Severe and fatal adverse events of immune checkpoint inhibitor combination therapy in patients with metastatic renal cell carcinoma: a systematic review and meta-analysis

INTRODUCTION: Immune checkpoint inhibitor (ICI) combination therapy has changed the treatment landscape for metastatic renal cell carcinoma (mRCC). However, little evidence exists on the treatment-related severe adverse events (SAEs) and fatal adverse events (FAEs) of ICI combination therapy in mRCC. METHOD: We searched PubMed, Embase, and Cochrane Library databases to evaluate randomized controlled trials (RCTs) of ICI combination therapy versus conventional tyrosine kinase inhibitor (TKI)-targeted therapy in mRCC. Data on SAEs and FAEs were analyzed using revman5.4 software. RESULTS: Eight RCTs (n=5380) were identified. The analysis showed no differences in SAEs (60.5% vs. 64.5%) and FAEs (1.2% vs. 0.8%) between the ICI and TKI groups (odds ratio [OR], 0.83; 95%CI 0.58−1.19, p=0.300 and OR, 1.54; 95%CI 0.89−2.69, p=0.120, respectively). ICI-combination therapy was associated with less risk of hematotoxicities, including anemia (OR, 0.24, 95%CI 0.15–0.38, p<0.001), neutropenia (OR, 0.07, 95%CI 0.03–0.14, p<0.001), and thrombocytopenia (OR, 0.05, 95%CI 0.02−0.12, p<0.001), but with increased risks of hepatotoxicities (ALT increase [OR, 3.39, 95%CI 2.39–4.81, p<0.001] and AST increase [OR, 2.71, 95%CI 1.81−4.07, p<0.001]), gastrointestinal toxicities (amylase level increase [OR, 2.32, 95%CI 1.33–4.05, p=0.003] and decreased appetite [OR, 1.77, 95%CI 1.08–2.92, p=0.020]), endocrine toxicity (adrenal insufficiency [OR, 11.27, 95%CI 1.55–81.87, p=0.020]) and nephrotoxicity of proteinuria (OR, 2.21, 95%CI 1.06−4.61, p=0.030). CONCLUSIONS: Compared with TKI, ICI combination therapy has less hematotoxicity in mRCC but more specific hepatotoxicity, gastrointestinal toxicity, endocrine toxicity, and nephrotoxicity, with a similar severe toxicity profile. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42023412669.