Lorlatinib, a third-generation anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK TKI), is a preferred standard-of-care first-line therapy for patients with advanced ALK-positive non-small cell lung cancer (ALK+ NSCLC) according to the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines.¹ In the phase 3 CROWN study, lorlatinib significantly improved progression-free survival (PFS) vs. crizotinib at the planned interim analysis, with median PFS by blinded independent central review (BICR) not reached after 18.3 months of follow-up; this benefit was sustained at the 5-year analysis, where median PFS by investigator remained not reached with lorlatinib.¹

At the 2026 ASCO Annual Meeting, Professor Mok, Shu-Kam Tony, from the Chinese University of Hong Kong, presented the 7-year update from the phase 3 CROWN study, reporting long-term efficacy, safety, and biomarker analyses that demonstrated durable PFS, sustained intracranial disease control, and a consistent long-term safety profile of lorlatinib.¹

CROWN was a global, randomized, phase 3 study that enrolled patients with stage IIIB or IV ALK+ NSCLC who had not received prior systemic treatment for metastatic disease, had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, and ≥1 extracranial measurable target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.¹ Patients with asymptomatic treated or untreated central nervous system (CNS) metastases were eligible.¹ Participants were randomized 1:1 to receive lorlatinib 100mg once daily (n=149) or crizotinib 250mg twice daily (n=147), with randomization stratified by the presence of brain metastases and ethnicity.¹

This post hoc analysis presented was based on the data cutoff at October 31, 2025.¹ After a median duration of follow-up of 83.0 months in the lorlatinib arm and 77.2 months in the crizotinib arm, median PFS remained not reached with lorlatinib vs. 9.1 months with crizotinib (HR=0.19; 95% CI: 0.13-0.26).¹ 55% of patients receiving lorlatinib were alive and progression-free vs. 3% receiving crizotinib at 84 months, with only seven new PFS events occurring between the 5-year and 7-year analyses.¹ Among patients who remained alive and progression-free during the first 24 months of lorlatinib treatment, the estimated probability of remaining alive and progression-free at 7 years was 79%.¹ PFS benefit consistently favored lorlatinib across all prespecified patient subgroups, including patients with or without brain metastases and Asian and non-Asian patients.¹

Lorlatinib also demonstrated durable intracranial disease control.¹ Median time to intracranial progression was not reached with lorlatinib vs. 16.4 months with crizotinib (HR=0.06; 95% CI: 0.03-0.12), with 92% of patients receiving lorlatinib remaining free from intracranial progression at 84 months.¹ This durable intracranial benefit was further supported by the absence of new intracranial progression events after the first 30 months in the lorlatinib arm.¹ Consistent with these findings, sustained benefit was observed in both patients with and without baseline brain metastases, with median time to intracranial progression not reached in either subgroup.¹ The sustained plateau indicates prolonged protection against new brain metastases and sustained control of existing intracranial disease.¹

Notably, circulating tumor DNA (ctDNA) analyses detected no emerging new ALK resistance mutations at the end of lorlatinib treatment.¹ In addition, baseline ctDNA analyses showed that early progressors had a higher number of genomic alterations and higher tumor mutation burden than long-term responders.¹

The safety profile of lorlatinib remained consistent with previous analyses, with no new safety signals identified during longer follow-up.¹ The frequency of grade 3 or 4 adverse events did not increase since the 5-year analysis.¹ Similarly, CNS adverse events remained consistent with longer follow-up, with most being grade 1 or 2.¹ Although hyperlipidemia occurred more frequently with lorlatinib, no increase in cardiovascular adverse events was observed compared with crizotinib1.¹ Treatment-related discontinuations occurred in 5% of patients within the first 26 months.¹ Despite dose reductions in 34% of lorlatinib-treated patients after a median of 25 weeks, long-term efficacy was similar in patients with and without dose reduction.¹

In conclusion, the 7-year update from the phase 3 CROWN study demonstrated durable systemic and intracranial disease control with lorlatinib, supported by sustained PFS and a consistent long-term safety profile.¹ Collectively, these findings support the long-term clinical benefit of lorlatinib and suggest its potential to transform advanced ALK-positive non-small cell lung cancer (ALK+ NSCLC) into a chronic condition for a substantial proportion of patients.¹