lorlatinib — Drug Monograph

Brand names: Lorbrena

Drug class: ALK Inhibitor

Mechanism of Action

Lorlatinib is a third-generation, macrocyclic ALK and ROS1 tyrosine kinase inhibitor rationally designed to overcome resistance to first- and second-generation ALK inhibitors and to achieve robust CNS penetration. Its macrocyclic structure confers unique conformational rigidity that enables tight, selective binding to the ALK kinase domain across all known resistance mutations, including the compound G1202R+L1196M and other solvent-front and gatekeeper mutations that cause resistance to earlier-generation inhibitors. By blocking ALK autophosphorylation, lorlatinib suppresses downstream…

FDA Indications

• Metastatic ALK-positive NSCLC — 1st-line treatment (2021, CROWN trial)
• Metastatic ALK-positive NSCLC previously treated with one or more ALK inhibitor(s) (2018; expanded indication)

Common Side Effects

• Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) — >80%
• Peripheral neuropathy (paresthesia, peripheral sensory neuropathy)
• Peripheral edema
• Cognitive effects (memory impairment, cognitive slowing, confusion)
• Mood effects (depression, irritability, anxiety)
• Speech effects (dysarthria, word-finding difficulty)
• Fatigue
• Elevated weight/lipase
• Hypertension
• Diarrhea

Clinical Pearl

Lorlatinib's CNS-penetrant macrocyclic structure was specifically engineered to address the unmet need of brain metastases in ALK-positive NSCLC — in the CROWN trial, intracranial response rates exceeded 60% in patients with measurable brain metastases, and lorlatinib significantly reduced the risk of developing new brain metastases versus crizotinib. The nearly universal hyperlipidemia (>80%) is mechanistically distinct from dietary dyslipidemia and typically requires statin initiation rather…

Related Therapies & Mechanisms

• Brigatinib (Alunbrig) — ALK Inhibitor · NSCLC
• Ceritinib (Zykadia) — ALK Inhibitor · NSCLC
• Crizotinib (Xalkori) — ALK Inhibitor · NSCLC
• Adagrasib (Krazati) — NSCLC