Background: The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2–7% of lung adenocarcinomas, with higher incidence (17–20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown. Methods: We report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with continued next-generation regimens upon progression. Results: The tumor showed progression on crizotinib, but long tumor control was achieved following the incremental administration of next-generation ALK inhibitors, despite lack of evident resistance mechanisms. Conclusion: TP53 status should be taken into consideration when selecting ALK-inhibitor treatment for personalized therapies. In TP53-mutant tumors, switching TKI generations may overcome treatment exhaustion even in the absence of ALK-dependent resistance mechanisms.