Lorlatinib After Five Years: TP53 and EML4::ALK Variant 3 Refine Prognosis but Do Not Define Benefit in ALK
A long-term study on the drug lorlatinib for ALK-positive lung cancer patients shows that while certain genetic markers like TP53 affect prognosis, they do not negate the drug's efficacy. The findings suggest that lorlatinib remains a viable treatment option across various biomarker-defined subgroups.
Why it matters
This research refines clinical decision-making for oncologists, ensuring that patients are not unnecessarily excluded from effective targeted therapies based on specific genetic variants.
Long-term follow-up from the global phase II lorlatinib study provides a more mature view of how tumor biology influences outcomes in ALK-positive advanced non–small cell lung cancer . Published online September 16, 2026, in the Journal of Thoracic Oncology , the final biomarker and efficacy analysis examined EML4::ALK fusion variants, TP53 co-mutations, circulating tumor DNA, and acquired ALK resistance mutations across treatment-naïve and previously treated patients receiving lorlatinib.
The analysis provides an important distinction between prognostic biology and treatment sensitivity. TP53 mutation was consistently associated with shorter overall survival across treatment cohorts, while EML4::ALK variant 3 was associated with poorer survival than variants 1 or 2 in patients previously treated with crizotinib. Yet neither biomarker identified a population in which lorlatinib lacked substantial activity. After more than five years of follow-up, the investigators concluded that prolonged survival with lorlatinib was observed across biomarker-defined subgroups.
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