of patients in the MGH and B7461001 cohorts, respectively. In the MGH cohort, psychiatric illness (p = 0.02) and stimulants (p = 0.01) were associated with developing mood effects whereas brain surgery (p = 0.020), psychiatric medications (p < 0.001), benzodiazepines (p = 0.002), and sedatives (p = 0.034) were associated with developing mood effects in B7461001. Psychotic effects were infrequent (MGH: 3%, B7461001: 9%) and were associated with brain surgery in the MGH cohort (p = 0.001) and age in B7461001 (p = 0.014). Speech effects were observed in 23% and 11% of patients in the MGH and B7461001 cohorts, respectively. Brain radiation (p = 0.012) and antiepileptics (p < 0.001) were associated with speech effects in B7461001. Dose reductions were implemented for 52% and 18% of patients with NAEs in MGH and B7461001 cohorts, respectively, with mitigating effect. Neurocognitive effects from lorlatinib are common. Lorlatinib-related NAEs may be influenced by multiple factors, including brain metastases, brain radiation, psychiatric illness, and use of neurotropic medications.