A network meta-analysis of efficacy and safety of first-line and second-line therapies for the management of metastatic renal cell carcinoma.

What Is Known And Objective: Metastatic renal cell carcinoma (mRCC) is the most common type of kidney cancers. Disease-specific survival for mRCC has been significantly improved with the introduction of new targeted agents since 2005. However, there is a lack of head-to-head clinical trials comparing the efficacy between therapies. This study compared indirectly progression-free survival (PFS) and overall survival (OS) among first-line and second-line therapies in patients with mRCC using network meta-analysis (NMA).

Methods: The PubMed, MEDLINE, Cochrane Library and Web of Science were searched to identify phase II or phase III randomized controlled trials (RCTs) of targeted and biological therapies in patients with mRCC published between January 2000 and June 2020. The Bayesian fixed-effect NMA was performed to evaluate relative PFS and OS of first-line and second-line therapies of axitinib, bevacizumab, cabozantinib, everolimus, lenvatinib, nivolumab, ipilimumab, pazopanib, sorafenib, sunitinib, temsirolimus, tivozanib, avelumab and pembrolizumab, which were approved by the Food and Drug Administration or European Medicines Agency. End points were compared using hazard ratio (HR) and 95% credible interval (CrI). The surface under the cumulative ranking curve (SUCRA) was estimated to assess the probability of being the best treatment.

Results And Discussion: A total of 26 RCTs (first line: 19, second line: 9) with 13 893 patients were included in the NMA. For the first-line therapy, cabozantinib was associated with the highest improved PFS (HR = 0.26, 95% CrI = 0.14-0.44) followed by avelumab + axitinib and pembrolizumab + axitinib (HR = 0.27, SUCRA = 90%). Pembrolizumab + axitinib had a high likelihood of being the preferred treatment when using OS as the outcome measure (HR = 0.41, 95% CrI = 0.16-0.85). Avelumab + axitinib had the lowest HR compared with placebo + interferon on discontinuations due to AE (HR = 1.04, 95% CrI = 0.54-1.86). For second-line therapy, cabozantinib was identified as the most effective treatment option when assessing PFS (HR = 0.17, 95% CrI = 0.12-0.24). Axitinib had the lowest HR of OS and discontinuation due to AE (HR = 0.54, 95% CrI = 0.40-0.71; HR = 0.98, 95% CrI = 0.42-1.97, respectively). Pazopanib was the second choice in terms of OS (HR = 0.56, 95% CrI = 0.28-1.00; SUCRA = 76%) compared with placebo.

What Is New And Conclusion: With respect to PFS and OS improvement, cabozantinib, avelumab + axitinib and pembrolizumab + axitinib are likely to be the preferred options for the first-line therapy and cabozantinib and axitinib for the second-line therapy in the management of mRCC. Regarding safety, avelumab + axitinib and temsirolimus were considered preferred treatment options in first-line and second-line therapies. More future research is needed to establish subgroup analyses, allowing evaluation of the impact of some of the differences in patient characteristics, including treatment effect modifiers.