Countermeasures after resistance to entrectinib/luoshengquan

Entrectinib: Although its performance in ROS1 fusion non-small cell lung cancer and NTRK fusion solid tumors is widely recognized, as a targeted therapy drug, drug resistance is an almost inevitable problem. Once a patient finds signs of tumor activity again or imaging shows progression after using it for a period of time, he or she may enter the drug-resistant stage. Facing the critical node of drug resistance, timely and scientific treatment strategies are particularly important and are also the key to long-term treatment planning.

First of all, entrectinib resistance usually involves two types of mechanisms: one is that new genetic changes occur within the tumor, causing the receptor structure to change, so that it can no longer be effectively bound by the drug; the other is that the tumor activates other alternative signaling pathways, so that the cells no longer rely on the original driver genes. In either case, retesting, including liquid biopsy or tumor tissue testing, is needed to confirm the resistance pattern. This step is the basis for all subsequent decisions.

For patients with ROS1-positive non-small cell lung cancer, if resistance is confirmed, clinical practice often considers higher-level drugs with more specific targets, such as third-generation ROS1 inhibitors or options with stronger central activity. Some new drugs have shown clear advantages in targeting specific drug-resistant mutations, so re-genetic analysis is critical and can provide direction for new targeting strategies.

For patients with NTRK gene fusion tumors, if entrectinib is no longer effective due to acquired mutations, the subsequent steps are also targeted optimization based on the type of mutation. Some second-generation NTRK inhibitors have shown breakthrough effects against drug-resistant mutations. Especially when structural mutations lead to obstruction of drug binding, new drugs can bind to the receptor in different ways, thereby restoring inhibitory capabilities.

Reference materials:https://www.roche.com/products/rozlytrek