Amivantamab in EGFR -mutated NSCLC with refractory brain or leptomeningeal metastases: A multi-center real-world study.

8521 Background: The central nervous system (CNS), particularly after progression on third-generation EGFR TKIs, represents a common yet challenging scenario. While recent trials establish amivantamab-lazertinib for EGFR-mutant NSCLC, their real-world applicability is limited by patient complexity and access barriers, highlighting an urgent need for flexible, real-world solutions. Methods: To evaluate the intracranial efficacy of amivantamab, used as monotherapy or in combination, we conducted a multi-center, retrospective study of patients with EGFR-mutated NSCLC and brain parenchymal metastases (BM) and/or leptomeningeal metastases (LM) treated with amivantamab monotherapy or combination based on routine clinical practice. The cohort included two key populations: heavily pretreated patients with sensitizing exon19del/L858R mutations after progression on third-generation EGFR TKIs, and treatment-limited patients with atypical mutations. Efficacy endpoints included intracranial progression-free survival (PFS) and intracranial objective response rate (ORR) by RANO-BM and/or RANO-LM. Exploratory endpoints included symptom improvement, and longitudinal cerebrospinal fluid (CSF) biomarker dynamics. Results: Thirty-one patients from seven centers were included (BM, n=13; BM+LM, n=18). Most (25/31, 80.6%) harbored EGFR sensitizing mutations and had progressed on third-generation EGFR TKIs; six (19.4%) carried atypical EGFR mutations. Over half (17/31, 54.8%) had received ≥4 prior lines. Amivantamab monotherapy was received in 10/31 patients (32.3%). Median intracranial PFS was 10.3 months (95% CI, 4.5-16.1). Among 24 evaluable patients, intracranial ORR was 25.0% (n=6), and disease control rate was 91.7% (n=22). CNS-related symptoms improved in 26/31 (83.9%). CSF analyses showed decreased pressure and CEA, reduced EGFR amplification, and clearance of EGFR C797S. Conclusions: In real-world settings, amivantamab-based regimens demonstrate promising intracranial efficacy in EGFR-mutated NSCLC patients with refractory brain or leptomeningeal metastases. These findings support the use of amivantamab as a viable therapeutic strategy in this challenging population and suggest that CSF biomarkers can serve as a valuable tool for monitoring treatment response.