What to do after resistance to crizotinib/Xalkori

Crizotinib has brought significant benefits to patients with ALK-positive and ROS1-positive non-small cell lung cancer (NSCLC), but like most targeted drugs, resistance problems are almost inevitable. After patients take crizotinib for a period of time, the drug may fail due to tumor progression or new lesions discovered on imaging. This process is usually closely related to the resistance mechanism at the genetic level.

The mechanism of resistance to crizotinib is complex. The most common one is ALK secondary mutation, which means that tumor cells undergo new genetic changes under drug pressure, thus weakening the binding ability of crizotinib. Other patients may develop drug resistance due to activation of bypass signaling pathways (such as EGFR or KIT), and a few cases may manifest phenotypic transformation of tumor cells, such as transformation into small cell lung cancer. Differentiated clinical response strategies will be adopted for these different situations.

On the one hand, sequential treatment with second- or third-generationALK inhibitors is the main option. Ceritinib, alectinib, brigatinib and higher-generation lorlatinib have all been approved in the international and domestic markets. They cover more resistance mutations and have shown significant efficacy in the treatment of crizotinib resistance. On the other hand, if the patient only develops local progression, such as brain metastasis or a single lung lesion, doctors may recommend local radiotherapy or surgical intervention followed by maintenance crizotinib treatment to delay the progression of overall resistance.

In addition, chemotherapy and immunotherapy are still backup options for patients who no longer benefit from targeted drugs. In recent years, some studies have also explored the combination treatment of targeted drugs with immune checkpoint inhibitors and anti-angiogenic drugs, which may provide more options for patients with drug resistance.

Reference materials:https://go.drugbank.com/drugs/DB08865