In a post hoc analysis from the phase III CROWN trial reported in the Journal of Clinical Oncology, Benjamin J. Solomon, MBBS, PhD, and colleagues found that progression-free survival and the risk of central nervous system (CNS) progression were improved with lorlatinib vs crizotinib in previously untreated patients with advanced ALK-positive non–small cell lung cancer (NSCLC) with or without baseline brain metastases.
Previously reported findings from the study showed that lorlatinib improved progression-free survival vs crizotinib among all patients and was associated with a higher CNS response rate among those with brain metastases.
Benjamin J. Solomon, MBBS, PhD
Study Details
In the trial, patients were randomly assigned to receive 100 mg of lorlatinib once daily (n = 149) or 250 mg of crizotinib twice daily (n = 147); no crossover was permitted. Patients with asymptomatic treated or untreated brain metastases were eligible.
In total, baseline brain metastases on blinded independent committee review were present in 38 patients (26%) in the lorlatinib group and 40 (27%) in the crizotinib group. Prior brain radiotherapy had been received by 8 (21%) and 10 (25%) of these patients.
Key Findings
Among patients with baseline brain metastases, median progression-free survival on blinded independent committee review was not reached (95% confidence interval [CI] = 18.2 months–not reached) in the lorlatinib group vs 7.2 months (95% CI = 3.7–9.2 months) in the crizotinib group (hazard ratio [HR] = 0.20, 95% CI = 0.10–0.43, P < .0001), with 12-month rates of 78% vs 22%.
Among patients without baseline brain metastases, median progression-free survival was not reached (95% CI = not reached–not reached) vs 11 months (95% CI = 9.0–14.6 months; HR = 0.32, 95% CI = 0.20–0.49, P < .0001), with 12-month rates of 78% vs 45%.
The cumulative incidence of CNS progression was 7% vs 72% among patients with baseline brain metastases (HR = 0.07, 95% CI = 0.02–0.24) and 1% vs 18% among those without baseline metastases (HR = 0.05, 95% CI = 0.01–0.42).
KEY POINTS
- Among patients with baseline brain metastases, median progression-free survival on blinded independent committee review was not reached in the lorlatinib group vs 7.2 months in the crizotinib group, with 12-month rates of 78% vs 22%.
- The cumulative incidence of CNS progression was 7% vs 72% among patients with baseline brain metastases and 1% vs 18% among those without baseline metastases.
- According to the authors, “Half of all CNS adverse events resolved without intervention or with lorlatinib dose modification.”
CNS adverse events occurred in 35% of patients in the lorlatinib group vs 11% of the crizotinib group (90% vs 100% being grade 1–2, 10% vs 0% being grade 3). Among a total of 86 adverse events in the lorlatinib group, 62% were managed without intervention and 23% were managed with lorlatinib dose modification (reduction or interruptions) with or without concomitant medication; lorlatinib was discontinued in two patients. At time of analysis, 56% of adverse events had resolved (33% without intervention, 17% with lorlatinib dose modification) and 38% were unresolved; 24 of 33 unresolved events did not require intervention.
The investigators concluded, “First-line lorlatinib improved progression-free survival outcomes and reduced CNS progression vs crizotinib in patients with advanced ALK-positive non–small cell lung cancer with or without brain metastases at baseline. Half of all CNS adverse events resolved without intervention or with lorlatinib dose modification.”
Dr. Solomon, of Peter MacCallum Cancer Centre, Melbourne, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Pfizer. For full disclosures of the study authors, visit ascopubs.org.
