Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is expected over time and can arise through EGFR-dependent mutations or EGFR-independent pathways. Third-generation TKIs like osimertinib are designed for mutant-selective binding, but resistant clones can still emerge, and mechanisms often differ depending on prior treatment history.1 Repeat molecular testing at progression is increasingly considered when identifying resistance mechanisms could influence subsequent treatment selection, and plasma-based liquid biopsy has expanded its feasibility when tissue biopsy is impractical. Optimal testing strategies and their impact on long-term clinical outcomes continue to evolve.1–3
When a targetable resistance mutation is identified, matched therapy may be an option.2 When it is not, or when disease has progressed on osimertinib plus chemotherapy, several non-TKI approaches are available, including chemotherapy-based regimens and antibody-drug conjugates such as datopotamab deruxtecan-dlnk, a trophoblast cell-surface antigen 2 (TROP2)-directed therapy that delivers a cytotoxic payload to tumor cells and has received accelerated FDA approval and is being incorporated into treatment discussions for certain patients with EGFR-mutated non-small cell lung cancer (NSCLC) following progression after prior EGFR-directed therapy and platinum-based chemotherapy.3,4
Beyond mechanism, practical factors shape real-world choices: oral TKIs require daily adherence, while infusion-based regimens involve more frequent visits and toxicity monitoring, including pulmonary, hematologic, gastrointestinal, and, for some antibody-drug conjugates, ophthalmologic assessment.4,5 These differences can matter as much as efficacy data when patients weigh treatment burden alongside clinical benefit.
No single sequencing pathway fits every patient. Choice depends on prior therapy, resistance findings when available, comorbidities, and tolerability.
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