Lorlatinib/lorlatinib belongs to which generation of targeted drugs

Lorlatinib/lorlatinib (Lorlatinib) is a targeted drug for specific types of non-small cell lung cancer (NSCLC) and is a third-generation ALK inhibitor. It is mainly used to treat patients who have progressed despite treatment with first- and second-generation ALK inhibitors. Compared with the previous two generations of ALK inhibitors, lorlatinib was designed with the ability to overcome multiple mutations, especially those tumor cells with drug-resistant mutations.

Lorlatinib is a third-generation oral TKI that targets ALK and ROS1. Unlike second-generation inhibitors, lorlatinib is engineered to penetrate the central nervous system (CNS) and overcome existing secondary resistance mutations within the ALK tyrosine kinase domain. In preclinical studies, lorlatinib showed greater potency than earlier TKIs when treating non-mutated ALK. Furthermore, it maintains its efficacy against well-known individual ALK resistance mutations, such as the highly challenging G1202R solvent front mutation.

First generationAlthough first-generation ALK inhibitors such as Crizotinib have achieved certain clinical efficacy, many patients will develop drug resistance over time, usually due to new genetic mutations in tumor cells. Second-generation ALK inhibitors such as alectinib and brigatinib have solved this problem to a certain extent and can combat some common drug-resistant mutations, but they still have limitations that cannot be fully overcome.

Lorlatinib emerged to fill this gap. Its structural design allows it to effectively penetrate the blood-brain barrier, thereby enhancing its efficacy against metastatic lesions in the central nervous system. Additionally, lorlatinib was well tolerated and showed antitumor activity in clinical trials, particularly in patient populations following first- and second-generation therapies.