CROWN: lorlatinib versus crizotinib as first treatment for ALK-positive lung cancer
The third-generation ALK inhibitor lorlatinib kept ALK-positive lung cancer under control for years longer than crizotinib and largely prevented brain metastases; at five years most patients on lorlatinib had still not progressed.
Open-label phase 3 trial of 296 patients with untreated advanced ALK-positive NSCLC randomised to lorlatinib or crizotinib. Primary endpoint was PFS by blinded review.
At the interim analysis, 12-month PFS was 78% vs 39% (HR 0.28) with intracranial responses in 82% of patients with measurable brain metastases. The 2024 five-year update reported 5-year PFS of 60% vs 8% (HR 0.19), with median PFS still not reached, the longest PFS recorded for a targeted therapy in metastatic NSCLC.
- 12-month PFS 78% vs 39%; HR 0.28 (95% CI 0.19-0.41).
- Intracranial objective response 82% vs 23% in patients with measurable brain metastases.
- Five-year update (JCO 2024): 5-year PFS 60% vs 8%, HR 0.19; median PFS not reached; time to intracranial progression HR 0.06.
- Grade 3-4 adverse events 72% vs 56%, driven by hyperlipidaemia, weight gain, oedema and cognitive or mood effects.
For ALK-positive advanced lung cancer, lorlatinib as the first drug offers the possibility of many years without progression and strong protection against brain metastases. Alectinib and brigatinib remain alternatives with a gentler side-effect profile; the choice weighs lorlatinib's cognitive, metabolic and weight effects against its unmatched duration of control.
- Open-label; no direct comparison with alectinib or brigatinib, the other first-line standards.
- Neurocognitive and mood adverse events require counselling and sometimes dose reduction.
- Overall survival data remain immature because so few patients have progressed.
- Small trial; crizotinib is no longer a relevant comparator.