High-dose furmonertinib in EGFR -mutant NSCLC with brain metastases after EGFR-TKI resistance.

e14028 Background: Patients with EGFR-mutant non–small cell lung cancer (NSCLC) who develop central nervous system (CNS) metastases after progression on prior EGFR tyrosine kinase inhibitors (EGFR-TKIs) represent a therapeutically challenging population. High-dose furmonertinib has been explored as a strategy to enhance CNS penetration and overcome resistance; however, its pooled efficacy and safety outcomes have not been systematically quantified. Methods: A single-arm meta-analysis was performed using random-effects models to pool proportions for extracranial and intracranial tumor responses and adverse events. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), assessed according to RECIST criteria. Safety outcomes included any-grade and grade ≥3 treatment-related adverse events (AEs). Results: A total of five studies with 285 patients were included. Extracranial efficacy was evaluable in 164 patients. The pooled extracranial ORR was 62% (95% CI, 41–79%), with a DCR of 84% (95% CI, 68–93%). CRs were uncommon (4%, 95% CI 1–10%), while PR and SD occurred in 29% (95% CI 13–54%) and 32% (95% CI 25–39%) of patients, respectively. Extracranial PD was observed in 16% (95% CI 7–32%). Intracranial responses were assessable in 90 patients. The pooled intracranial ORR was 53% (95% CI, 43–63%), and the intracranial DCR was 79% (95% CI, 51–93%). Intracranial CR was rare (1%, 95% CI 0–6%), whereas PR and SD were observed in 28% (95% CI 20–38%) and 19% (95% CI 12–28%), respectively. Intracranial PD occurred in 10% (95% CI 5–18%). High-dose furmonertinib demonstrated a manageable safety profile (Table 1). Elevated AST/ALT and rash were most common adverse events. Conclusions: The concordance between extracranial and intracranial disease control suggests that dose intensification may partially overcome pharmacokinetic limitations and resistance mechanisms that contribute to CNS progression after earlier-generation TKIs. Notably, the low rates of primary intracranial progression and infrequent grade ≥3 toxicities indicate that improved CNS exposure is achieved without a proportional increase in severe adverse events. These findings support the biological and clinical rationale for high-dose furmonertinib as a CNS-active salvage strategy in the post–EGFR-TKI resistance setting, particularly for patients with active or progressive brain metastases who have limited therapeutic options. Adverse event profiles across pooled studies. Adverse event Grade Pooled incidence % (95% CI) Elevated AST/ALT Any 10% (95% CI 4-22%) ≥3 3% (95% CI 1-8%) Elevated serum creatinine Any grade 7% (95% CI 2-22%) ≥3 1% (95% CI 0-6%) Oral mucositis Any grade 5% (95%CI 2-11%) ≥3 2% (95% CI 0-9%) Rash Any grade 16% (95% CI 1-77%) ≥3 3% (95% CI 0-27%)