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Both tissue and plasma-based next generation sequencing (NGS) facilitate the identification of actionable oncogene alterations at diagnosis and resistant mechanisms on progression. The value of longitudinal profiling is less established among patients with ALK-rearranged NSCLC, underpinned by concerns of limited treatment options post-progression and assay sensitivity. We report a case of a patient with ALK-rearranged NSCLC with serial tissue and plasma NGS performed post-progression, whose results helped to guide sequencing of treatment options leading to an overall survival exceeding 8 years from diagnosis of metastatic disease.