Mechanisms of resistance after crizotinib or second-generation ALK therapy in advanced non-small cell lung cancer

Compared with crizotinib, next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) reported improved progression free survival (PFS) and higher intracranial activity, becoming the new standard of care in the first-line treatment of advanced ALK-positive non-small cell lung cancer (NSCLC) patients. As there are several ALK-TKI, upon progression, the optimal sequential ALK TKI strategy at progression is relevant, and this may have an impact on patients' outcome. Secondary ALK resistance mutation subtypes have a prognostic and predictive value and are crucial for the selection of the optimal sequential ALK-TKI. In the current review we summarize the mechanism of acquired resistance (AR) in crizotinib-refractory tumors as well as after second-generation ALK TKI with a focus on circulating tumor DNA (ctDNA) analysis. This liquid biopsy may provide real-time information on the molecular evolution of the disease upon ALK-TKI therapy, which may guide clinicians in their sequencing approaches instead of blinded treatment decisions. Indeed, ctDNA analysis at progression on ALK TKI has reported other than acquired ALK mutations such as MET amplification. Future challenges are to elucidate the ALK mutation portrait when next generation ALK TKI are used in the first-line setting, as well as the efficacy of MET inhibitors in the subset of tumors with acquired MET amplification.