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

Lorlatinib Tolerability and Association With Clinical Outcomes in Patients With Advanced ALK- or ROS1-Rearranged NSCLC: A Brief Report

“…The most common TRAEs associated with first dose reductions were edema (n = 14; 10%), cognitive or memory impairment (n = 11; 8%), neuropathy (n = 11; 8%), hallucinations (n = 6; 4%), and mood changes (n = 5; 3%); only one patient required dose reduction for hyperlipidemia (a case of hypertriglyceridemia). In total, dose reductions in 34 of these 58 patients (59%) were owing to neurocognitive effects (cognitive, mood, psychotic, or speech effects) 5 or neuropathy. Eleven patients (8%) discontinued lorlatinib owing to AEs.…”

“… 1 , 8 Among patients in the phase 3 CROWN trial of first-line lorlatinib versus crizotinib in ALK + NSCLC, 1 28% of patients treated with lorlatinib experienced at least one dose reduction, 7 whereas a recent report revealed wide disparities in frequencies of dose reductions for neurocognitive AEs among patients treated with lorlatinib in the context of prospective clinical trials at the Massachusetts General Hospital (54%) versus in the registrational phase 1/2 study B7461001 (17%). 5 The relatively high rate of dose reductions observed in our study may have been related to multiple factors, including treatment setting, and our cohort being fully comprised of patients treated in the second-line or later setting in which toxicities may be more common or difficult to manage. Regardless, our results generally support recent posthoc analyses of the CROWN trial reporting comparable 12-month PFS rates 7 and intracranial efficacy 9 among patients with or without early lorlatinib dose reductions in the first-line setting.…”

“… 3 Compared with other ALK and ROS1 inhibitors, lorlatinib is associated with a distinct spectrum of treatment-related adverse events (TRAEs), including hyperlipidemia, peripheral neuropathy, and neurocognitive effects. 4 , 5 , 6 In most cases, lorlatinib TRAEs are managed with either temporary dose interruptions or reductions; however, the observed frequencies of lorlatinib TRAE-related dose reductions have varied across clinical contexts, 1 , 5 , 7 , 8 including clinical trial versus real-world settings, and the impact of lorlatinib dose reductions on long-term clinical outcomes remains unclear. To address these questions, we assembled a multicenter cohort of patients treated with lorlatinib in the second-line setting or later to provide insight into the spectrum of lorlatinib TRAEs, frequency of dose reductions, and association of dose reductions with long-term clinical outcomes.…”

Patients With Brain Metastases Deserve Better—A Hard-Won Perspective

“…Those treatment options that are known to enter and act in the brain more effectively—lorlatinib, for instance—are associated with increased neurocognitive adverse effects and deficits, which are even more common and pronounced in those who have had brain metastasis, stereotactic radiosurgery, and/or brain surgery …”

Podcast on Lorlatinib as a First-Line Treatment Option for Patients with ALK-Positive Metastatic NSCLC with Brain Metastasis

“…That may play a role in terms of the potential neurocognitive side effects that the patients in that study experienced. And, as I mentioned earlier, a recent retrospective study identified potentially brain metastases, prior radiation, baseline psychiatric diagnoses, or use of neurotropic medications as potential risk factors for these neurocognitive side effects on lorlatinib [ 27 ].…”