crizotinibresistant

Crizotinibresistant describes tumors that have developed resistance to crizotinib, a tyrosine kinase inhibitor that targets ALK, ROS1, and, to some extent, MET. The term is most often used in non-small cell lung cancer with ALK or ROS1 rearrangements, where patients may experience an initial response followed by progression as the disease evolves. Resistance mechanisms are diverse and influence subsequent treatment choices.

Resistance can be on-target, with secondary mutations in ALK or ROS1 that impair crizotinib binding, or off-target, involving activation of alternative signaling pathways such as EGFR, MET, or HER family members. In some cases, histologic transformation to small cell carcinoma occurs. Additionally, crizotinib’s limited penetration of the central nervous system can lead to CNS-dominant progression even when systemic disease is controlled.

Diagnosis of crizotinib resistance typically involves tissue re-biopsy or circulating tumor DNA analysis to identify the responsible mechanism and to guide therapy. Management usually entails switching to next-generation ALK or ROS1 inhibitors that retain activity against certain resistance mutations; examples include alectinib, brigatinib, ceritinib, and lorlatinib for ALK rearrangements, and entrectinib or lorlatinib for ROS1. Local therapies may be used for oligoprogression, and clinical trials are strongly considered.

Prognosis after resistance varies with the mechanism and treatment options, but outcomes improve when effective downstream therapies are available and CNS disease can be treated aggressively. Ongoing molecular profiling and multidisciplinary care are standard components of managing crizotinibresistant disease.