ALK metamorphosis: a diagnostic and therapeutic challenge

Introduction: Histological transformation to squamous cell carcinoma represents an uncommon mechanism of therapeutic resistance in patients with ALK fusions treated with third-generation inhibitors. Case report: We report a 48-year-old woman with metastatic adenocarcinoma (EML4-ALK) who achieved an initial response to lorlatinib. Upon progression, a repeat biopsy revealed transformation to a squamous phenotype while retaining the molecular profile. Following subsequent chemoimmunotherapy failure, disease control was achieved through a local approach (lobectomy and radiotherapy), and lorlatinib was reintroduced. Discussion: This treatment-induced transformation reflects the profound complexity of lung cancer in patients with specific molecular alterations. It represents a therapeutic challenge and demonstrates how tumors can adapt and require new therapeutic strategies. Conclusion: Reassessment of the systemic strategy following conversion underscores the clinical need for an adapted, dynamic, and personalized approach, guided by the tumor’s histological evolution and the patient’s molecular profile.