EGFR-mutant NSCLC: Future Directions

At ASCO 2024, a pivotal trial demonstrated that consolidation osimertinib following chemoradiation in unresectable stage III EGFR-mutant non-small cell lung cancer significantly improves progression-free survival. The reported hazard ratio indicated an approximately 84% reduction in the risk of disease progression or death, marking a major advancement for this challenging patient population. Although mature overall survival data are still pending, the magnitude of progression-free survival benefit is clinically meaningful, especially given the historically poor outcomes in stage III disease. The ability of this drug to penetrate the blood-brain barrier also offers a critical advantage by potentially delaying or preventing brain metastases, which are common and devastating in this high-risk group.

In the early-stage setting, emerging data highlight the promise of targeted therapy combined with chemotherapy in the neoadjuvant context. Recent trial results showed that adding osimertinib to neoadjuvant chemotherapy in resectable stage II-III EGFR-mutant lung cancer achieved major pathologic responses, with over 90% tumor cell kill after treatment. This approach reflects a shift toward aggressively targeting early disease to improve the chance of cure. However, longer follow-up is needed to understand the full impact on event-free and overall survival. The importance of comprehensive molecular testing at diagnosis is emphasized to guide these treatment strategies effectively, ensuring that patients receive the most appropriate targeted therapies from the outset.

Additionally, novel antibody-drug conjugates (ADCs) are showing encouraging activity in patients who have progressed on osimertinib and chemotherapy. A newly presented ADC demonstrated a significant progression-free survival advantage compared to chemotherapy, along with a more favorable toxicity profile. These advancements suggest a growing arsenal of well-tolerated and effective therapies in EGFR-mutant lung cancer, offering hope for improved disease control and quality of life in both advanced and earlier-stage settings.