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

J Clin Oncol. 2022 Nov 1;40(31):3593-3602. doi: 10.1200/JCO.21.02278. Epub 2022 May 23.


Purpose: Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced ALK-positive non-small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN.

Methods: 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. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted.

Results: PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose modification), and 38% were unresolved; most required no intervention. Lorlatinib dose modification did not notably influence PFS.

Conclusion: First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced ALK-positive non-small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.

Trial registration: NCT03052608.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Brain Neoplasms* / drug therapy
  • Brain Neoplasms* / secondary
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Crizotinib / adverse effects
  • Humans
  • Lactams, Macrocyclic / adverse effects
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Protein Kinase Inhibitors / therapeutic use
  • Quality of Life


  • lorlatinib
  • Crizotinib
  • Anaplastic Lymphoma Kinase
  • Lactams, Macrocyclic
  • Protein Kinase Inhibitors

Associated data