Disease Progression Workup and Resistance Testing

At disease progression, comprehensive tumor characterization becomes as important as initial diagnosis. Dr. Camidge argues against using regimens that don't require resistance mechanism identification, emphasizing that understanding heterogeneous resistance mechanisms guides optimal therapy selection.

Both liquid and tissue biopsies have roles in progression workup. Liquid biopsies offer rapid turnaround but cannot be trusted when negative due to false-negative rates. Dr. Camidge typically orders biopsies while obtaining liquid results, potentially canceling tissue sampling if circulating tumor DNA provides actionable information.

Dr. Devarakonda favors tissue biopsy when feasible, particularly for identifying histological transformation including squamous differentiation or small cell transformation that liquid biopsies cannot detect. These represent approximately 10% to 15% of resistance mechanisms with distinct treatment implications.

Dr. Rotow emphasizes patient education about biopsy necessity despite associated risks and discomfort. Beyond genomic data, tissue biopsies provide protein-based biomarkers including immunohistochemistry markers that may be actionable, particularly with expanding therapeutic options.

Current second-line approved therapies aren't predicated on specific resistance mechanisms identified through progression testing. However, emerging therapies targeting MET amplification, C797S mutations, and other specific resistance pathways require comprehensive characterization for optimal treatment selection.

The panel advocates for increased resistance testing not only for immediate patient benefit but for advancing scientific understanding of resistance mechanisms and developing targeted interventions for specific molecular escape pathways.