High-dose furmonertinib plus bevacizumab in EGFR-mutant non-small cell lung cancer with brain metastases after resistance to third-generation EGFR-TKIs: A retrospective study

Introduction

Third-generation EGFR tyrosine kinase inhibitors (TKIs) have improved outcomes in EGFR-mutant non–small cell lung cancer (NSCLC), but resistance occurs, especially in patients with Brain metastases (BMs). Antiangiogenic therapy may enhance CNS drug delivery and EGFR-TKI efficacy​. We evaluated the efficacy of high-dose furmonertinib plus bevacizumab in patients with BMs after third-generation EGFR-TKI failure.

Methods

We conducted a single-center retrospective study in EGFR-mutant NSCLC patients with BMs (leptomeningeal and/or parenchymal) who had progressed after ≥1 third-generation EGFR-TKI. Patients received furmonertinib 160 mg daily plus bevacizumab 7.5 mg/kg every 3 weeks until progression or unacceptable toxicity. Primary endpoints were intracranial and overall progression-free survival (iPFS, PFS); secondary endpoints were intracranial and systemic objective response rates (iORR, ORR) and safety.

Results

Among the 78 enrolled patients (median follow-up: 11.8 months), median iPFS and PFS were 7.2 months (95 % CI: 5.6–10.5) and 5.85 months (95 % CI: 4.6–7.4), respectively. The iORR was 37.1 %, and ORR was 28.6 %. OS data remain immature at the time of analysis. In patients with both parenchymal and leptomeningeal metastases (n = 47), median iPFS was 7.63 months (95 % CI: 5.0–10.8), and median PFS was 5.7 months (95 % CI: 4.5–10.0); iORR and ORR were 40.5 % and 34.2 %, respectively. In the parenchymal-only subgroup (n = 31), median iPFS and PFS were 7.20 months (95 % CI: 5.5–NR) and 6.4 months (95 % CI: 4.4–11.3), iORR and ORR were 32 % and 20 %. In multivariate analysis, EGFR exon 19 deletion was independently associated with prolonged iPFS (HR = 0.32, P = 0.011) and PFS (HR = 0.47, P = 0.047). CNS radiotherapy administered during treatment also emerged as an independent prognostic factor for both iPFS (HR = 0.34, P = 0.022) and PFS (HR = 0.40, P = 0.018).

Conclusion

In this retrospective study, high-dose furmonertinib combined with bevacizumab demonstrated favorable intracranial and systemic activity with an acceptable safety profile in EGFR-mutant NSCLC patients with CNS metastases after resistance to third-generation EGFR-TKIs. These findings provide preliminary evidence supporting the potential clinical benefit of this chemotherapy-sparing strategy. Importantly, these findings warrant further validation in biomarker-stratified prospective trials to guide patient selection and optimize treatment outcomes.