Entrectinib belongs to the first generation of targeted therapy drugs

Entrectinib (Entrectinib) is a broad-spectrum multi-target oral small molecule targeted drug, mainly targeting patients with solid tumors carrying NTRK1/2/3, ROS1 or ALK fusion genes. Different from the traditional generational approach of targeted therapy drugs represented by EGFR or ALK, the design concept of entrectinib is closer to the "target first" and "tissue agnostic" treatment strategies, so it cannot be simply classified into the first, second or third generation targeted drug classification system. However, judging from its status in the TRK and ROS1 pathways and its development time points, entrectinib can be regarded as a first-generation TRK inhibitor. At the same time, in the field of ROS1 targets, it is a "new generation targeted drug" with greater central nervous system penetration capabilities.

The initial development background of entrectinib was to solve the problem of insufficient control of brain metastases by traditional targeted drugs, especially for ROS1-positive non-small cell lung cancer patients with a high incidence of brain metastases, as well as a small number of solid tumor patients with NTRK fusion mutations. It has a clear ability to penetrate the blood-brain barrier and can effectively maintain drug concentrations in the central nervous system, thereby achieving a broader anti-tumor effect. This is also one of the important features that distinguishes it from the older generation of targeted drugs. Entrectinib was approved by the FDA for the treatment of NTRK fusion-positive and ROS1 fusion-positive tumors. It no longer distinguishes the organ of tumor origin, but uses gene mutation as the premise for targeted therapy. It represents the "tissue agnostic" concept in precision medicine, and this concept has also become an important direction for the development of targeted drugs in the future.

In the field of TRK inhibition, alongside entrectinib is larotrectinib. Both drugs are currently widely recognized TRK-targeting drugs worldwide. In terms of ROS1 inhibition, entrectinib has higher central activity than crizotinib and has become an alternative. In terms of ALK targets, although entrectinib also has a certain role, it is not a mainstream indication.

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