After resistance to brigatinib/brigatinib and alectinib, how to choose third-generation ALK targeting drugs

Brigatinib/Brigatinib (Brigatinib) and alectinib (Alectinib) are both second-generation ALK inhibitors, which can effectively overcome the first-generation resistance problem of crizotinib and have better control effects on patients with brain metastases from non-small cell lung cancer. However, when a patient's disease progresses again after taking brigatinib or alectinib, especially when it progresses in the lungs or central nervous system, it often indicates that new ALK mutations or alternative pathway activation signals have occurred. At this time, it is particularly critical to select the appropriate third-generation ALK targeting drug.

In the current ALK treatment pathlorlatinib is widely considered to be the representative drug among the third-generation ALK inhibitors. Its design goal is to solve multiple ALK mutations (including G1202R and other resistance sites to second-generation inhibitors). It also has strong blood-brain barrier penetration capabilities and can effectively control brain metastases. Research and clinical observations have shown that a considerable number of patients can still benefit from lorlatinib after resistance to brigatinib or alectinib, especially if the ALK mutation is clearly present, it is more targeted.

Before choosing third-generation ALK drugsIt is recommended that patients conduct resistance mechanism analysis, especially the detection of ALK mutation types in tumor tissue or liquid biopsy through next-generation sequencing (NGS). If it is clear that it is an ALK-dependent mutation (such as G1202R, L1196M, etc.), lorlatinib will be given priority because of its strong ability to inhibit such mutation sites. If the test results show ALK-independent drug resistance mechanisms, such as MET, EGFR, and PI3K pathway activation, comprehensive consideration needs to be given to switching to combination therapy or other targeted pathways.

In addition, the side effect spectrum of third-generation ALK drugs is different from that of second-generation drugs. For example, lorlatinib may cause neuropsychiatric side effects, hyperlipidemia, etc. Therefore, patients must be fully aware of the potential risks before use and receive close follow-up monitoring during treatment. New third- or fourth-generation ALK inhibitors may be available in the future, providing more options for drug-resistant patients.

Reference materials:https://www.alunbrig.com/