Efficacy And Safety Of Anti-PD-1/PD-L1 Antibodies In Combination With Bevacizumab And Metronomic Cyclophosphamide In Patients With Non-Small Cell Lung Cancer And Cutaneous Melanoma Previously Treated With Immune Checkpoint Blockade

Overview

This study will evaluate efficacy and safety of anti-PD-1/PD-L1 antibodies combined with bevacizumab and metronomic cyclophosphamide in patients with metastatic non-small cell lung cancer (NSCLC) and cutaneous melanoma previously treated with immune checkpoint blockade (ICB). The hypotheses of this study are that a combination of ICB, cyclophosphamide, and bevacizumab prolongs progression-free survival and overall survival, and also increases rates of objective responses and disease control.

The main challenge in treating metastatic non-small cell lung cancer (NSCLC) and cutaneous melanoma is acquired resistance to PD-1/PD-L1 blockade. Mechanisms of resistance include loss of antigen expression, defects in the IFN-γ signaling pathway, decreased PD-L1 expression, and upregulation of alternative immune checkpoints. Additionally, changes in the tumor microenvironment, such as an increase in regulatory T cells (Tregs), myeloid-derived suppressor cells, and angiogenesis, create an immunosuppressive environment that reduces T-cell activity. Bevacizumab, a monoclonal antibody against VEGF-A, has demonstrated the ability to "normalize" tumor vasculature, thereby improving perfusion, reducing hypoxia, and facilitating immune cell infiltration into tumors. Results from several phase III trials in renal cell carcinoma, NSCLC, and hepatocellular carcinoma have shown that combining PD-1/PD-L1 antibodies with anti-VEGF therapy significantly improves ORR and progression-free survival (PFS) compared to using either immunotherapy alone or standard chemotherapy. Metronomic chemotherapy involves administering low doses of cytotoxic agents continuously. This therapy targets tumor endothelial cells and modulates the immune milieu rather than direct cytotoxic elimination of malignant cells. Metronomic cyclophosphamide specifically depletes cells and activates effector cells. Additionally, metronomic cyclophosphamide can boost antigen presentation by activating dendritic cells, enhancing anti-tumor T-cell responses. In preclinical NSCLC models, combining metronomic cyclophosphamide with PD-1 blockade led to lasting tumor regression. This was due to the antiangiogenic and immunomodulatory properties of metronomic cyclophosphamide, resulting in reduced microvessel density and increased CD8⁺ T-cell infiltration. Targeting multiple pathways of acquired resistance simultaneously with three agents can result in synergistic effects. This approach can convert immunologically "cold" tumors into "hot" ones. In preclinical studies, combining PD-L1 blockade with VEGF blockade increased T-cell infiltration and remodeled the vasculature, while combining PD-L1 blockade with metronomic chemotherapy improved antigen presentation and increased the ratio of effector-to-regulatory T-cells. In our recent retrospective study of 43 patients with metastatic NSCLC previously treated with ICIs, the safety and efficacy of rechallenging with ICIs and metronomic cyclophosphamide with or without bevacizumab were evaluated. The combination of ICIs with cyclophosphamide produced an ORR of 16.7%, a DCR of 75.0%, a median PFS of 5.8 months, and an OS of 15.4 months. In the cohort receiving oral cyclophosphamide plus bevacizumab, the ORR was 26.3%, DCR 78.9%, PFS 6.8 months, and OS 17.6 months. Adverse events related to treatment did not lead to discontinuation of the investigational therapy in either group.