OBJECTIVES: To review the available literature on efficacy and safety for patients with previously untreated, advanced or metastatic renal cell carcinoma (aRCC) in randomized controlled trials (RCTs). METHODS: An update to the existing systematic literature review (SLR) from March 2018 was carried out by two independent reviewers to identify publications up to September 2019. Inclusion criteria were in line with previous standards: phase II, III or II/III RCTs in previously untreated aRCC patients. Databases and sources included: MEDLINE (in-Process), Embase, Cochrane, trial registries, and conference proceedings. RESULTS: In total, 111 relevant publications were identified. Amongst identified therapies, sunitinib was most frequently investigated (n=22), followed by sorafenib (n=13) and pazopanib (n=8). Of the included studies, patients’ median age ranged from 49-68 years. Most frequent efficacy outcomes were median progression-free survival (mPFS), median overall survival (mOS), and overall response rate (ORR), ranging from 1.9-17.3 months, 7.1-42.7 months, and 0%-59.3%, respectively for patients that were not stratified according to MSKCC/IMDC risk status. Respectively, identified mPFS and mOS reported by MSKCC/IMDC risk status ranged between 5.7-16.7 months and 26.9-37.2 months in favorable risk patients, between 4-13.3 months and 13.9-22.6 months in intermediate risk patients, and between 1-10.9 months and 1.6-6.6 months in poor risk patients. Experience of any grade AEs ranged between 48% and 100% and grade ≥3 ranged between 4% and 88%. Most common all grade AEs were diarrhea (3%-88%), fatigue (8%-93%), and hypertension (0%-81%). Novel immuno-oncology (IO) therapies under investigation, such as nivolumab + ipilimumab, have shown promising results in aRCC, with long follow-up and mOS yet to be reached. CONCLUSIONS: This updated SLR highlighted that there is still a considerable unmet need for improved survival in aRCC patients, with novel IO therapies showing assuring results. The results are consistent with the earlier review presented in 2018.