Lorlatinib in First-Line Treatment of Patients with Advanced ALK-Positive NSCLC With or Without Brain Metastases

Additional post hoc analyses of data from the phase III CROWN study show that lorlatinib improved progression-free survival (PFS) outcomes and reduced central nervous system (CNS) progression compared with crizotinib in patients with previously untreated advanced ALK-positive non-small cell lung cancer (NSCLC) with or without brain metastases at baseline. Intracranial responses were durable, and many CNS adverse events resolved without intervention, or with lorlatinib dose modification and/or concomitant medication. These data support the use of lorlatinib as first-line treatment in patients with advanced ALK-positive NSCLC with or without brain metastases according to Dr. Benjamin J. Solomon of the Peter MacCallum Cancer Centre in Melbourne, Australia and colleagues who published the findings on 23 May 2022 in the Journal of Clinical Oncology.

Lorlatinib is a potent, third-generation ALK inhibitor. In the phase III CROWN study, independently assessed PFS was significantly improved with first-line lorlatinib compared with crizotinib (hazard ratio for disease progression or death 0.28; 95% confidence interval 0.19 to 0.41; p < 0.001) in adult patients with ALK-positive metastatic NSCLC.

The authors wrote in the background that approximately 29% to 40% of patients with ALK-positive NSCLC have brain metastases at initial evaluation, and more than half will develop brain metastases. Development of brain metastases is associated with poor prognosis, high symptom burden, and decreased quality of life. Although alectinib, brigatinib, and ensartinib have demonstrated superior efficacy to crizotinib in patients with brain metastases, prognosis among patients with NSCLC and brain metastases remains poor.

Lorlatinib treatment in CROWN was associated with intracranial activity resulting in higher complete and partial intracranial response rates than with crizotinib in patients with brain metastases. Among the 78 patients with baseline measurable or non-measurable brain metastases, the intracranial objective response rate as assessed by blinded independent central review (BICR) was 66% with lorlatinib and 20% with crizotinib. Complete intracranial responses were seen in 61% and 15% of patients.

The safety profile of lorlatinib in CROWN was consistent with that described in the preceding phase I/II study. The potential clinical impact of CNS adverse events, such as cognitive and mood effects, following lorlatinib treatment has been debated. It has been reported that most adverse events with lorlatinib can be effectively managed by dose modification and concomitant medication, with low rates of permanent treatment discontinuation.

In the latest article, the CROWN study investigators present post hoc exploratory efficacy and safety outcomes, including subgroup analyses in patients with and without brain metastases at baseline, and data on the incidence and management of CNS-related adverse events.

Eligible patients were randomly assigned 1:1 to first-line lorlatinib 100 mg once daily or crizotinib 250 mg twice a day. No crossover between treatment arms was permitted. Tumour assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted.

In comparison with crizotinib, PFS by BICR was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline with 12-month PFS rates of 78% versus 22% and 78% versus 45%. Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% versus 72%) and without (1% versus 18%) brain metastases at baseline.

In total, 35% of patients had CNS adverse events with lorlatinib, most of grade 1 severity. Occurrence of CNS adverse events did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS adverse events had resolved of which 33% without intervention and 17% with lorlatinib dose modification; 38% were unresolved. Most adverse events required no intervention. Lorlatinib dose modification did not influence on PFS.

The authors concluded that lorlatinib has potent and durable efficacy in patients with advanced ALK-positive NSCLC with and without brain metastases at baseline, regardless of prior brain radiotherapy use. In some patients, CNS adverse events can be managed either without any intervention or through appropriate dose modification.


Solomon BJ, Bauer TM, Ou S-HI, et al. Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients With ALK-Positive Advanced Non–Small-Cell Lung Cancer From the Phase III CROWN Study. JCO; Published online 23 May 2022. DOI: 10.1200/JCO.21.02278