State of the art and future perspectives

The clinical success of ALK inhibition through targeted therapies is manifestly evident in ALK-rearranged non-small cell lung cancer (NSCLC). Deciphering resistance mechanisms to targeted agents in ALK-positive NSCLC has been crucial to develop novel inhibitors and novel treatment strategies, with a continued and reciprocal exchange of evidence between clinical and preclinical research. With the advent of the third-generation ALK inhibitor lorlatinib in the clinical setting, as well as with the availability of second-generation agents (e.g., alectinib) in the upfront treatment of ALK-rearranged NSCLC, novel scenarios of resistance have recently emerged. In parallel, moving ALK inhibition in disease setting earlier than the advanced/metastatic one would likely demand new concepts and methodologies. Whereas the evidence of resistance mechanisms to ALK inhibitors are scarce in ALK-dependent tumors other than lung cancer, biological and clinical specificities can be recognized. The relevant results obtained in NSCLC should serve as an example for other ALK-driven diseases.