How long can the resistance period of lorlatinib/lorlatinib last?

Lorlatinib is a third-generation ALK (anaplastic lymphoma kinase) and ROS1 tyrosine kinase inhibitor designed to overcome resistance to previous generation targeted drugs. Its advent provides a more long-term and stable treatment option for ALK-positive and ROS1 rearrangement-positive patients with non-small cell lung cancer (NSCLC). However, there is no absolutely fixed number as to how long the drug resistance period can last, mainly because the formation of drug resistance is affected by a variety of complex factors, including the patient's tumor biological characteristics, gene mutation background, individual differences in drug metabolism, previous targeted therapy, and whether it is combined with other treatments (such as immunotherapy, radiotherapy and chemotherapy, etc.).

Judging from existing clinical trends and overseas treatment experience, lorlatinib has a longer resistance period in first-line treatment than when used as second- or third-line treatment. Specifically, many patients develop drug resistance after using first- and second-generation ALK inhibitors such as crizotinib or alectinib, while lorlatinib can continue to maintain disease control for several months or even more than a year. In some forms of ALK mutations, such as G1202R and other drug-resistant mutations, lorlatinib still has a unique ability to inhibit such mutations, so it is often regarded as the "last line of defense after treatment."

The mechanisms of resistance to lorlatinib are still under investigation. The resistance pathways discovered in current research mainly include ALK double mutations, activation of alternative pathways (such as activation of signaling pathways such as MET and EGFR), and histological transformation. Until these resistance mechanisms develop, lorlatinib maintains its ability to inhibit tumor growth. Even after the disease progresses, some patients can still extend the effective time by combining other drugs or adjusting the dose.

References：https://www.lorbrena.com/