CNS and Leptomeningeal Disease Management in EGFR-Mutated Non-Small Cell Lung Cancer and Future Outlook

Dr. Leal addresses CNS disease management in EGFR-mutated NSCLC, noting that baseline brain metastases represent a high-risk feature associated with worse prognosis and shorter PFS. Potent EGFR tyrosine kinase inhibitors, particularly osimertinib and lazertinib, remain most valuable for CNS control and reducing CNS progression risk in patients without baseline brain involvement. Amivantamab, an EGFR-MET bispecific antibody, has also demonstrated CNS benefit in both MARIPOSA and MARIPOSA-2. Notably, datopotamab deruxtecan, an antibody-drug conjugate not traditionally expected to cross the blood-brain barrier effectively, also demonstrated CNS activity in the pooled TROPION-Lung01/05 analysis. She emphasizes the importance of investigating CNS efficacy early in drug development to inform sequencing strategies that control CNS disease, reduce progression risk, and delay whole brain radiation given its neurologic toxicity.

For leptomeningeal disease, a particularly difficult-to-treat, life-limiting complication with high prevalence in EGFR-mutated NSCLC, she notes that international multicenter cohort data from the US and China demonstrate that EGFR-targeted therapy has improved OS even in patients with leptomeningeal involvement, representing the primary contributor to delaying this complication. Emerging amivantamab-lazertinib data are of interest, and she advocates for future trial designs that explicitly include patients with leptomeningeal disease to generate dedicated evidence in this underserved population.

Closing her top takeaways, Dr. Leal emphasizes: combination therapy should be the default consideration for most patients with EGFR-mutated NSCLC given the prevalence of high-risk features (CNS metastases, L858R mutation, positive ctDNA, TP53 co-mutation); ongoing work aims to better tailor specific combinations to individual patients while balancing toxicity; and shared decision-making incorporating patient voice remains essential given the multiple effective options now available. Looking ahead, she highlights anticipation for neoadjuvant and perioperative strategies in early-stage EGFR-mutated NSCLC, including the LAURA trial (osimertinib after chemoradiation in unresectable disease), the ADAURA trial (adjuvant osimertinib), and the forthcoming ADAURA2 trial in stage 1 disease, with hope that these approaches will extend the substantial survival gains seen in advanced disease to earlier-stage, potentially curable patients.