Immune checkpoint inhibitors (ICIs) with or without anti-angiogenic agents (AAAs) and cardiovascular toxicity: A meta-analysis.

Abstract

e24084 Background: ICIs have extended survival across many tumor types at the cost of immune-related adverse events (irAEs) that can involve any organ or system, including cardiovascular system. Emerging evidence suggest that ICIs may have a role in promoting the atherosclerotic plaque progression, thus leading to acute vascular events (AVEs) This may represent a concern when combining ICIs with other anti-cancer agents burdened by cardiovascular toxicity, such as anti-angiogenic agents (AAAs), that are associated with increased risk of hypertension (HTN) and AVEs. In the present meta-analysis, we aimed to evaluate the odds of adverse events (AEs), irAEs, HTN and AVEs with ICI+AAAs, as compared with AAAs alone. Methods: Phase III randomized controlled trials were identified by searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts, from inception until June 2022. Systematic review and metanalysis were conducted according to PRISMA guidelines. AEs, irAEs, HTN and AVEs were collected (main outcomes of this metanalysis), objective response rate (ORR) and progression free survival (PFS) were also collected (secondary outcomes). AVEs were defined as stroke, myocardial infarction, thrombotic events, pulmonary embolism. Severe AEs, irAE, HTNs and AVEs were defined as grade ≥3 according to the National Cancer Institute Common Terminology for Adverse Events (CTCAE) version 4.0 or 4.03, as reported in each trial. Results: Twelve trials with a total of 8124 patients (4159 in the experimental arms and 3965 in the control arms) were included in the meta-analysis. The addition of ICIs to AAAs did not increase the rate of AEs (any grade, OR 1.15, 95%CI 0.71-1.85; severe, OR 1.18, 95% CI 0.96-1.44). In contrast, the incidence of irAE was significantly higher in the ICIs+AAA- group versus AAAs (any grade: OR 1.97, 95%CI 1.21-3.21, p = 0.007; severe: OR 3.20, 95%CI1.41-7.29, p = 0.006), as expected. There was no difference in terms of any grade HTN between the 2 groups (OR 1.17, 95%CI 0.91-1.50, p > 0.05), but severe HTN was higher among patients treated with ICIs+AAAs as compared with those receiving AAAs alone (OR 1.24, 95%CI 1.01-1.53, p = 0.04). AVEs rates were low in both groups (2.2% and 1.9% for ICI+AAA and AAA alone, respectively). A subset analysis of trials specifically reporting AVEs did not show any increase in ICIs+AAAs versus AAAs alone (any grade: OR 1.21, 95%CI 0.68-2.16, p > 0.05; severe: OR 1.14, 95%CI 0.61-2.15, p > 0.05). Overall, the ORR and PFS were higher in the ICIs+AAAs group as compared to AAAs alone (OR 2.25, 95%CI 1.70-2.97, p < 0.001; OR 4.37, 95%CI 2.91-5.83, p < 0.001, respectively). Conclusions: The addition of ICIs to AAAs significantly increased the risk for irAEs and severe HTN, but not the risk for AVEs.