Lorlatinib/lorlatinib is the first generation of targeted drugs

Lorlatinib/lorlatinib (Lorlatinib) is a third-generation targeted drug. Generally speaking, it is a new third-generation ALK inhibitor that is more effective than second-generation inhibitors in biochemical and cellular assays and has the broadest coverage of identified ALK resistance mutations. Larlatinib is designed to cross the blood-brain barrier to achieve high exposure to the central nervous system. Lorlatinib is the most advanced, effective and selective ALK tyrosine kinase inhibitor (TKI) currently clinically used to treat ALK-positive non-small cell lung cancer (NSCLC).

Although most patients have a clear initial response toALK TKIs, tumors inevitably develop drug resistance, leading to disease progression. In 50% to 60% of patients treated with second-generation ALK TKIs (eg, ceritinib, alectinib, brigatinib), resistance is caused by the acquisition of secondary mutations in the ALK kinase domain. In Phase 1 and 2 studies, lorlatinib demonstrated potent antitumor activity following the failure of previous ALK inhibitors. In particular, lorlatinib demonstrated significant intracranial activity in patients previously treated for baseline CNS disease, including leptomeningeal disease.

Therefore, among all ALK TKIs currently approved by the U.S. Food and Drug Administration (FDA),lorlatinibis considered to be the standard treatment option for ALK-positive patients who are ineffective in treatment with one or moreALK inhibitors, and is also the most effective treatment option for ALK-positive non-small cell lung cancer that is resistant to second-generation ALK TKIs. However, studies have shown that resistance to lorlatinib has also emerged in some patients. Therefore, patients with ALK-positive non-small cell lung cancer urgently need to develop new fourth-generation ALK TKIs to overcome compound mutation-mediated resistance to lorlatinib.