Evaluation of Anti-Angiogenic Therapy Combined with Immunotherapy and Chemotherapy as a Strategy to Treat Locally Advanced and Metastatic Non-Small-Cell Lung Cancer.

Simple Summary: Around 25–30% of non-small-cell lung cancers (NSCLC) present with locally advanced, unresectable disease where treatment with concurrent chemo/radiation followed by durvalumab remains the standard of care. However, only about one third of patients are alive without progression at 5 years. Therefore, there is a great need for improvement. Due to flaws of the past trial designs, the use of anti-angiogenic agents with radiation have been abandoned for Stage III NSCLC. We review how to use anti-angiogenic therapy safely in the locally advanced setting and discuss its expected beneficial effects. We also will review the how combined chemotherapy, anti-angiogenic therapy and immunotherapy (AIC) can be used in the metastatic setting and how it can be used as a strategy of choice for patients with liver/brain metastases as well as those with mutations that are considered to be less responsive to immunotherapy, such as, STK11, KRAS, and KEAP1. Additionally, we review trials and discuss the benefits of using AIC therapy in patients with metastatic EGFR mutations in the thirdline setting. Innovative trial designs are proposed using AIC therapy in the locally advanced setting as well as for the upfront treatment of patients suffering from brain metastases. Immunotherapy has made recent improvements in disease-free survival (DFS) and/or overall survival (OS) in all stages of non-small-cell lung cancer (NSCLC). Here, we review the tumor microenvironment and its immunosuppressive effects and discuss how anti-angiogenic therapies may potentiate the anti-carcinogenic effects of immunotherapy. We also review all the past literature and discuss strategies of combining anti-angiogenic therapy and immunotherapy +/− chemotherapy and hypothesize how we can use this strategy for non-small-cell lung cancer in metastatic previously untreated/previously treated settings in previously treated EGFR-mutated NSCLC for the upfront treatment of brain metastases prior to radiation therapy and for the incorporation of this strategy into stage III unresectable disease. We assert the use of anti-angiogenic therapy and immunotherapy when combined appropriately with chemotherapy and radiotherapy has the potential to increase the long-term survivals in both the stage III and metastatic setting so that we can now consider more patients to experience curative treatment. [ABSTRACT FROM AUTHOR]