Lorlatinib on the PBS

Lorlatinib was recently added to the Pharmaceutical Benefits Scheme (PBS) for the treatment of metastatic non-small cell lung cancer (NSCLC). To be eligible for subsidised therapy, patients must have evidence of an anaplastic lymphoma kinase (ALK) gene rearrangement and have experienced disease progression following treatment with an ALK inhibitor other than crizotinib.

Lorlatinib is a tyrosine kinase inhibitor with activity against ALK and the structurally similar protein, c-ros oncogene 1 (ROS1) kinase. Inhibition of these kinases impairs signalling pathways involved in cell proliferation and survival in lung and other cancers. ALK inhibitors, such as crizotinib, alectinib, and ceritinib, have improved the prognosis for ALK-positive tumours. However, relapse and disease progression are common due to acquired resistance.

Lorlatinib is a third-generation ALK inhibitor that overcomes some of the resistance mechanisms of other agents in this class. It also demonstrates improved penetration of the blood-brain barrier compared to crizotinib, which provides better intracranial disease control.

In a Phase I/II study, the most commonly reported adverse events included hypercholesterolaemia, hypertriglyceridaemia, oedema, peripheral neuropathy, cognitive effects, and diarrhoea. Serious adverse events were reported in just over a third of the cohort, and 2.7% of patients permanently discontinued lorlatinib due to treatment-related adverse events.