Abstract

The efficacy and safety of anti-angiogenic combination therapy in patients with driver gene-negative non-small cell lung cancer (NSCLC) with brain metastases (BM) are uncertain. Eighty-eight records of driver gene-negative patients with NSCLC treated with craniocerebral radiotherapy (RT) and programmed death factor-1 (PD-1) inhibitors between May 2021 and May 2023 were collected. Based on whether anti-angiogenic therapy (AT) is combined or not, patients are categorized into the AT group and the non anti-angiogenic therapy (NAT) group. The NAT group patients received craniocerebral RT and PD-1 inhibitor and those in the AT group received craniocerebral RT and PD-1 inhibitor with ≥ 4 cycles of AT. Comparing the clinical efficacy and safety in these two patient cohorts was the main goal of the study. By May 1, 2024, the iORR was 94.0% and 63.2% for AT and NAT group, respectively. The 1- and 2-year iLPFS for AT and NAT group were 93.6%, 80.9% and 69.7%, 36.4%, respectively. The 1- and 2-year iDPFS were 86.7%, 56.3% and 59.1%, 48.3%, respectively. The 1- and 2-year OS were 82.0%, 36.6% and 68.4%, 34.6%, respectively. Compared to the standard treatment (RT and PD-1 inhibitors), the addition of AT prolonged the median iLPFS (NR vs. 22.0 months, hazard ratio [HR] = 11.004, P < 0.001) and the median iDPFS (NR vs. 20.0 months, HR = 8.732, P = 0.003), but was not significant in the extension of the OS (21.0 vs. 19.0 months, HR = 1.601, P = 0.206). Multivariable analysis showed that combination therapy with AT is significantly associated with prolonged iLPFS (HR = 4.233, P = 0.002) and iDPFS (HR = 2.824, P = 0.007), whereas only GPA score is significantly associated with improved OS (HR = 0.589, P = 0.019). The incidence of hypertension in the AT group showed an increasing trend, and no significant increased risk of radiation-induced brain necrosis was found. No drug-related intracranial hemorrhage events occurred. Combining AT, RT, and PD-1 inhibitors can substantially improve iLPFS and iDPFS for patients with driver gene-negative NSCLC with BM; however, it is not significantly associated with better OS.