Lorlatinib shows durable benefit in ALK+ NSCLC
By Sudha Thakor
Durable benefit is demonstrated with lorlatinib versus crizotinib in previously untreated patients with advanced anaplastic lymphoma kinase positive (ALK+) non–small-cell lung cancer (NSCLC), report the phase 3 CROWN trial (NCT03052608) investigators.
After approximately 7 years of follow-up, median progression-free survival (PFS) remained unreached with lorlatinib in the intention-to-treat population. At 84 months, 55% of patients remained progression-free, compared with 3% of patients with crizotinib. The hazard ratio for disease progression or death remained 0.19, Tony Mok (Chinese University of Hong Kong, Hong Kong, China) told delegates at the American Society of Clinical Oncology (ASCO) Congress 2026 in Chicago, USA.
These findings support continued use of lorlatinib as a first-line option, with sustained disease control over prolonged follow-up, including in the central nervous system (CNS).
Additional key long-term findings from CROWN include:
- 79% probability of remaining progression-free at 7 years on lorlatinib among patients without a PFS event at 24 months
- 92% of patients on lorlatinib remained free from CNS progression at 7 years
Most progression events occurred within the first 2 years of treatment, with relatively few additional events beyond this point. No new CNS progression events were observed after approximately 30 months in the lorlatinib arm.
Mok stated that the findings “give insight [into] an effective targeted therapy [that] may both systemically and intracranially control the disease.” He also noted that overall survival analysis was not yet permitted at this data cut due to an insufficient number of events, stating that investigators “were not allowed to look at the overall survival analysis at that time.”
Safety findings were consistent with earlier 5-year analyses, with no new safety signals observed over long-term follow-up. Key safety observations included:
- Common but largely manageable adverse events (AEs), with all-cause grade 3/4 AEs in 77% of patients with lorlatinib and 57% of patients with crizotinib
- 34% of patients receiving loratinib required dose reductions, most within the first 6 months
- 5% discontinued treatment with loratinib due to AEs, primarily within the first 2 years, in comparison to 6% of patients treated with crizotinib
Dose reductions did not appear to affect long-term efficacy (PFS or intracranial outcomes).
The CROWN trial (NCT03052608) randomized 296 treatment-naive patients with advanced ALK+ NSCLC to receive lorlatinib 100 mg once daily (n=149) or crizotinib 250 mg twice daily (n=147).
Further follow-up of the CROWN study is ongoing, including planned analyses of overall survival. These longer-term data may clarify survival outcomes with first-line lorlatinib in patients with advanced ALK+ NSCLC.
Review more expert insights from ASCO 2026.
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