In recent randomized clinical trials (RCTs), immune checkpoint inhibitor (ICI) and anti-angiogenic tyrosine kinase inhibitor (VEGFi) combinations have been investigated as front-line therapy in advanced renal cell carcinoma (aRCC). We conducted a meta-analysis of phase 3 RCTs to determine the risk of various gastrointestinal (GI) and hepatic toxicities associated with first line use of ICI and VEGFi combination for the treatment of aRCC. Methods: We conducted a systematic search in PUBMED, MEDLINE, EMBASE, and meeting Abstracts from inception until May 2019. We included phase 3 RCTs using ICI and VEGFi combinations in the intervention arm for the first line treatment of aRCC. We used the Mantel-Haenszel method utilizing random effects model to calculate pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value. Results: Two RCTs JAVELIN Renal 101 and KEYNOTE-426 randomizing 1727 patients were included in the final analysis. JAVELIN Renal 101 used avelumab + axitinib, and KEYNOTE-426 used pembrolizumab + axitinib in the intervention arms, while sunitinib was used in the control arms in both studies. Randomization was 1:1 in both studies. Pooled RR of any-grade GI and hepatic toxicities are — diarrhea 1.26 (95% CI: 1.15-1.38, P<0.00001, I2 =0%); dyspepsia:0.40 (95% CI: 0.30-0.53, P<0.00001, I2 = 0%); nausea: 0.87(95% CI: 0.76-1.00, P=0.05, I2 =0%); vomiting: 0.88(95% CI: 0.72-1.07, P= 0.20, I2 =0%), abdominal pain: 1.50 (95% CI:1.13-1.99, P=0.005, I2 = 0%), elevation of AST: 1.43(95% CI: 1.10-1.87, P= 0.007, I2 =33%), elevation of ALT: 1.66 (95% CI: 1.34-2.05, P< 0.00001, I2 =0%). The pooled RR of grade 3 and higher GI and hepatic toxicities are — diarrhea: 2.12 (95% CI: 1.40-3.19, P= 0.0003, I2 = 0%); nausea: 0.91(95% CI: 0.39-2.14, P=0.83, I2 =0%); vomiting: 0.47(95% CI: 0.16-1.37, P= 0.17, I2 =0%), abdominal pain: 1.44 (95% CI:0.19-10.64, P=0.72, I2 = 65%), elevation of AST: 2.45(95% CI: 1.45-4.15, P= 0.0009, I2 =0%), elevation of ALT: 3.32(95% CI: 1.85-5.95, P< 0.0001, I2 =40%). Conclusions: ICI and VEGFi combinations have significant GI and hepatic toxicities. The risk of any-grade and high-grade diarrhea, abdominal pain, elevation of AST/ALT was higher in combination arms compared to sunitinib arms. Risk of all grade dyspepsia and nausea was lowered in combination arms. Careful monitoring of patient symptoms and liver function with initiation of appropriate supportive care is critically important.