EGFR L858R–Mutant NSCLC With Brain Metastases With a TP53 Mutation: What Is the Best Initial Treatment Approach?

The group discussed a challenging case of a middle-aged woman with a history of smoking who presented with advanced lung cancer characterized by a large primary tumor, bilateral pulmonary nodules, and multiple small, asymptomatic brain metastases. Molecular testing revealed an EGFR mutation alongside a TP53 comutation, while her performance status remained good. The discussion focused on how to best approach treatment in this high-risk patient, weighing options between single-agent targeted therapy vs combination strategies that include chemotherapy or antibody-drug conjugates. Most agreed that because of the patient’s young age, good performance status, brain metastases, and adverse molecular markers, intensified up-front treatment would likely provide the best chance of durable disease control.

Participants emphasized the importance of shared decision-making, considering not only the disease and molecular characteristics but also the patient’s preferences, values, and tolerance for potential toxicities. They highlighted that although combination regimens may be more aggressive and challenging because of increased adverse effects and logistics, they often offer better overall survival outcomes. However, patient education is critical, especially as many newly diagnosed patients face overwhelming amounts of information and emotional distress. Clinicians shared strategies such as multivisit discussions, providing educational materials, and reassuring patients that treatment plans can be adjusted based on response and tolerance to optimize quality of life.

The panel also acknowledged real-world challenges such as delays in molecular testing, insurance authorization hurdles, and the need to start treatment promptly in the setting of brain metastases. Some favored initiating monotherapy quickly with plans to escalate therapy once more information or patient readiness was achieved. Overall, the discussion underscored the complexity of balancing clinical evidence, patient-specific factors, and psychosocial aspects in tailoring therapy for patients with EGFR-mutant lung cancer with high-risk features, emphasizing the art of oncology alongside the science.