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Circulating tumor DNA could predict who's at risk of early treatment failure on lorlatinib. New analyses from the phase 3 CROWN trial found that TP53 mutations, higher baseline genomic complexity, and detectable methylation-based tumor fraction were all linked to earlier disease progression in ALK-positive NSCLC patients. Notably, no new ALK resistance mutations emerged at progression — suggesting resistance is largely driven by off-target mechanisms.
New ctDNA data from the phase 3 CROWN trial are shedding light on why some ALK-positive non-small cell lung cancer (NSCLC) patients on first-line lorlatinib progress early — and how blood-based biomarkers might help identify them sooner. Presented at the 2026 ESMO Congress, the exploratory analyses found that early progressors (PFS event within 12 months) had more genomically complex tumors at baseline and more frequent TP53 mutations compared to long-term responders (progression-free at 84 months).
On the treatment monitoring side, patients with undetectable methylation-based tumor fraction at baseline had a median PFS that was not reached, versus 80.3 months for those with detectable tumor fraction. Clearance of tumor fraction by week 4 of treatment was also associated with significantly longer PFS — a potentially actionable early signal.
Key Takeaways:
Why it matters: Despite lorlatinib's impressive long-term efficacy, roughly 30% of patients still progress within 2 years. These ctDNA findings could help clinicians identify high-risk patients earlier and potentially guide decisions around treatment intensification — a critical step toward personalizing care in ALK+ NSCLC.
