Case Report: Lorlatinib for the treatment of ALK-rearranged poorly differentiated thyroid carcinoma after progression to prior ALK-specific tyrosine-kinase inhibitor

ALK rearrangements are rare but actionable oncogenic drivers in thyroid cancer, particularly in aggressive histologies such as poorly differentiated thyroid carcinoma (PDTC), and evidence supporting sequential ALK inhibition in this setting is scarce. We report a 19-year-old male with ALK-rearranged, radioiodine-refractory PDTC who started systemic therapy with ceritinib, achieving a complete metabolic response. After treatment discontinuation and subsequent progression despite ceritinib reintroduction, lorlatinib was initiated. Treatment with the third-generation ALK inhibitor led to a deep and durable complete metabolic response, sustained for more than four years, including persistence of remission after treatment discontinuation, with minimal toxicity. This case highlights the potential role of sequential ALK inhibition to overcome acquired resistance in ALK-rearranged TC and underscores the importance of comprehensive molecular profiling to guide personalized treatment strategies in rare aggressive thyroid cancers.