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Anaplastic lymphoma kinase (ALK) gene rearrangement is detected in approximately 3–5% of non-small cell lung cancer (NSCLC) cases. Tyrosine kinase inhibitors (TKIs) targeting ALK rearrangement (ALK–TKIs) have shown significant efficacy and improved the survival of patients with NSCLC exhibiting ALK rearrangement. However, almost all patients exhibit disease progression during TKI therapy owing to resistance acquired through various molecular mechanisms, including both ALK-dependent and ALK-independent. Here, we review the mechanisms underlying resistance to second-generation ALK–TKIs, and the clinical management strategies following resistance in patients with ALK rearrangement-positive NSCLC. Treatment strategies following the failure of second-generation ALK–TKIs failure should be based on resistant mechanisms. For patients with  ALK  mutations who exhibit resistance to second-generation ALK–TKIs, lorlatinib is the primary treatment option. However, the identification of resistance profiles of second-generation ALK–TKIs can aid in the selection of an appropriate treatment strategy. In cases of  ALK -dependent resistance mutations, lorlatinib could be the first choice as it exhibits the broadest coverage of mutations that lead to resistance against second-generation ALK–TKIs, such as G1202R, and L1196M. In cases of no resistance mutations, atezolizumab, bevacizumab, and platinum-based chemotherapy could be the alternative treatment options.

Treatment of advanced ALK-rearranged NSCLC following second-generation ALK–TKI failure