Even more challenging are cases with off-target resistance when suitable targeted compounds are not available (e.g., KRAS mutation, HER2 amplification): despite presence of the additional alteration, in some cases the disease remains ALK-dependent and the switch from second-generation ALK TKI to the more potent lorlatinib can facilitate tumor responses lasting several months (unpublished personal observation of the authors). Here, ALK is linked to neoplasm.