Impact of treatment timing and sequence of immune checkpoint inhibitors and anti-angiogenic agents for advanced non-small cell lung cancer: A systematic review and meta-analysis

Objective Several studies have demonstrated that anti-angiogenic agents (AAs) have the ability to regulate immune-related cells in the tumor microenvironment and may affect the clinical effect of immune checkpoint inhibitors (ICIs). Therefore, we investigated the drug interaction between ICI and AA for advanced non-small cell lung cancer (NSCLC). Materials and methods We systematically searched PubMed-MEDLINE, Embase-Scopus, and ISI Web of Science before August 23, 2021. ICI and AA therapy included the concomitant and sequential use of ICIs and AAs. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of patients who received ICI and AA therapy were evaluated and compared to those of patients who received either monotherapy. Subgroup analyses were performed to clarify the cause of heterogeneity; the timing and sequence of ICI and AA administration were predefined as the subgroups. Results Thirteen studies involving 2414 patients were included in the meta-analysis. ICI and AA therapy had significantly higher ORR than either monotherapy (OR [95% CI]: 0.61 [0.50–0.74]; p < 0.001; I2 = 29%). PFS and OS were favorable benefits in ICI and AA therapy; however, significant heterogeneity was identified in these analyses (I2 = 80% and 59%, respectively). According to the administration timing and sequence, ICI immediately after AA showed no PFS and OS benefits compared to ICI monotherapy (HR [95 % CI]: 1.54 [1.14–2.08] and 1.50 [1.04–2.15], respectively), whereas favorable PFS and OS were demonstrated when AA was concomitantly administered with ICI (HR [95 % CI]: 0.57 [0.43–0.76] and 0.80 [0.61–1.05], respectively) or when AA was administered immediately after ICI (HR [95 % CI]: 0.58 [0.34–1.00] and 0.56 [0.40–0.80], respectively). Conclusion ICI and AA therapy can provide favorable clinical effects compared to either monotherapy; however, ICI administered immediately after AA may not show survival benefits.