Lorlatinib versus crizotinib as first-line treatment for advanced ALK-positive non-small-cell lung cancer: 7-year update from the phase III CROWN study

Shaw, AT; Solomon, BJ; Felip, E; Bauer, TM; Liu, G; Goto, Y; Wu, YL; Soo, RA; Mazieres, J; Kim, DW; Wang, IM; Paolini, J; Polli, A; Rifi, N; Toffalorio, F; Mok, TSK

Author(s): Shaw, AT; Solomon, BJ; Felip, E; Bauer, TM; Liu, G; Goto, Y; Wu, YL; Soo, RA; Mazieres, J; Kim, DW; Wang, IM; Paolini, J; Polli, A; Rifi, N; Toffalorio, F; Mok, TSK;
Details: Publication Year 2026-09,Volume 37,Issue #9,Page 1242-1252
Journal Title: Annals of Oncology
Publication Type: Research article
Abstract: BACKGROUND: Due to the unprecedented progression-free survival (PFS) benefit with lorlatinib after 5 years of follow-up in the phase III CROWN study, we aimed to quantify long-term outcomes at 7 years. PATIENTS AND METHODS: Treatment-naive patients (N = 296) with advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) were randomly assigned 1:1 to receive lorlatinib 100 mg once a day (n = 149) or crizotinib 250 mg twice a day (n = 147). This post hoc analysis presents investigator-assessed efficacy outcomes, safety, and biomarker analyses. RESULTS: With a median follow-up of 83.0 and 77.2 months, median PFS was not reached (NR) with lorlatinib [95% confidence interval (CI), 68.5-NR] and was 9.1 months (95% CI 7.4-10.9) with crizotinib [hazard ratio (HR) 0.19, 95% CI 0.13-0.26]; 7-year PFS was 55% and 3%, respectively. With lorlatinib, patients without a PFS event at the end of 24 months had a 79% probability of survival without progression at year 7. No new intracranial progression events occurred after the first 30 months on lorlatinib. Median time to intracranial progression was NR (95% CI NR-NR) with lorlatinib and 16.4 months (95% CI 12.7-21.9) with crizotinib (HR 0.06, 95% CI 0.03-0.12). Overall survival follow-up is ongoing; the number of events for a protocol-specified analysis has not been met. The safety profile was consistent with the 5-year results. With lorlatinib, treatment-related adverse events did not lead to discontinuations after the first 26 months. More genetic alterations were detected in circulating tumor DNA samples from early progressors than in long-term responders on lorlatinib; new potential resistance mechanisms were identified. CONCLUSIONS: With median PFS yet to be reached after 7 years of follow-up in CROWN, lorlatinib continues to show unprecedented long-term benefit in patients with advanced ALK-positive NSCLC. Patients without progression within 24 months on lorlatinib have a low risk of progression or death at year 7 and may continue long-term treatment. Findings suggest that sustained long-term disease control with first-line lorlatinib may enable advanced ALK-positive NSCLC to evolve toward a chronic condition.
Publisher: Elsevier
Keywords: Humans; *Carcinoma, Non-Small-Cell Lung/drug therapy/pathology/genetics/mortality; *Crizotinib/administration & dosage/adverse effects/therapeutic use; Lactams; *Lung Neoplasms/drug therapy/pathology/genetics/mortality; *Lactams, Macrocyclic/administration & dosage/adverse effects/therapeutic use; Aminopyridines; *Pyrazoles/administration & dosage/adverse effects/therapeutic use; Female; *Anaplastic Lymphoma Kinase/genetics/metabolism/antagonists & inhibitors; Male; Middle Aged; Aged; Progression-Free Survival; Adult; *Protein Kinase Inhibitors/adverse effects/therapeutic use/administration &; dosage; Crown; crizotinib; lorlatinib; non-small-cell lung cancer
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1016/j.annonc.2026.05.692
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-06-04 04:32:20

Last Modified: 2026-09-14 05:56:13