Structural and Compound ALK Resistance Mutations: A Unified Framework to Understand Lorlatinib Failure and Beyond

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have dramatically transformed the clinical management of ALK-rearranged non-small cell lung cancer (NSCLC). Successive generations of ALK inhibitors have been developed to overcome resistance mediated by kinase domain mutations, culminating in the third-generation inhibitor lorlatinib. Despite these advances, resistance remains inevitable, and durable disease control is rarely achieved. While resistance driven by single ALK mutations has been extensively characterized and structurally classified, the emergence of compound ALK mutations under sequential TKI therapy represents a qualitatively distinct and insufficiently conceptualized resistance state. This issue is becoming more complex as lorlatinib is increasingly used in the first-line setting, where resistance may arise from an ALK TKI-naïve background rather than from tumors already shaped by sequential ALK inhibition. In this review, we propose a unified framework that integrates structural single ALK resistance mutations (Types 1–3) with compound ALK mutations (Type 4) as a distinct evolutionary entity. We argue that compound mutations mark a critical inflection point at which ALK dependency reaches its functional limit, explaining the failure of even highly potent inhibitors such as lorlatinib. Importantly, we discuss how certain compound mutations paradoxically restore sensitivity to earlier-generation TKIs, highlighting the value of structural interpretation over linear drug sequencing. Finally, we discuss the transition toward ALK-independent resistance and future strategies incorporating dynamic molecular monitoring and structure-agnostic therapies. This framework may help clinicians interpret resistance mechanisms and guide rational treatment selection in daily practice.