OncoMatch/Clinical Trials/Lorlatinib

Lorlatinib (Lorbrena) Clinical Trials

Lorlatinib (Lorbrena, PF-06463922) is a third-generation, macrocyclic ALK tyrosine kinase inhibitor with additional activity against ROS1, designed to overcome resistance mutations that develop on first- and second-generation ALK inhibitors and to achieve deep CNS penetration. The Phase 3 CROWN trial demonstrated a significant progression-free survival benefit over crizotinib as first-line therapy in ALK-positive advanced NSCLC, with a 5-year PFS rate of approximately 60% and high intracranial response rates — including complete intracranial responses in a substantial proportion of patients with brain metastases — supporting its FDA approval as a preferred first-line option. Active trials investigate lorlatinib in combination with novel agents for acquired resistance, in earlier-stage (resectable and stage III) ALK-positive NSCLC, and in post-lorlatinib resistance settings. Eligibility requires confirmed ALK rearrangement; resistance-setting trials typically require prior lorlatinib or second-generation ALK TKI therapy.