Sequencing Beyond Frontline: Resistance, Later-Line Options, and Emerging Directions in EGFR-Mutant NSCLC

This closing segment addresses how first-line choice shapes later options and how to approach progression. The faculty stress re-characterizing the tumor at progression with both tissue and liquid biopsy to identify resistance mechanisms, bypass pathways, histologic transformation, and protein-level targets that circulating DNA cannot capture. They review a spectrum of later-line strategies: local therapy for limited progression, continuing targeted therapy with added chemotherapy for systemic progression, antibody-drug conjugates, cross-over to the alternative combination, and reintroduction of targeted therapy after intervening treatment, while keeping clinical trials front of mind. Looking ahead, they highlight novel tyrosine kinase inhibitors, promising antibody-drug conjugates likely to move into earlier lines, and the longer-term goal of harnessing immune responses, along with biomarker tools to guide escalation and de-escalation. The panel closes with practical takeaways: build supportive-care infrastructure, listen to patient goals, test thoroughly, and confirm the specific mutation.