Treatment options and considerations for acquired resistance in EGFR mutation-positive non-small-cell lung cancer

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), alone or as part of combination regimens, remain the standard first-line treatment for patients with EGFR-mutation positive (EGFRm-positive) advanced non-small-cell lung cancer (NSCLC). Optimal therapy after development of resistance is not yet well established. In this review, we explore the latest clinical trial data summarizing potential treatment approaches designed to overcome acquired resistance to EGFR TKIs in EGFRm-positive advanced NSCLC. After progression while on EGFR TKIs, repeat biopsy should be strongly considered to detect histological transformation, for which platinum-based chemotherapy remains standard treatment. Identification of actionable resistance mutations may also inform a personalized approach for subsequent treatments, but current clinical data are not convincing enough to make this a clear standard of care. Several treatment approaches have shown improved progression-free survival or overall survival in patients with acquired EGFR TKI resistance. We review data for combinations with immune therapy, bispecific antibodies, and antibody-drug conjugates, including the activity of the combinations in patients with brain metastases. As more options become available, the role for shared physician-patient decision making regarding anticipated side-effects, treatment schedule, and efficacy becomes more important.