Lorlatinib is a third-generation ALK tyrosine kinase inhibitor designed to inhibit ALK signaling while maintaining activity in the central nervous system.
Pharmacology
Lorlatinib targets ALK and was developed to address resistance mechanisms associated with earlier ALK inhibitors. Its CNS penetration is an important characteristic in the treatment of ALK-positive NSCLC.
Pharmacokinetics
The current U.S. prescribing information describes lorlatinib as an orally administered medicine with pharmacokinetic properties that support once-daily dosing. Its metabolism involves CYP3A and UGT pathways, which helps explain the importance of CYP3A-related drug interactions.
Drug interaction relevance
Because lorlatinib is affected by CYP3A modulators, concomitant medicines can materially alter exposure. This is why the current label contains specific recommendations for strong and moderate CYP3A inducers and inhibitors.
CROWN study
CROWN was a phase III randomized study involving 296 patients with previously untreated advanced ALK-positive NSCLC.
Patients were randomized to:
- Lorlatinib 100 mg once daily
- Crizotinib 250 mg twice daily
Five-year results
After approximately five years of follow-up:
| Outcome | Lorlatinib | Crizotinib |
|---|---|---|
| Median PFS | Not reached | 9.1 months |
| 5-year PFS | 60% | 8% |
| HR for progression/death | 0.19 | Reference |
| Median time to intracranial progression | Not reached | 16.4 months |
| 5-year probability free of intracranial progression | 92% | 21% |
The study was not designed to prove that every patient will achieve these outcomes. Trial results describe a study population and should not be interpreted as an individual prognosis.
Seven-year update
A 2026 CROWN update reported a 55% probability of remaining alive without disease progression at seven years with lorlatinib, compared with 3% with crizotinib. Median PFS remained unreached in the lorlatinib group.
CNS efficacy
The five-year analysis showed strong intracranial disease control. In patients who entered the study with brain metastases, the hazard ratio for progression or death favored lorlatinib, and the probability of remaining free of intracranial progression at five years was 83% in the lorlatinib group.
Safety evidence
The long-term CROWN analysis did not identify a new major safety signal, although adverse events remain clinically important. Grade 3 or 4 adverse events occurred in 77% of patients receiving lorlatinib in the five-year analysis, compared with 57% receiving crizotinib.
Evidence limitations
Clinical-trial findings cannot establish how a particular patient will respond. Treatment history, tumor biology, coexisting conditions, drug interactions and other factors influence outcomes.