Progress in treatment and research of concomitant epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement in non-small cell lung cancer

The coexistence of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements represents a rare but clinically significant subtype in non-small cell lung cancer (NSCLC), challenging the classical principle of mutually exclusive driver genes. This review, based on a literature search from PubMed, synthesizes current evidence on this dual alteration. The phenomenon manifests primarily in two distinct clinical scenarios: synchronous co-occurrence at diagnosis and metachronous acquisition of ALK rearrangement as a bypass resistance mechanism following EGFR tyrosine kinase inhibitor (TKI) therapy. The therapeutic management of these patients remains highly challenging due to a lack of standardized guidelines. A critical analysis reveals apparent paradoxes in treatment efficacy, where outcomes with EGFR-TKIs or ALK-TKIs are not uniform but are significantly influenced by granular molecular characteristics. Reported responses to EGFR-TKIs and ALK-TKIs are heterogeneous and may vary according to the temporal pattern of the alterations, EGFR mutation subtype, ALK fusion characteristics, biopsy site, prior treatment, and clinical context. However, the available evidence is derived predominantly from retrospective cohorts, small case series, and case reports; therefore, no preferred initial, sequential, or combined targeted-therapy strategy has been established. This review underscores the importance of comprehensive molecular profiling at diagnosis and progression, while emphasizing the need for cautious interpretation of quantitative molecular findings and the need for prospective clinical evidence.