Breaking Down Combination Strategies: PD-1/PD-L1 Inhibitors with Chemotherapy, Anti- Angiogenesis, or Both in Driver Gene-Negative NSCLC Clinical Outcomes and Mechanistic Insights

Background: Brain metastasis from lung adenocarcinoma poses clinical challenges. Patients with driver gene-negative lung adenocarcinoma brain metastases have a relatively poor prognosis, and conventional treatments are inadequate. Immune checkpoint inhibitors (ICIs) represent a cornerstone in first-line therapy for metastatic non-small cell lung cancer. This study aims to explore the efficacy and mechanisms of ICIs combined with chemotherapy and anti-angiogenesis therapy, providing a theoretical basis and potential intervention points for treating driver gene-negative lung adenocarcinoma brain metastases. Methods: Clinical data of patients with driver gene-negative lung adenocarcinoma brain metastases who received immunotherapy from May 2020 to July 2022 at Nanchang University the Second Hospital center were collected. The study validated efficacy and mechanisms at cellular and animal model levels, including the hypoxia status and blood-brain barrier permeability and immune micro-environment status. Results: This study enrolled 179 patients with driver gene-negative non-small cell lung cancer brain metastases who received immunotherapy. Comparison among PD-1/PD-L1 inhibitor plus chemotherapy and anti-angiogenesis therapy (n=37), PD-1/PD-L1 inhibitor plus chemotherapy (n=54), anti-angiogenesis therapy alone (n=53), and PD-1/PD-L1 inhibitor monotherapy (n=35) showed median overall survival (OS) of 21.20 vs 16.00 vs 16.53 vs 9.30 months, respectively (P=0.013), and median intracranial progression-free survival (iPFS) of 15.20 vs 11.30 vs 9.03 vs 8.10 months, respectively (P=0.118). In a brain metastasis animal model, mice treated with PD-1 inhibitor plus bevacizumab and pemetrexed exhibited the lowest tumor fluorescence intensity. The combined therapy significantly improved tumor hypoxia, enhanced blood-brain barrier permeability in mice, and increased coverage of perivascular cells. The combination therapy decreased M2-type macrophages and increased M1-type macrophages in mouse brain tissue, elevated PD-L1 expression, and increased CD8+ T cells. Conclusion: PD-1/PD-L1 inhibitor combined with chemotherapy and anti-angiogenesis therapy appears to be an optimal strategy for driver gene-negative lung adenocarcinoma brain metastases. This combination therapy activates the immune micro-environment, improve hypoxia, enhance blood-brain barrier permeability and promote vascular normalization.