EGFR mutant NSCLC: Treatment Options upon Progression after 1L Therapy

After patients progress on frontline therapy, the treatment approach largely depends on what therapies were used initially and the nature of the progression. If the progression is limited to a single site, local treatments like stereotactic radiosurgery (SRS) can still be considered while continuing the current systemic therapy. However, in cases of systemic progression with multiple sites involved, it’s crucial to thoroughly evaluate the molecular landscape through biopsy and plasma testing before deciding the next steps. A tissue biopsy, if feasible, is highly valuable because it helps detect critical changes such as small cell transformation, which dramatically alters the treatment paradigm. Missing such a transformation could lead to ineffective treatments, underscoring the importance of this diagnostic step.

With the availability of newer agents and combinations like the ones studied in recent trials, sequencing therapy has become more complex but also more promising. Treatment choice depends on the initial regimen, the timing of progression, and specific resistance mechanisms identified via molecular testing, including liquid biopsies and tissue analysis. For example, if a patient initially received one combination and then shows MET pathway activation on progression, switching to a different regimen targeting that pathway might be beneficial. Conversely, if progression occurs after starting a MET-targeted therapy, other strategies or clinical trials might be explored. The presence of other alterations, such as HER2 or MET amplifications, can further guide personalized treatment decisions.

Clinical trials remain a vital option, especially for patients without clearly defined resistance mechanisms. They provide access to novel agents targeting diverse resistance pathways and are often a key part of the treatment landscape in academic centers. Ultimately, treatment sequencing is highly individualized, depending on molecular findings, prior therapies, and patient-specific factors, making thorough testing and multidisciplinary discussion essential for optimizing outcomes.