First-Line Treatments for Advanced Renal-Cell Carcinoma with Immune Checkpoint Inhibitors: Systematic Review, Network Meta-Analysis, and Cost-Effectiveness Analysis

Background: Immune checkpoint inhibitors (ICIs) are effective for advanced renal-cell carcinoma (aRCC) but can increase costs. This study would compare the efficacy, safety, and cost-effectiveness of ICIs for aRCC patients. Methods: We searched PubMed, EMBASE and the Cochrane Central Register of Controlled Trials from their earliest records to March 19, 2019. Randomized controlled trials (RCTs) evaluating ICI regimens as first-line treatment for newly diagnosed aRCC were included. A network meta-analysis (NMA) was conducted using a frequentist fixed-effects model, and a cost-effectiveness analysis was performed from the payer's perspective in the US using a Markov model. The key outcomes were overall survival (OS) and progression-free survival (PFS) in the meta-analysis and quality-adjusted life years (QALYs), costs in US dollars and the incremental cost-effectiveness ratio (ICER) over 10 years in the cost-effective analysis. Findings: Four RCTs involving 3,758 patients were analysed. Avelumab plus axitinib, pembrolizumab plus axitinib, nivolumab plus ipilimumab and atezolizumab plus bevacizumab improved OS and PFS compared with sunitinib in the overall population, where pembrolizumab plus axitinib ranked highest. Nivolumab plus ipilimumab and pembrolizumab plus axitinib achieved more health benefits than the other ICI regimens and sunitinib in PD-L1-positive and negative tumours, respectively. The risks of serious adverse drug reactions with nivolumab plus ipilimumab and atezolizumab plus bevacizumab were lower than that other ICI regimens and sunitinib. Among the four ICI regimens, only the ICERs of nivolumab plus ipilimumab over sunitinib were lower than the willingness-to-pay threshold ($150,000/QALY) in the overall, PD-L1-positive and negative populations, respectively. Interpretation: The NMA and cost-effectiveness analysis revealed that nivolumab plus ipilimumab is the most favourable first-line treatment for PD-L1-positive aRCC compared with other ICI regimens and sunitinib. Pembrolizumab plus axitinib is likely an alternative for PD-L1-negative aRCC due to its more favourable health advantages. Funding: No funding supported this work. Declaration of Interest: None of the authors have anything to declare. Ethical Approval: This study was based on a literature review and modelling techniques; this study did not require approval by an institutional research ethics board.