Resistance Patterns, the Need to Rebiopsy, and Sequencing Strategies

Resistance mechanisms after treatment with targeted therapies in EGFR-mutant lung cancer are increasingly important when considering subsequent lines of therapy. Both tissue and liquid biopsies are valuable tools in this setting. While liquid biopsies provide a less invasive means to detect emerging alterations, tissue biopsies remain critical, especially to identify histologic transformations such as small cell changes that can dramatically affect treatment decisions and prognosis. Even though actionable acquired genetic alterations are relatively uncommon, assessing these changes is crucial, particularly with new regimens still being evaluated. Combining liquid and tissue biopsies allows for a comprehensive understanding of the tumor’s evolving biology, ensuring that management strategies can be appropriately tailored.

The data from recent studies highlight a decrease in certain resistance alterations, such as EGFR and MET, likely influenced by the mechanism of action of novel agents. Despite this, histologic transformation remains a key consideration, necessitating repeated biopsies when feasible and safe. Importantly, while molecular testing can uncover a variety of alterations, caution is advised when interpreting these results, especially when considering off-label targeted therapies or untested drug combinations. Without robust clinical evidence, such approaches can introduce unnecessary toxicity and potentially harm patients. Thus, incorporating molecular findings into clinical decision-making requires a careful balance between enthusiasm for precision medicine and prudence to avoid premature or harmful interventions.

Ultimately, the management of resistance in EGFR-mutant lung cancer benefits greatly from multidisciplinary collaboration and clinical trial involvement. Expert consultation and access to trial opportunities are invaluable in navigating complex resistance patterns and therapeutic options. The heterogeneity of resistance mechanisms, coupled with challenges such as clonal hematopoiesis and tumor heterogeneity, makes this an evolving field where clinical judgment must guide the integration of biopsy data and molecular findings. Prioritizing patient safety and evidence-based strategies remains paramount in optimizing outcomes for patients experiencing disease progression after targeted therapy.