Recent advancements in the treatment of metastatic clear cell renal cell carcinoma: A review of the evidence using second-generation p-values

The therapeutic options for advanced or metastatic renal cell carcinoma (mRCC) have drastically evolved over the past 20 years. High-dose interleukin-2 (HD IL-2), which led to durable complete responses in a small fraction of patients by activating the interleukin-2 (IL-2) pathway, faded in popularity with the advent of oral tyrosine kinase inhibitors directed against the VEGF pathway (VEGFR-TKI) showing better tolerability, wider applicability, higher objective response rates, and longer progression-free survival than HD IL-2. More recently, new insights on how to more efficiently harness the immune system led to the development of immune checkpoint inhibitor (ICI) therapies, which rapidly became an integral component of mRCC treatment. The recently approved regimen combining the PD-1 inhibitor, nivolumab, and the CTLA-4 inhibitor, ipilimumab, and the recently approved regimens combining the oral VEGFR-TKI, axitinib, with the PD-1 inhibitor, pembrolizumab, or the PD-L1 inhibitor, avelumab, were shown to yield improved outcomes compared with sunitinib, the VEGFR-TKI that was used as a comparator. The present review discusses the evidence behind the treatment approvals for mRCC and provides an overview of the current therapeutic landscape. We evaluated the results of randomized clinical trials for mRCC based on the effect size differences between treatments on relative scales and used second-generation p-values as a descriptive summary of the statistical evidence.