Common metastatic sites after crizotinib/Xalkori resistance

Crizotinib/Crizotinib is the first oral small molecule ATP competitive inhibitor. It was originally developed as a cMET kinase inhibitor and was subsequently found to inhibit ALK and ROS1 kinases in biochemical identification. This resulted in crizotinib being approved after investigation for the treatment of patients with ALK- and ROS1-positive small cell lung cancer, and subsequently for the treatment of anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT) with ALK-positive mutations.

TakingALK+ non-small cell lung cancer patients as an example, advanced disease often involves multiple sites, especially lymph nodes, pleural and pericardial surfaces, brain and liver. Although treatment with crizotinib can induce significant and often durable responses, the vast majority of treated patients eventually experience disease progression. Most relapse events occur during the first year of treatment, although long-term responses lasting beyond 6 years are very rare. For most patients, disease progression after crizotinib treatment also tends to involve multiple sites and is prone to central nervous system relapse, especially isolated central nervous system relapse.

Since the introduction of crizotinib into clinical practice, it has become apparent that many patients will relapse due to drug resistance. With the exception of lorlatinib, which effectively inhibits all identified resistance mutations, the choice of other targeted tyrosine kinase inhibitors (TKIs) needs to be selected on a case-by-case basis and the mutations detected.

In summary, crizotinib has achieved some success in the treatmentof patients with ALK- and ROS1-positive small cell lung cancer, as well as ALCL and ALCL with ALK-positive mutations. However, drug resistance and disease progression remain a challenge, requiring further research and development of more effective treatment strategies to improve patient survival and quality of life.