lorlatinib

Lorlatinib is a highly selective, brain-penetrant tyrosine kinase inhibitor of the anaplastic lymphoma kinase (ALK) and, to a lesser extent, ROS1. It is a third-generation ALK inhibitor designed to overcome resistance to earlier ALK inhibitors and to address central nervous system metastases commonly seen in ALK-positive non-small cell lung cancer. Lorlatinib is approved for adults with ALK-positive metastatic NSCLC. In the United States it is indicated for disease that has progressed on or is intolerant to crizotinib, and it has been evaluated as a potential first-line therapy in clinical trials.

Mechanism of action: Lorlatinib binds to the ATP-binding pocket of ALK and ROS1 kinases, inhibiting their phosphorylation and downstream signaling, thereby halting tumor cell proliferation and survival. Its high central nervous system penetration provides activity against brain metastases.

Pharmacokinetics and interactions: It is taken orally and is primarily metabolized by CYP3A enzymes. Strong CYP3A inhibitors or inducers can affect lorlatinib levels, requiring dose adjustments or avoidance; concomitant use with certain agents should be avoided.

Adverse effects: Common adverse events include hyperlipidemia (elevated cholesterol and triglycerides), edema, peripheral neuropathy, cognitive and mood changes, weight gain, and liver enzyme elevations. Serious risks include hepatotoxicity and rare cases of interstitial lung disease or pneumonitis; monitoring lipid panels, liver function, and neuropsychiatric symptoms is recommended.

Regulatory status: Lorlatinib is marketed by Pfizer under the brand name Lorbrena. It received FDA approval in 2018 for ALK-positive metastatic NSCLC after progression on at least one prior ALK inhibitor, with subsequent approvals expanding indications in certain jurisdictions.