Abstract
Three drug combinations, ipilimumab-nivolumab (Ipi-Nivo), pembrolizumab-axitinib (Pembro-Axi), and avelumab-axitinib (Ave-Axi), have received regulatory approval in the USA and Europe for the treatment of metastatic renal cell carcinoma with clear cell component (mRCC). However, no head-to-head comparison data are available to identify the best option. Therefore, we aimed to compare these new treatments in a first-line setting. We conducted a systematic search in PubMed, the Cochrane Library, and clinicaltrials.gov for any randomized controlled trials of treatment-naïve patients with mRCC, from January 2015 to October 2019. The process was performed according to PRISMA guidelines. We performed a Bayesian network meta-analysis with two different approaches, a contrast-based model comparing HRs and ORs between studies and arm-based using parametric modeling. The outcomes for the analysis were overall survival, progression-free survival (PFS), and objective response rate. Our search identified 3 published phase 3 randomized clinical trials (2835 patients). In the contrast-based model, Ave-Axi (SUCRA = 83%) and Pembro-Axi (SUCRA = 80%) exhibited the best ranking probabilities for PFS. For overall survival (OS), Pembro-Axi (SUCRA = 96%) was the most preferable option against Ave-Axi and Ipi-Nivo. Objective response rate analysis showed Ave-Axi as the best (SUCRA: 94%) and Pembro-Axi as the second best option. In the parametric models, the risk of progression was comparable for Ave-Axi and Ipi-Nivo, whereas Pembro-Axi exhibited a lower risk during the first 6 months of treatment and a higher risk afterwards. Furthermore, Pembro-Axi exhibited a net advantage in terms of OS over the two other regimens, while Ave-Axi was the least preferable option. Overall evidence suggests that pembrolizumab plus axitinib seems to have a slight advantage over the other two combinations.
Highlights
Over the past few years, the treatment for metastatic renal cell carcinoma with clear cell component has drastically changed with the introduction of targeted therapy, immunotherapy, and a better understanding of RCC biology [1,2,3,4]
We investigated models that may have taken into account various confounding factors, such as the between-study unbalanced prognostic risk groups, in order to allow for sufficient flexibility in the modelling of these new combinations complexities
Our results support the importance of the International Metastatic RCC Database Consortium (IMDC) risk score for the comparative efficacy assessment of new combinations in the first-line setting of metastatic clear-cell renal cell carcinoma
Summary
Over the past few years, the treatment for metastatic renal cell carcinoma with clear cell component (mRCC) has drastically changed with the introduction of targeted therapy, immunotherapy, and a better understanding of RCC biology [1,2,3,4]. Four combinations have demonstrated either progression-free survival (PFS) or overall survival (OS) improvements over the VEGFR tyrosine kinase inhibitor (TKI) standard of care (SOC) sunitinib in the first-line setting for advanced or metastatic RCC with clear cell component: nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) [8], pembrolizumab (anti-PD-1) plus axitinib (VEGFR-TKI) [9], avelumab (anti-PD-L1). We still lack predictive biomarkers and prognostic characteristics in patients or the disease to guide treatment allocation. Results of these phase 3 trials should be interpreted in the context of the International Metastatic RCC Database Consortium (IMDC) risk classification, which has proven its utility since the targeted therapy era [12,13]
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