EGFR mutated NSCLC: Treatment Advances and Highlights from ASCO 2025 - Episode 12
Panelists discuss that managing systemic progression in EGFR-mutant lung cancer requires thorough molecular profiling via tissue and liquid biopsies to identify resistance mechanisms like histologic transformation and MET amplification, with comprehensive testing guiding next-line targeted therapies or clinical trial enrollment to optimize patient outcomes.
When patients experience systemic progression involving multiple sites, changing systemic therapy requires a comprehensive understanding of the tumor’s molecular profile, just as at the initial diagnosis. Ideally, a tissue biopsy is obtained from a progressing or new FDG-avid lesion to provide detailed information. Simultaneously, a liquid biopsy is performed for faster results that may guide immediate treatment decisions. It is essential to rule out histologic transformations such as small cell or squamous cell carcinoma, as well as to identify acquired secondary mutations like C797S or amplifications such as MET. Additional markers, including HER2, are also evaluated due to the development of emerging targeted therapies beyond oral EGFR inhibitors.
A significant proportion of patients may not have clearly identifiable resistance mechanisms, necessitating broader treatment strategies or enrollment in clinical trials. Access to such trials is especially important in academic centers where novel therapies targeting specific resistance pathways are being developed. Histologic transformation, particularly to small cell lung cancer, occurs in a minority of cases but is associated with a more aggressive disease course. This transformation is more likely in patients with baseline alterations in genes such as TP53 or RB1, underscoring the importance of obtaining tissue biopsies when rapid progression is observed. Open communication with patients about the waiting period for comprehensive molecular profiling, which can take up to two weeks, is vital for managing expectations and ensuring adherence to appropriate next-line therapies.
Identification of MET amplification remains a critical and complex component of resistance evaluation. While next-generation sequencing from liquid or tissue biopsies may suggest amplification, confirmatory testing using immunohistochemistry or fluorescence in situ hybridization is often required to accurately assess copy number. Recent approvals of MET-targeted tyrosine kinase inhibitors have expanded treatment options for patients exhibiting high-level MET amplification, providing additional precision medicine strategies in the resistant setting. Overall, comprehensive molecular testing, including fusion panels and MET evaluation, is essential for tailoring treatment and improving patient outcomes in the face of resistance.