The Role of Angiogenesis Inhibitors in the Era of Immune Checkpoint Inhibitors and Targeted Therapy in Metastatic Non-Small Cell Lung Cancer

The treatment of advanced non-small cell lung cancer (NSCLC) has evolved to include targeted therapy, immunotherapy as well as chemotherapy for selected patients in the first-line setting. Angiogenesis inhibitors have been used in combination with chemotherapy in the first-line and maintenance settings providing improved progression-free survival (PFS) and objective response rate (ORR), as well as overall survival (OS) in selected studies. Biologic rationale exists for combining anti-angiogenic agents with immunotherapy and targeted kinase inhibitors (TKIs). A recent study has demonstrated improved survival when anti-PD-L1 therapy was added to chemotherapy plus bevacizumab. Subgroup analysis of patients with mutations in the epidermal growth factor receptor (EGFR) gene and rearrangements in the anaplastic lymphoma kinase (ALK) gene also demonstrated benefit with combined anti-PD-L1, bevacizumab, and platinum chemotherapy. Further investigation into combination therapy is warranted in the EGFR- and ALK-positive population given this signal. Anti-angiogenics combined with EGFR-targeted treatment in the wild-type population have shown modest PFS benefit with no OS benefit, and their routine use has not been adopted. The combination of EGFR inhibitors plus vascular endothelial growth factor (VEGF) inhibitors in the EGFR mutation-positive population has demonstrated substantial improvements in response and PFS; however, given the higher toxicity and lack of survival benefit to date, combination therapy in this group should be used with caution. At the present time, use of bevacizumab can be recommended with atezolizumab and chemotherapy for the first-line treatment of non-squamous NSCLC patients. Data with other checkpoint inhibitors and anti-angiogenics are too early to make firm recommendations regarding their use.